Liver transplantation (LT) offers the best chance of cure for patients with hepatocellular carcinoma (HCC), as it addresses simultaneously the underlying disease and the tumour. The Milan criteria has been the standard for over 3 decades in selecting patients with HCC who will benefit from LT. While, early studies showed higher recurrence rates for HCC following living donor LT (LDLT), recent series, especially in the past decade have shown LDLT to have equal oncological outcomes as compared to deceased donor LT (DDLT) for HCC, even in patients beyond Milan criteria. Further, the intention to treat analysis data suggests that LDLT may actually provide a survival advantage. In the west, factors such as improved outcomes on par with DDLT, ability to time the LT etc., have led to a steadily increased number of LDLTs being performed for this indication. On the other hand, in the east, given its geo-socio-cultural idiosyncrasies, LDLT has always been the predominant form of LT for HCC, consequently resulting in an increased number of LDLTs being performed for this indication across the world. While LDLT in HCC has its distinctive advantages compared to DDLT, the double equipoise of balancing the donor risk with the recipient outcomes has to be considered while selecting patients for LDLT. There have been several advances including the application of downstaging therapies and the use of biological markers, which have further helped improve outcomes of LDLT for this indication. This review aims to provide an update on the current advances in the field of transplant oncology related to the practice of LDLT in HCC.

Hepatocellular carcinoma (HCC) poses a significant global health challenge, and liver transplantation (LT) remains the best curative option. Living donor liver transplantation (LDLT) emerged as a potential solution to organ scarcity, reducing waitlist times. This comprehensive review explores LDLT practices, focusing on patient selection criteria and oncologic outcomes. A systematic review following PRISMA guidelines included 50 studies (2004-2023) with 8062 patients. Data encompassed baseline characteristics, HCC features, and oncologic outcomes. Further analysis categorized results by geography and publication year. Heterogeneity in patient demographics, tumor burden, and transplant characteristics was observed. Recent LDLT series demonstrated a shift towards refined selection criteria, increased neoadjuvant treatment, and improved oncologic outcomes. Geographic disparities revealed unique challenges in Eastern and Western practices. LDLT proves effective for HCC, addressing donor shortages. Evolving practices highlight the importance of refining inclusion criteria and optimizing tumor management. While geographic differences exist, LDLT, when judiciously applied, offers promising outcomes.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the eighth most common cancer in women worldwide. It is also the second leading cause of cancer death worldwide, with 780,000 deaths in 2018. Seventy-two percent of HCC cases occur in Asia, 10% in Europe, 8% in Africa, 5% in North America, and 5% in Latin America (Singal et al. in J Hepatol 72(2):250-261, 2020 [1]).

Research comparing patients who received liver transplantation (LT) for hepatocellular carcinoma (HCC) has produced varying outcomes regarding survival and disease-free survival. The objective of this study is to determine the factors that influence the disease-free and overall survivals of those who have undergone LT for HCC and to compare the outcomes of living versus deceased donor liver transplants.

We retrospectively analyzed data on patients aged 18 and above who received LT for HCC from 2006 to 2022. Patients with a follow-up period of less than 6 months and who did not meet the University of California San Francisco criteria were excluded. The data from 58 patients were analyzed. We split the patients into living donor liver transplantation (LDLT) (group 1) and deceased donor liver transplantation (DDLT) (group 2).

The mean age was 56 ± 8.1 years. There were 49 males and 9 females. The median of the alphafetoprotein (AFP) level and model for end-stage liver disease score was 10.1 ng/mL and 11, respectively. The 1-, 3-, 5-, and 10-year disease-free survival rates were 86%, 76.5%, 76.5%, and 76.5%, respectively. The survival rates for the same periods were 94.8%, 74.9%, 70.6%, and 67.4%. The receiver operating characteristic analysis revealed that AFP > 31.8 ng/mL and a total tumor size >3.85 cm raise the likelihood of HCC recurrence post-LT.

Based on the current literature, the overall survival and disease-free survival rates are influenced by factors such as AFP value, total tumor number, and total tumor diameter. In our study, the AFP value and total tumor size had an impact on the recurrence of HCC, and the survival rates were comparable on LDLT and DDLT.

A potential solution to the deceased organ shortage is to include live organ donations and to identify patients with lower rates of HCC recurrence to fairly allocate liver grafts. Our aims were to detect the long-term outcomes of LDLT versus DDLT for HCC and predictors of recurrence after transplantation.

PubMed, Scopus, Web of Science, Cochrane library were searched for eligible studies from inception to July 2021 and a systematic review and meta-analysis were done.

35 studies with a total of 7822 patients were included. The 1-, 3-, 4 year-OS showed trivial improvement for LDLT recipients. However, the two modalities had similar 5-, 6- and 10-year OS. A significant improvement in the ITT-OS was observed for LDLT recipients. Regarding the DFS and recurrence after transplantation, no significant difference was observed between LDLT and DDLT. In addition to that, the pooled hazard ratio of the included studies showed that Milan criteria, level of AFP, presence of vascular invasion, tumor differentiation were significant predictors of recurrence.

The cancer biology (not the graft type) is the most important determinant of recurrence and survival after LT. However, LDLT provided much better survival benefits to HCC patients especially in regions that suffer from low deceased organ availability.

The long-term outcomes after living donor liver transplantation (LDLT) vs deceased donor liver transplantation (DDLT) for hepatocellular carcinoma (HCC) remain controversial. We compared the long-term outcomes between LDLT and DDLT in patients with HCCs within or beyond the Milan criteria.

This retrospective study included 896 patients who underwent liver transplantation (829 LDLTs and 67 DDLTs) for HCC from June 2005 to May 2015. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method with log-rank test.

RFS at 1, 3, 5, and 10 years after LDLT was 89.6%, 84.6%, 82.4%, and 79.6%, respectively, and, after DDLT, was 92.4%, 86.2%, 82.4%, and 82.4%, respectively, and OS at 1, 3, 5, and 10 years after LDLT was 96.1%, 88.1%, 85.6%, and 82.7%, respectively, and, after DDLT, was 97.0%, 83.6%, 82.1%, and 77.3%, respectively, with no significant differences in RFS (P = .838) or OS (P = .293) between groups. No statistically significant differences after LDLT or DDLT were identified in RFS (89.8% vs 98.1%, respectively, at 5 years; P = .053) or OS (90.4% vs 90.6% , respectively, at 5 years; P = .583) for HCCs meeting the Milan criteria as well as for those beyond the Milan criteria (RFS, 37.8% vs 28.6%, respectively, at 5 years; P = .560 and OS, 57.3% vs 50.0%, respectively, at 5 years; P = .743).

Patients who underwent LDLT for HCCs showed comparable long-term outcomes to patients who underwent DDLT. Patients with HCCs within the Milan criteria demonstrated acceptable long-term outcomes after both LDLT and DDLT.

Living donor liver transplantation (LDLT) provides an alternative to deceased donor liver transplantation (DDLT) for patients with end-stage liver disease in the circumstance of scarcity of deceased grafts. However, the outcomes of LDLT remain controversial.

A systematic review and meta-analysis were performed to compare the outcomes of LDLT with DDLT. Twelve outcomes were assessed.

Thirty-nine studies involving 38563 patients were included. LDLT was comparable in red blood cell transfusion, perioperative mortality, length of hospital stay, retransplantation rate, hepatitis C virus recurrence rate, and hepatocellular carcinoma recurrence rate with DDLT. Cold ischemia time was shorter and duration of recipient operation was longer in LDLT. Postoperative intra-abdominal bleeding rate occurred less frequently in LDLT recipients (odds ratio (OR) = 0.64, 95%confidence interval (CI) = 0.46 - 0.88, P = 0.006), but this did not decrease the perioperative mortality. LDLT was associated with significantly higher biliary (OR = 2.23, 95%CI = 1.59 - 3.13, P < 0.00001) and vascular (OR = 2.00, 95%CI = 1.31 - 3.07, P = 0.001) complication rates and better overall survival (OS) (1 year: OR = 1.32, 95%CI = 1.01 - 1.72, P = 0.04; 3 years: OR = 1.39, 95%CI = 1.14 - 1.69, P = 0.0010; and 5 years: OR = 1.33, 95%CI = 1.04 - 1.70, P = 0.02). According to subgroup analysis, biliary complication rate and OS improved dramatically as experience increased, while vascular complication rate could not be improved because it was mainly caused by the difference of the donor type itself.

LDLT remains a valuable option for patients in need of liver transplantation for it provides an excellent alternative to DDLT without compromising recipient outcomes. Further refinement in biliary and vascular reconstruction techniques and the accumulation of liver transplantation centers' experience are the key factors in expanding the application of LDLT.

The aim of this study was to evaluate the effect of the Milan criteria on the hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) recurrence in patients who underwent living donor liver transplantation due to HBV-induced cirrhosis and HCC.

We evaluated a total of 142 patients, 88 who underwent transplantation due to HBV-induced cirrhosis and 54 due to HCC, between 2009 and 2014. In the posttranplant period, after the HBsAg seroconversion, 400 IU of hepatitis B immunoglobulin were applied intramuscularly every 2 weeks, and daily nucleos(t)ide analogs were continued as prophylaxis. The HBV recurrence was defined as the presence of HBsAg in serum. Patients were screened for alpha-fetoprotein levels and imaging for evaluation of HCC recurrence.

The average follow-up period was 26 (2-65) months. Fifty-four patients had HCC. The HCC recurrence was observed in 12 patients during the follow-up period. The HBV recurrence was observed in four patients. Three of the patients who developed HBV recurrence had liver transplantation due to HCC. Tumor recurrence was observed 1.4-12 months following the HBV recurrence. The HCC recurrence within the Milan criteria and beyond the Milan criteria was 0% vs. 28.4 % in the first year and 3.4% vs. 47.5% in the third year. The cumulative incidence of the HBV recurrence was 2.8% and 3.7% for the first year and 3.7% for the third year. The HBV recurrence was more frequently detected in patients with HCC (p=0.048), especially with HCC beyond the Milan criteria (p=0.044).

The HBV recurrence should be evaluated as a predictor of the HCC recurrence in patients who underwent liver transplantation due to HCC with exceeding Milan criteria.

There are conflicting reports on the outcomes after live donor liver transplantation in patients with hepatocellular carcinoma (HCC). We aimed to compare the survival of patients with HCC, with a potential live donor (pLDLT) at listing vs. no potential donor (pDDLT), on an intention-to-treat basis.

All patients with HCC listed for liver transplantation between 2000-2015 were included. The pLDLT group was comprised of recipients with a potential live donor identified at listing. Patients without a live donor were included in the pDDLT group. Survival was assessed by the Kaplan-Meier method. Multivariable Cox regression was applied to identify potential predictors of mortality.

A total of 219 patients were included in the pLDLT group and 632 patients in the pDDLT group. In the pLDLT group, 57 patients (26%) were beyond the UCSF criteria whereas 119 patients (19%) in the pDDLT group were beyond (p = 0.02). Time on the waiting list was shorter for the pLDLT than the pDDLT group (4.8 [2.9-8.5] months vs. 6.2 [3.0-12.0] months, respectively, p = 0.02). The dropout rate was 32/219 (14.6%) in the pLDLT and 174/632 (27.5%) in the pDDLT group, p <0.001. The 1-, 3- and 5-year intention-to-treat survival rates were 86%, 72% and 68% in the pLDLT vs. 82%, 63% and 57% in the pDDLT group, p = 0.02. Having a potential live donor was a protective factor for death (hazard ratio [HR] 0.67; 95% CI 0.53-0.86). Waiting times of 9-12 months (HR 1.53; 95% CI 1.02-2.31) and ≥12 months (HR 1.69; 95% CI 1.23-2.32) were predictors of death.

Having a potential live donor at listing was associated with a significant decrease in the risk of death in patients with HCC in this intention-to-treat analysis. This benefit is related to a lower dropout rate and a shorter waiting period.

Liver transplantation (LT) offers the best chance of survival for patients with hepatocellular carcinoma and can be performed using grafts from deceased donors or live donors. In this work, we aimed to assess the differences in survival after live donor LT when compared to deceased donor LT. We studied 219 patients listed for live donor LT and 632 patients listed for deceased donor LT. Patients who had a potential live donor at the time of listing had a higher survival rate. Therefore, being listed for a live donor LT was a protective factor against death.

The outcomes of living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT) for HCC patients were not well defined and it was necessary to reassess.

A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, Google Scholar and WanFang database for eligible studies. Perioperative and survival outcomes of HCC patients underwent LDLT were pooled and compared to those underwent DDLT.

Twenty-nine studies with 5376 HCC patients were included. For HCC patients underwent LDLT and DDLT, there were comparable rates of overall survival (OS) (1-year, RR = 1.04, 95%CI = 1.00-1.09, P = 0.03; 3-year, RR = 1.03, 95%CI = 0.96-1.11, P = 0.39; 5-year, RR = 1.04, 95%CI = 0.95-1.13, P = 0.43), disease free survival (DFS) (1-year, RR = 1.00, 95%CI = 0.95-1.05, P = 0.99; 3-year, RR = 1.00, 95%CI = 0.94-1.08, P = 0.89; 5-year, RR = 1.01, 95%CI = 0.93-1.09, P = 0.85), recurrence (1-year, RR = 1.41, 95%CI = 0.72-2.77, P = 0.32; 3-year, RR = 0.89, 95%CI = 0.57-1.39, P = 0.60; and 5-year, RR = 0.85, 95%CI = 0.56-1.31, P = 0.47), perioperative mortality within 3 months (RR = 0.89, 95%CI = 0.50-1.59, p = 0.70) and postoperative complication (RR = 0.99, 95%CI = 0.70-1.39, P = 0.94). LDLT was associated with better 5-year intention-to-treat patient survival (ITT-OS) than DDLT (RR = 1.11, 95% CI = 1.01-1.22, P = 0.04).

This meta-analysis suggested that LDLT was not inferior to DDLT in consideration of comparable perioperative and survival outcomes. However, in terms of 5-year ITT-OS, LDLT was a possibly better choice for HCC patients.

to compare the outcome of liver transplantation for hepatocarcinoma in submitted or not to locoregional treatment and downstaging regarding survival and risk of recurrence in transplant waiting list patients.

retrospective study of patients with hepatocarcinoma undergoing liver transplantation in the metropolitan region of São Paulo, between January 2007 and December 2011, from a deceased donor. The sample consisted of 414 patients. Of these, 29 patients were included in the list by downstaging. The other 385 were submitted or not to locoregional treatment.

the analysis of 414 medical records showed a predominance of male patients (79.5%) with average age of 56 years. Treatment of the lesions was performed in 56.4% of patients on the waiting list for transplant. The most commonly used method was chemoembolization (79%). The locoregional patients undergoing treatment had a significant reduction in nodule size greater (p<0.001). There was no statistical difference between groups with and without locoregional treatment (p=0.744) and on mortality among patients enrolled in the Milan criteria or downstaging (p=0.494).

there was no difference in survival and recurrence rate associated with locoregional treatment. Patients included by downstaging process had comparable survival results to those previously classified as Milan/Brazil criteria.

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and it is linked with chronic liver disease. Liver transplantation (LT) is the best curative treatment modality, since it can cure simultaneously the underlying liver disease and HCC. Milan criteria (MC) are the benchmark for selecting patients with HCC for LT, achieving up to 91% 1-year survival post transplantation. However, when considering intention-to-treat (ITT) rates are substantially lower, mainly due dropout. Additionally, Milan criteria (MC) are too restrictive and more inclusive criteria have been reported with good outcomes. Mainly, in Eastern countries, deceased donors are scarce, therefore Asian centers have developed living-donor liver transplantation (LDLT) to a state-of-art status. There are many eastern centers reporting huge numbers of LDLT with outstanding results. Regarding HCC patients, they have reported many criteria including more advanced tumors achieving reasonable outcomes. Western countries have well-established deceased-donor liver transplantation (DDLT) programs. However, organ shortage and restrictive criteria for listing patients with HCC endorses LDLT as a good option to offer curative treatment to more HCC patients. However, there are some controversial reports claiming higher rates of HCC recurrence after LDLT than DDLT. An extensive review included 30 studies with cohorts of HCC patients who underwent LDLT in both East and West countries. We reported also the results of our Institution, in Brazil, where it was performed the first LDLT. This review also addresses the eligibility criteria for transplanting patients with HCC developed in Western and Eastern countries.

Liver transplantation for hepatocellular carcinoma (HCC) is the best treatment option for patients with early-stage tumours and accounts for ∼20-40% of all liver transplantations performed at most centres worldwide. The Milan criteria are the most common criteria to select patients with HCC for transplantation but they can be seen as too restrictive. Several proposals have been made for a moderate expansion of the criteria, which result in good outcomes but with an increase in the risk of tumour recurrence. In this Review, we provide a comprehensive overview of the outcomes after liver transplantation for HCC, focusing on tumour recurrence in terms of surveillance, prevention and treatment. Additionally, novel surgical techniques have been developed to increase the available pool of organs for liver transplantation (such as living donor liver transplantation, donation after circulatory death and split livers), but the effect of these techniques on patients with HCC is still under debate. Thus, we will describe these techniques and expose the benefits and disadvantages of each surgical approach. Finally, we will comment on the limitations of the current priority policies for liver transplantation and the need to further refine them to better serve the population.

With the increasing prevalence of living-donor liver transplantation (LDLT), the possible increased recurrence rate of hepatocellular carcinoma (HCC) in LDLT recipients in comparison with deceased-donor liver transplantation (DDLT) recipients has become a matter of debate. The aim of this review is to encompass current opinions and clinical reports regarding differences in the outcome, especially the recurrence of HCC, between LDLT and DDLT. In reviewing literatures, some studies reported increased recurrence rates among LDLT recipients, a majority of authors, including large database studies, reported comparable recurrence-free survival and recurrence rates between LDLT and DDLT. The postulated reasons for the increased recurrence in LDLT were the effect of graft regeneration on tumor progression, fast-tracking of patients into liver transplantation, and the more aggressive tumor characteristics in LDLT, however, many Asian LDLT centers have reported the comparable outcomes with those of DDLT in Western countries, even with the expanded criteria for HCC. In the absence of a prospective study regarding the use of LDLT versus DDLT for HCC patients, there is no evidence to support the higher HCC recurrence after LDLT than DDLT, and LDLT remains a reasonable treatment option for HCC patients with cirrhosis, especially in Asian countries where the number of deceased donor is scarce.

Several expanded criteria for liver transplantation for hepatocellular carcinoma (HCC) have been suggested out of concern that the Milan criteria may be too strict, and thereby exclude patients who could benefit from this surgical procedure. However, most expanded criteria were designed for deceased donor liver transplantation. Living donor liver transplantation (LDLT) differs from that of deceased donor liver transplantation primarily because LDLT liver grafts are not public resources.

In Asian countries, where HCC is endemic, LDLT is the main currently available treatment option for HCC. High-volume LDLT centers throughout Asia have adopted their own expanded selection criteria for LDLT for HCC with acceptable long-term results. Some centers utilize tumor markers as one of the criterion to help select suitable candidates. Indeed, such adjunctive biomarkers may have prognostic relevance for patients with HCC. The use of both biological and histomorphologic parameters may increase the number of transplantable patients.

The overall chance of survival, and recipient/donor preferences as well as the risk of recurrence are considered in the LDLT setting. Therefore, the selection criteria for liver transplantation for HCC could benefit from expansion for LDLT.

This work aims to evaluate the impact of 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) combined 5-fluorouracil (5-FU) for the activity of CD90+ liver cancer cells derived from the human liver cancer cell line MHCC97H. MHCC97H sphere-forming cells (MSFCs) were amplified in serum-free medium and CD90+ cells were isolated from bulk MSFCs using flow cytometry. The phenotype of these CD90+ cells which show liver cancer stem cells (LCSCs) behavior was validated in vitro and in a xenograft model in nude mice. MSFCs, CD90+ liver cancer cells (CD90+ LCCs), and parental MHCC97H cells were treated with no drug, LY294002 alone, 5-FU alone, or both drugs together and then compared in terms of stem cell-related gene expression, proliferation, and invasion. Stem cell phenotype increased with increasing proportion of CD90+ cells, in ascending order: parental MHCC97H cells, MSFCs, and CD90+ liver cancer cells. LY294002 reduced the expression of CD90, Nanog, SALL4, and SHP2 in a concentration-dependent manner in CD90+ LCCs and MSFCs, but not in parental cells. LY294002 blocked AKT phosphorylation via the PI3K/AKT signaling pathway and inhibited CD90+ LCCs proliferation and tumorigenicity in vitro and in vivo. CD90+ liver cancer cells can express liver cancer stem cell phenotype. LY294002 inhibits the proliferation and invasion of MHCC97H-derived CD90+ LCCs and sensitized CD90+ LCCs-derived tumors to 5-FU in the current study which may provide insight into the association between the LY294002 combined 5-FU and liver cancer stem cell (LCSCs).

Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., "non-oncological factors"), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.

Hepatocellular carcinoma (HCC) is the second cause of death due to malignancy in the world, following lung cancer. The geographic distribution of this disease accompanies its principal risk factors: Chronic hepatitis B virus and hepatitis C virus infection, alcoholism, aflatoxin B1 intoxication, liver cirrhosis, and some genetic attributes. Recently, type II diabetes has been shown to be a risk factor for HCC together with obesity and metabolic syndrome. Although the risk factors are quite well known and it is possible to diagnose HCC when the tumor is less than 1 cm diameter, it remains elusive at the beginning and treatment is often unsuccessful. Liver transplantation is thus far considered the best treatment for HCC as it cures HCC and the underlying liver disease. Using the Milan criteria, overall survival after liver transplantation for HCC is about 70% after 5 years. Many attempts have been made to go beyond the Milan Criteria and according to recent works reasonably good results have been achieved by using a histochemical marker such as cytokeratine 19 and the so-called "up to seven criteria" to divide patients into categories according to their risk of relapse. In addition to liver transplantation other therapies have been proposed such as resection, tumor ablation by different means, embolization and chemotherapy. An important step in the treatment of advanced HCC has been the introduction of sorafenib, the first oral, systemic drug that has provided significant improvement in survival. Treatment of HCC patients must be multidisciplinary and by using the different approaches discussed in this review it is possible to offer prolonged survival and quite good and sometimes even excellent quality of life to many patients.