Hepatocellular carcinoma recurrence after liver transplantation: risk factors, targeted surveillance and management options
0 
,
Abstract
Hepatocellular carcinoma (HCC) represents a well-recognized indication for liver transplantation (LT), with improving graft and patient survival rates due to medical and surgical advancements over time. Despite the implementation of selection criteria to ensure the highest transplant benefit, post-LT recurrence of HCC is not uncommon and is often associated with poor outcomes. Therefore, a post-transplant surveillance strategy appears to be a cost-effective approach, particularly in the early post-surgery period when the recurrence rate is high. Although specific guidelines are still lacking, emerging strategies tailored to pre-transplant tumor history and explant pathology show promise. Moreover, new immunosuppressive therapy schemes and aggressive management of post-transplant medical complications can be implemented to reduce the risk of cancer recurrence. Finally, multimodal oncological strategies are increasingly used to improve survival even after cancer recurrence. This paper reviews the evidence on HCC recurrence after LT, providing insights into risk factors, targeted surveillance, and management strategies.
Keywords
INTRODUCTION
The landscape of liver transplantation (LT) is rapidly changing in terms of indications, outcomes, available organs, and medical and surgical advancements[1]. Over the last few decades, hepatocellular carcinoma (HCC) became a solid indication for LT, leading to a steady increase in the number of patients undergoing transplantation for this indication in most transplant programs worldwide. This trend is due to multiple factors, including a reduction in end-stage liver disease patients with active hepatitis B and C, a steady increase in new HCC diagnoses, and excellent post-transplant survival outcomes. Consequently, the selection of HCC patients for LT has been refined over time, with a wise expansion of the selection criteria[2-4]. Among treatments for HCC, LT can provide the largest survival benefit[5].
HCC recurrence represents a cornerstone in the natural history of transplanted patients. The recurrence rate is about 16%, more frequent within three years after transplantation[6-8]. In the landmark study by Mazzaferro et al., 8% of patients after four years of follow-up developed tumor recurrence[2,9], but further studies reported a recurrence rate of 10%-16% in patients within Milan criteria based on pre-transplant imaging data[10-14]. The risk of HCC recurrence seems closely related to the tumor burden at the time of transplant, and it increases proportionally as the patients exceed the Milan criteria[15]. Most recurrences (66%) are extrahepatic, mainly in the lungs, bones, adrenal glands, peritoneum, soft tissues, and central nervous system[6,16-19]. As expected, tumor recurrence significantly impairs post-transplant prognosis, with a median survival of about two years after diagnosis.
Given the great number of patients being transplanted for HCC and the wise expansion of transplant criteria, it seems appropriate to implement strategies to reduce the risk of recurrence and adopt active post-LT surveillance strategies to capture any recurrence as soon as possible[16,20]. Moreover, it is of utmost importance to establish multimodal strategies (surgical, radiological, oncological) to treat the recurrence itself, both intra- and extrahepatic[21,22].
In this review, we will first analyze the prognostic factors of post-LT HCC recurrence and then provide insights specifically into targeted surveillance and multimodal treatment.
PREDICTING HCC RECURRENCE
LT in HCC patients should be offered after balancing the survival benefit derived from the transplant (i.e., transplant benefit) with the risk of tumor recurrence (i.e., transplant utility)[23]. Post-LT HCC recurrence has a detrimental effect on the prognosis of patients transplanted for this indication and on the postoperative outcome. Thus, approaches for rapidly identifying patients at high risk of post-LT recurrence are urgently needed.
Several factors have been identified as predictors of post-LT recurrence, including tumor-related characteristics (e.g., tumor burden, biomarkers, tumor biology), transplant procedures, and post-transplant management (e.g., immunosuppression) [Figure 1]. Tumor-specific variables have been incorporated in several pre-transplant selection criteria and prognostic models to expand the pool of possible candidates to LT, possibly maintaining an acceptable risk of post-transplant recurrence and without disadvantaging non-HCC patients on the waiting list [Table 1]. Moreover, post-LT variables have also been included in some post-transplant prognostic models. Although intriguing, the role of donor characteristics and recipient gender as risk factors for tumor recurrence remains controversial and requires further exploration[42,43]. To enhance our ability to predict post-LT HCC recurrence, a valuable tool could be the combination of pre- and post-transplant risk factors in predictive models with artificial intelligence and machine learning[44]. Some preliminary experiences demonstrate that machine learning models could accurately stratify transplanted patients for their probability of HCC recurrence[45,46], but further studies are needed.
Figure 1. Factors affecting HCC recurrence (pre-LT, LT and post-LT variables) and factors influencing post-recurrence survival. HCC: Hepatocellular carcinoma; PIVKA: protein induced by vitamin K absence; AFP: alpha-fetoprotein; PET: positron emission tomography; RM: risk management; LT: liver transplantation.
Proposed pre-transplant selection criteria and prediction models
| Model name (year) | Design | Variables | Performance | ||
| tumor burden | Biomarker | Other criteria | |||
| Milan criteria (1996)[2] | Prospective single-center study | Single tumor > 5 cm or ≤ 3 tumors ≤ 3 cm | - | No vascular invasion or lymph nodes | 5-year OS: 85% 5-year RFS: 92% |
| UCSF criteria (2001)[24,25] | Retrospective evaluation of prospectively collected data, single center[24] | Single nodule ≤ 6.5 cm or 2-3 nodules ≤ 4.5 cm and total tumor diameter ≤ 8 cm | - | No vascular invasion | 5-year OS: 75.2% in[24] 5-year RFS 80.9% in[25] |
| Prospective single-center study[25] | |||||
| Padua criteria (2004)[26,27] | Retrospective evaluation of prospectively collected data, single center[26] | Any size or number of tumors | - | No vascular invasion/extrahepatic spread No poorly differentiated tumor (grade III and IV) | 5-year OS: 75% 5-year RFS: 92% In[27] 1-, 3- and 5-year ITT survival rates were: 95%, 85% and 79% in Milano out 84%, 69% and 69% in Milano in |
| Prospective single-center study [27] | |||||
| Seoul criteria (2007)[28] | Retrospective single-center study | Tumor size (≤ 3, 3.1-5, 5.1-6.5, > 6.5 cm) and number (1, 2-3, 4-5, > 5) | AFP (≤ 20, 20.1-200, 200.1-1,000, > 1,000 ng/mL) | - | Score 3-6 (transplantable): 3-year RFS: 87% 3-year OS: 79% Score 7-12 (non-transplantable): 3-year RFS: 31% 3-year OS: 38% |
| SMC criteria (2007)[29] | Retrospective single-center study | Tumor size ≤ 5 cm | AFP level ≤ 400 ng/mL | - | Within criteria: 5-year DFS: 88.4% 5-years OS: 86.8% Outside criteria: 5-year DFS: 42.1% 5-year OS: 23.3% |
| Up-to-7 criteria (2009)[15] | Retrospective multicenter study | Sum of the largest tumor size and number of lesions < 7 | - | - | 5-year OS: 71.2% (beyond Milano and within up-to-7 criteria) |
| AFP-French model (2012)[30] | Retrospective multicenter study (training + validation cohorts) | Tumor size (≤ 3, 3-6, > 6 cm) and tumor number (1-3, ≥ 4) | log10(AFP) Simplified version: AFP level (≤ 100, 100-1,000, > 1,000 ng/mL) | - | Training cohort Low-risk (score ≤ 2) 5-year recurrence rate: 13.4% 5-year OS: 69.9% High-risk (score > 2) 5-year recurrence rate: 45.3% 5-year OS: 40.8% |
| AFP/TTD criteria (2012)[31] | Retrospective multicenter study | Total tumor diameter ≤ 8 cm | AFP ≤ 400 ng/mL | - | Recurrence rate (43 months of FU): In criteria: 4.9% Outside criteria: 33.0% 5-year DFS similar compared to Milan criteria: 74.4% vs. 72.9% |
| TTV/AFP model (2015)[32] | Prospective multicenter study | Total tumor volume < 115 cm3 | AFP < 400 ng/mL | No macrovascular invasion; no extrahepatic disease | 4-year DFS: 68.0% 4-year OS: 74.6% (beyond Milano and within TTV/AFP) |
| TRAIN score (2016)[33] | Retrospective evaluation of prospectively collected data, two centers (training + validation cohorts) | - | AFP slope ≥ 15 ng/mL/month | Radiological response to locoregional treatment (mRECIST) NLR ≥ 5 at liver transplant Length of waiting time (months) | In criteria (score < 1) 5-year ITT survival analysis: 67.5% 5-year recurrence rate: 8.9% Outside criteria (score ≥ 1) 5-year ITT survival analysis: 23.5% 5-year recurrence rate: 30.0% |
| Extended Toronto criteria (2016)[34] | Prospective single-center study | Any size or number of tumors | - | No vascular invasion; no extrahepatic disease No cancer-related symptoms (weight loss > 10 kg and or ECOG ≥ 1 in 3 months) No poorly differentiated tumors | Beyond Milano and within ETC: 10-year risk of recurrence: 33% (vs. 15% for Milano in) 10-year survival: 50% (vs. 60% for Milano in) |
| Pre-MORAL score (2017)[35] | Prospective single-center study | Largest tumor size > 3 cm | Maximum AFP > 200 ng/mL Preoperative NLR ≥ 5 | - | 5-year RFS: Low-risk group (score 0-2): 98.6% Medium-risk group (score 3-6): 69.8% High-risk group (score 7-10): 55.8% Very high-risk group (score > 10): 0% (1-year RFS 17.9%) |
| EurHeCaLT transplant benefit model (2017)[36] | Retrospective multicenter study | Single tumor > 5 cm or ≤ 3 tumors ≤ 3 cm (Milano in) considered as a negative factor | AFP ≥ 1,000 ng/mL considered as a negative factor | Considered as negative factors: MELD ≤ 13 CR or PD after locoregional treatment (mRECIST) | Transplant benefit: 3-4 negative factors: 0 months (no benefit) 2 negative factors: 20 months (small benefit) 1 negative factor: 40 months (moderate benefit) 0 negative factors: 60 months (large benefit) |
| HALT-HCC score (2017)[37] | Retrospective single-center study | Hypotenuse between lesion number and lesion size (TBS) | ln(AFP) | MELD-Na | Risk equation: 1.27*TBS + 1.85*ln(AFP) + 0.26*MELD-Na 5-year OS: Quartile 1: 78.7% Quartile 2: 74.5% Quartile 3: 71.8% Quartile 4: 61.5% |
| NYCA score (2018)[38] | Retrospective evaluation of prospectively collected data, multicenter | Maximum tumor size (0-3, 4-6, > 6) and maximum tumor number (1, 2-3, ≥ 4) | AFP response (max to final) | - | 5-year RFS: Low-risk (score 0-2): 90% Acceptable risk (score 3-6): 70% High-risk (score ≥ 7): 42% |
| Metroticket 2.0 model (2018)[39] | Retrospective evaluation of prospectively collected data, multicenter (training, internal and external validation cohorts) | Tumor number and size of the largest tumor† | AFP (< 200, 200-400, 400-1000, > 1000 ng/mL) † | - | 5-year RFS: within criteria 89.6% vs. beyond criteria 46.8% 5-year OS: within criteria 79.7% vs. beyond criteria 51.2% (with a tumor-specific survival of 93.5% within vs. 55.6% beyond) |
| Metroticket 2.0 + mRECIST criteria (2020)[40,41] | Retrospective evaluation of prospectively collected data, multicenter | Tumor number and size of the largest tumor | AFP (< 200, 200-400, 400-1,000, > 1,000 ng/mL) | Radiological response to neoadjuvant therapies (mRECIST criteria) | 5-year HCC-related death: CR: 3.1% PR/SD: 9.6% PD: 13.4% In comparison to Metroticket 2.0, the inclusion of radiological response resulted in the reclassification of 9.4% of patients who died from HCC-related death within 5 years from LT |
Tumor burden
Traditional transplant eligibility criteria relied only on tumor morphological characteristics (number and size of liver lesions) as determined by pre-LT imaging. It has been demonstrated that morphologic parameters are associated with microvascular invasion and poor differentiation[47], both of which are predictors of HCC recurrence after LT. The paradigm of morphologic selection criteria is represented by the Milan criteria[2], which became the benchmark for LT candidate selection and the comparator for other proposed criteria.
However, growing evidence suggests that these criteria may be excessively restrictive, leading to the exclusion of a subgroup of patients who could also benefit from LT. Therefore, other criteria have been proposed, with outcomes comparable to those of the Milan criteria. The use of the University of California San Francisco (UCSF) criteria (single nodule ≤ 6.5 cm or 2-3 nodules ≤ 4.5 cm with a total tumor diameter ≤ 8 cm) led to a favorable 5-year survival rate of 75.2% and a post-LT recurrence rate of 11.4%[24,25]. The “up-to-seven” criteria [the limit for transplantability is 7 as the sum of the diameter (cm) of the largest tumor and the number of nodules][15] demonstrated post-LT survival results comparable to those of patients meeting the Milan criteria[48,49].
As mentioned above, the further outside the Milan criteria, the greater the risk of recurrence[15,24,25,39]. However, patients with an initial tumor burden beyond morphologic criteria who meet transplant eligibility criteria through downstaging treatments (locoregional, surgical or systemic therapies) have similar post-LT outcomes in terms of HCC recurrence as compared to patients who were within criteria at presentation[50-52]. By contrast, tumors progressing despite locoregional treatments exhibit worse outcomes after LT, mainly related to aggressive tumor biology[53-55]. Therefore, downstaging represents an additional stratification tool in the selection of patients for LT because it merges morphologic and biologic features[50]. While the Milan criteria are often used as the endpoint of downstaging protocols, the upper limits of tumor burden for downstaging remain controversial[56]. Obviously, the greater the initial tumor burden that we bring back within the transplantability limits through downstaging, the higher the transplant benefit for the patient[57]. Among the available downstaging therapies, immunotherapy may have a role but additional data are necessary to estimate the risk of rejection after transplant[58].
Despite advances in cross-sectional imaging in recent decades, the staging of HCC through radiologic investigations is far from being perfect. Under-staging of HCC at imaging still occurs in 25%-30% of patients, especially after multiple locoregional procedures[59-62], and misdiagnosis (no HCC found on explant) has been reported in 11%-25% of cases[63,64].
Alpha-fetoprotein and other biomarkers
Alpha-fetoprotein (AFP) is a powerful prognostic and predictive biomarker for HCC patients. In the LT setting, it accurately predicts the risk of drop-out from the waiting list, the probability of post-LT recurrence, and the overall survival (OS). It has been largely evaluated both as a static and dynamic biomarker as a surrogate of tumor biology. An association between AFP levels before transplantation and post-LT mortality has been shown, with progressively worsening outcomes as the levels increase, starting from values as low as 16-20 ng/mL[65-67]. Therefore, AFP has been included in many prognostic models. However, the cut-off values that can accurately predict the risk of post-LT HCC recurrence differ significantly among these models[29-32,36,67-73] [Tables 1 and 2].
Post-transplant prognostic models
| Model name | Design | Variables | Performance | ||
| Tumor burden | Biomarker | Histologic criteria | |||
| Parfitt et al. and Aziz et al. (2007)[40,41] | Retrospective single-center study | Tumor size ≥ 3 cm | - | Microvascular invasion Satellitosis Giant/bizarre cells > 25% visible at low power | Recurrence in: Low-risk (score 0-4): 4.3% Intermediate-risk (score 7-7.5): 28.5% High-risk (score 10-14): 50.0% At the cut-off of 3.5: AUROC = 0.8, sensitivity 80%, specificity 79% |
| Decaens et al. (2011)[74] | Retrospective single-center study (training and validation cohorts) | Number of nodules (1, 2-3, ≥ 4) and maximal diameter of the largest nodule (≤ 2, 2-3, 3-5, > 5 cm) | - | Tumor differentiation (well, moderate, poor) | Training cohort: AUROC = 0.65 (95%CI: 0.59-0.71) 5-year tumor-free survival: 60.2% with a score < 4 and 36.4% with a score ≥ 4 (P < 0.0001) Validation cohort: AUROC = 0.63 (95%CI: 0.50-0.76) 5-year tumor-free survival: 82.8% with a score < 4 and 50.0% with a score ≥ 4 (P < 0.0001) |
| UCLA nomogram (2015)[19] | Retrospective evaluation of prospectively collected data, single-center | Within Milano/downstaged to Milano vs. Milano out Maximal radiological tumor diameter | AFP NLR Total cholesterol | Microvascular invasion Tumor grade | C statistic of 0.85 (95%CI: 0.82-0.89) Nomogram predicting 1-, 3- and 5-year recurrence risk for any individual patient with HCC |
| Post-Moral (2017)[35] | Retrospective evaluation of prospectively collected data, single-center | On explant pathology: Largest size > 3 cm Tumor number > 3 | - | Vascular invasion Tumor grade | 5-year RFS: Low-risk group (score 0-2): 97.4% Medium-risk group (score 3-6): 75.1% High-risk group (score 7-10): 49.9% Very high-risk group (score > 10): 22.1% |
| RETREAT score (2018)[65,66] | Retrospective cohort study | Explant largest viable tumor diameter + number of viable tumor (0 vs. 1-4.9 vs. 5-9.9 vs. > 10) | AFP at LT (0-20 vs. 21-99 vs. 100-999 vs. > 1,000 ng/mL) | Presence of microvascular invasion | 3-year recurrence risk: Score 0: 1.6% Score 1: 5.0% Score 2: 5.6% Score 3: 8.4% Score 4: 20.3% Score ≥ 5: 29.0% |
| R3-AFP score (2022)[75] | Retrospective multicenter study (training and validation cohorts) | Number of nodules (1-3 vs. ≥ 4) Major nodule diameter (≤ 3 vs. 3-6 vs. > 6 cm) | Last AFP available before LT (≤ 100 vs. 101-1,000 vs. > 1,000 ng/mL) | Microvascular invasion Grading > II | Risk of recurrence at 5 years: R3-AFP = 0: 5.5% (95%CI: 3.5-8.7) R3-AFP = 1-2: 15.1% (95%CI: 11.3-20.1) R3-AFP = 3-6: 39.1% (95%CI: 32.4-46.7) R3-AFP score > 6:73.9% (95%CI: 59.7-86.3) |
| RELAPSE score (2023)[76] | Retrospective multicenter study (training and validation cohorts) | Maximum tumor diameter (per-log SD) | Pre-LT maximum AFP, (per-log SD) Neutrophil-lymphocyte ratio (per-log SD) | Vascular invasion (none, microvascular, macrovascular) Differentiation (well, moderate, poor, necrotic/no viable tumor) | Prediction of HCC recurrence risk: Training cohort: C-statistic = 0.78 (95%CI: 0.75-0.80) Internal validation cohort: C-statistic = 0.76 (95%CI: 0.72-0.79) |
Other biomarkers, such as neutrophils to lymphocytes ratio (NLR), AFP-L3 and des-γ-carboxyprothrombin (DCP), have been correlated with tumor biology and have been considered for inclusion in pre-transplant prognostic models[19,77,78]. A recent prospective cohort study demonstrated that AFP-L3 and DCP outperformed AFP in the prediction of HCC recurrence after LT. Moreover, the combination of AFP-L3 ≥ 15% and DCP ≥ 7.5 predicted 61.1% of HCC recurrences, whereas HCC only recurred in 2.6% of patients without this dual positivity[79].
Available serum biomarkers are useful in predicting HCC recurrence after LT, so they have been integrated into prognostic tools to refine the prediction of HCC recurrence after LT. However, their accuracy is not excellent, so they cannot be used as a single factor but must be integrated with other tumor characteristics, such as radiological and biological features. Novel biomarkers under investigation should be more accurate than those currently being used, easy to use and reliable in different care settings.
Explant features predicting HCC recurrence
The presence of microvascular invasion on the explanted liver is strongly associated with HCC recurrence and worse prognosis after LT[40,80] [Table 2]. The likelihood of vascular invasion strongly correlates to the disease burden, with greater incidence in lesions > 5 cm[47,81] and in patients with multifocal disease[82]. Very high AFP levels (> 1,000 ng/mL)[81] and positive uptake on positron emission tomography[83] have also been associated with the presence of microvascular invasion. This tumor feature cannot be used as a stratification tool before transplant because it cannot be reliably assessed prior to LT due to the very low sensitivity of tumor biopsies for its detection[84].
Similarly, poorly differentiated tumor grade has been identified as a risk factor for post-LT HCC recurrence [Table 2]. In most cases, tumor biopsy is not performed for diagnostic purposes, thus limiting the possibility of integrating information regarding tumor differentiation into selection criteria and pre-transplant prognostic models. Transplanting only patients with well-differentiated tumors may confer very good survival rates after transplantation, minimizing cancer recurrence[26,27,34]. However, evaluating tumor biology through liver biopsy should take into account sampling bias, intratumoral heterogeneity, and finally, a poor concordance between pre-operative tumor histology and explant pathology[85,86]. Therefore, although tumor differentiation should theoretically be considered a robust predictor of post-transplant neoplastic disease recurrence, the aforementioned issues often prevent its universal application.
POST-TRANSPLANT HCC SURVEILLANCE
Planning an adequate surveillance program and appropriate management of HCC recurrence depends on understanding the timing and pattern of recurrence. To be cost-effective, post-LT surveillance should cover the majority of recurrences and use imaging modalities capable of evaluating anatomical sites where recurrences typically occur. Most HCC recurrences occur within 2-3 years after LT[12,13,20,87-89], although later recurrences (after 5 years from LT and, anecdotally, beyond 20 years after transplantation) have been described[13,90,91]. Consistent data show that earlier recurrence correlates with worse prognosis, likely due to more aggressive biology[20,90].
Retrospective data suggest that surveillance provides a survival benefit by increasing the likelihood of curative-intent retreatment, thus reducing post-recurrence mortality[92]. However, there are few studies on the optimal tests and their schedule, and no randomized trials have proven the cost-effectiveness of different surveillance protocols and their prognostic impact. Despite the absence of solid scientific evidence, there is broad consensus that periodic contrast-enhanced imaging and periodic AFP evaluation should be performed post-LT. The European Guidelines do not yet provide advice on the best surveillance follow-up for patients transplanted for HCC[93]. The American Association for the Study of Liver Diseases (AASLD) and The International Liver Transplantation Society (ILTS) Guidelines acknowledge that a fixed surveillance algorithm has not yet been validated but propose a reasonable scheme with chest-abdomen CT scans every 6 months for the first 3 years after transplant, possibly combined with serum AFP measurement[94,95]. However, the post-LT surveillance landscape is not homogeneous across Transplant Centers. A survey of many US LT Centers reported significant heterogeneity in the frequency, duration, and discontinuation of surveillance protocols. Moreover, surveillance protocols are tailored to risk stratification in only a minority of cases, and the schedule is rarely modified according to the expected risk of HCC recurrence[96].
Given the locations and patterns of HCC recurrence, standard surveillance strategies are based on chest and abdomen cross-sectional imaging [either contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI)]. Since recurrences frequently occur outside the liver, an ultrasound-based surveillance approach focused only on the graft seems inadequate for accurate postoperative follow-up. Although bones are commonly affected by HCC recurrence, routine bone scans are not recommended, unless there is a suspicion[84]. Due to its low cost and ease of determination, AFP is usually monitored in post-transplant surveillance, whereas other biomarkers (e.g., AFP-L3%, DCP) are not yet routinely used for this purpose[97,98].
Regarding the surveillance schedule, a 6-month interval between imaging investigations seems reasonable[84], as shorter intervals do not appear to provide additional benefit[99]. Since most cancers recur within 3 years after LT, a duration of at least 3 years is generally recommended for surveillance[84,94,95,100]. Most transplant programs discontinue surveillance 5 years after LT due to the low probability of recurrence thereafter, but strong recommendations are not possible due to the lack of data on the best and cost-effective surveillance length.
Refinement of surveillance: who deserves to be surveilled after LT?
Several post-transplant scores have been developed to predict HCC recurrence. These scores usually include tumor burden, tumor grade, and the presence or absence of microvascular invasion [Table 2]. Most of these scores also incorporate AFP or other biomarkers. To refine surveillance strategies after LT, these models help identify patients at high risk of tumor recurrence, allowing for the development of personalized follow-up schedules.
The first prognostic models included only HCC characteristics observed in explant histopathology. For example, the score proposed by Parfitt et al. and Aziz et al., which combines four histological tumor variables (size ≥ 3 cm, microvascular invasion, satellitosis, and giant/bizarre cells > 25% visible at low power), demonstrated good predictability of recurrence (a cut-off value of ≥ 3.5 has a sensitivity of 80% and a specificity of 79%)[40,41]. Tumor burden (number and size of tumors) and tumor differentiation have been combined by Decaens et al. in a score that discriminates patients according to their risk of HCC recurrence (5-year tumor-free survival: 82.8% with score < 4 and 50.0% with a score ≥ 4)[74]. However, both models lacked management guidance based on recurrence risk.
Similarly, Agopian et al. proposed a prognostic nomogram including several variables (tumor within Milan/downstaged to Milan vs. outside Milan, maximal radiological tumor diameter, AFP, NLR, total cholesterol, tumor grade, vascular invasion) to predict 1-, 3-, and 5-year recurrence probability (c-statistic of 0.85, 95%CI: 0.82-0.89). However, it was not useful for stratifying patient surveillance[19].
Conversely, the post-MORAL scoring system (based on tumor size > 3 cm, the number of tumors > 3 on explanted liver, tumor grading, and vascular invasion) accurately stratified patients according to recurrence risk (c-statistic 0.88, 95%CI: 0.83-0.93)[35]. This system identifies four groups based on 5-year recurrence-free survival (RFS), ranging from 97.4% in the low-risk group (score 0-2) to 22.1% in the very high-risk group (score > 10), providing a valuable tool to tailor surveillance according to predicted recurrence risk. The combo-MORAL score, which combines pre-MORAL and post-MORAL models, further improves accuracy (c-statistic 0.91, 95%CI: 0.87-0.95)[35].
Mehta et al. formally proposed tailoring the surveillance protocol according to their model’s estimated risk of recurrence[64]. They developed the RETREAT score, combining three parameters (serum AFP at LT, presence of microvascular invasion, and the sum of the largest viable tumor diameter and the number of viable tumors on explant) to obtain a scoring risk from 0 to > 5[65]. This score was externally validated in the United Network for Organ Sharing (UNOS) dataset and in European centers[66,101,102]. The score adequately categorized patients according to recurrence risk (3-year recurrence risk from 1.6% to 29% with RETREAT scores from 0 to ≥ 5)[66]. Based on this score, surveillance regimens were tailored: no surveillance for patients with a score of 0; surveillance every six months for two years post-LT for patients with a score of 1-3; every six months for five years for those with a score of 4; and strict surveillance (every 3-4 months) for the first two years followed by semestral surveillance for patients with the highest scores (≥ 5)[66].
Recently, the Recurrence Risk Reassessment (R3)-AFP score was developed based on the number of nodules, size of the largest nodule, microvascular invasion, tumor grading, and the last pre-LT AFP value. It was validated in a large international cohort[75]. This model stratified patients into four categories of 5-year recurrence risk: very low-risk (R3-AFP = 0 points: 5.5%; 95%CI: 3.5-8.7), low-risk (R3-AFP = 1-2 points: 15.1%; 95%CI: 11.3-20.1), high-risk (R3-AFP = 3-6 points: 39.1%; 95%CI: 32.4-46.7), and very high-risk (R3-AFP > 6 points: 73.9%; 95%CI: 59.7-86.3). Compared to the RETREAT score, this model showed similar discriminatory power and it is likely more applicable in real-life clinical practice since it includes patients beyond the Milan criteria for pre-LT imaging.
The most recent post-LT predictive score, RELAPSE, was proposed and validated in an American/European collaborative study using machine learning models[76]. Including the maximum pre-transplant AFP value, immediate pre-LT NLR, tumor size, vascular invasion, and tumor differentiation at explant pathology, the RELAPSE score showed a good prediction of HCC recurrence (c-statistic 0.78) in a large multicenter UNOS database. It demonstrated similar performance in a European validation cohort (AUC 0.74-0.77)[76].
Using a post-LT prediction model for personalized postoperative surveillance appears reasonable, though these scores have not been derived from prospective studies. Many questions remain unanswered, such as the approach for patients with incidental HCC at explant and the optimal time to discontinue surveillance. Artificial intelligence, which can explore complex, nonlinear relationships between patient and HCC-specific variables, may help answer these questions, especially when applied with innovative techniques exploring tumor biology in more depth[26,103,104]. Recent papers have preliminarily explored this topic, identifying several machine learning algorithms capable of improving the predictive accuracy of the conventional models currently in use. However, some key points remain to be clarified, such as the applicability of these models in real life and some intrinsic issues of artificial intelligence, such as overfitting[103,105,106].
STRATEGIES FOR PREVENTING HCC RECURRENCE
Type of immunosuppression and risk of HCC recurrence
The immunosuppressive regimen is a factor influencing the reappearance of HCC after a transplant, as the immune system is a major defense against cancer. Tacrolimus and cyclosporine [Calcineurin inhibitors (CNIs)] are the backbone of an immunosuppression schedule, but they impair the immune surveillance system, thus creating a permissive environment for the growth of cancer cells/micrometastases. Preclinical data demonstrated that CNIs promote tumor growth and cancer progression[107,108]. The tumor doubling time of Recurrent HCC after LT in patients receiving immunosuppression with cyclosporine and steroids has a lower doubling time compared to the growth rate of recurrent tumors after liver resection[109]. Additionally, CNI therapy, especially if high circulating levels of the drug are maintained in the early post-transplant period, is associated with an increased risk of post-LT malignancies and HCC recurrence[110-113].
The mammalian target of rapamycin inhibitors (mTORi) sirolimus and everolimus have both immunosuppressive and antiangiogenic activities. They inhibit T cell proliferation, regulate cell proliferation and apoptosis signaling, and modulate vascular endothelial growth factor (VEGF) - mediated pathways. Several retrospective studies and meta-analyses have demonstrated that using sirolimus in immunosuppressive regimens, compared to CNIs, is beneficial in terms of reducing HCC recurrence[114-122]. Toso et al. demonstrated improved OS for patients managed with sirolimus-based immunosuppressive therapy[117], whereas Yanik et al. showed reduced cancer-specific mortality and HCC recurrence in patients receiving sirolimus[118]. A systematic review of 3,666 patients transplanted for HCC showed that mTORi-containing regimens significantly reduce the risk of HCC recurrence compared to CNI (13.8% vs. 8.0%; P < 0.001)[121]. Another systematic review and meta-analysis confirmed these data[122,123].
A phase III trial showed that sirolimus therapy, added 6 weeks after transplantation, benefited OS in patients transplanted within the Milan criteria (i.e., low-risk patients). However, this positive effect was not maintained over time, as there were no differences in long-term RFS and OS between the two groups[124]. This benefit seemed to be highest in younger patients (< 60 years), those treated with sirolimus for ≥ 3 months, and those with AFP ≥ 10 ng/mL[125].
Regarding everolimus, a study on 192 patients with HCC undergoing LT did not show an association between this drug and tumor recurrence[126]. A monocentric retrospective study showed that patients receiving everolimus and CNIs had significantly longer time-to-recurrence and OS compared to patients receiving CNIs alone[127]. In another retrospective study, patients on everolimus showed a reduced risk of recurrence (7.7% vs. 16.9%; P = 0.002), and everolimus usage had an independent positive impact on the risk of transplant recurrence[128]. Stratifying patients according to pre-LT tumor burden, it seems that everolimus reduces the risk of recurrence in patients transplanted beyond the Milan criteria compared to tacrolimus (5.9% vs. 23.1%; P = 0.22), but not in patients transplanted within Milan (2.9% vs. 2.1%; P = 0.1)[129]. Further evidence on the role of everolimus in reducing post-LT recurrence risk is forthcoming, as a trial evaluating tacrolimus and everolimus versus tacrolimus and mycophenolate mofetil is currently ongoing[130].
How to choose immunosuppression on the basis of the risk of HCC recurrence
The aforementioned studies demonstrate the direct correlation between CNI and HCC recurrence, and the potential inverse correlation between mTORi and cancer reappraisal. Clinically, there are two possible alternatives: reduce the dose of CNI without increasing the risk of rejection, or replace CNIs with other immunosuppressors (e.g., mTORi), maintaining a very low risk of rejection. The first option is based on the link between high doses of CNI (usually in the early post-transplant phase) and HCC development, and involves the simultaneous introduction of CNI and mTOR inhibitors at low doses. The second option suggests the possibility of introducing a CNI-free therapy using mTORi from the beginning. A recent meta-analysis has shown that the early introduction of everolimus seems effective, with a satisfactory safety profile[131].
The optimal immunosuppressive therapy that minimizes the risk of HCC recurrence and improves survival has not yet been determined. The immunosuppression regimen should probably be personalized based on the individual risk of post-LT tumor recurrence. Despite the lack of solid evidence and while awaiting stronger data from prospective randomized trials, an mTOR inhibitor-based immunosuppressive algorithm may be pursued in patients perceived to be at high risk, especially if relevant risk factors for everolimus/sirolimus side effects (e.g., proteinuria, dyslipidemia) are absent[95,132-134].
Adjuvant therapy
Despite several proposed schemes[17], there is no evidence to support the use of adjuvant systemic chemotherapy to prevent post-LT HCC recurrence, and this strategy is currently not recommended. Indeed, HCC is recognized as a chemoresistant tumor. Initially, adjuvant treatment with sorafenib, a multi-tyrosine kinase that showed significant improvement in the survival of patients with advanced HCC, appeared to be potentially useful. Among the 14 patients included in a phase I trial with sorafenib at a maximum dose of 200 mg twice daily, one death and only four recurrences were registered after a median follow-up of 32 months[135]. However, the potential utility of sorafenib in the post-LT setting was not confirmed, even though all available data come from small single-center studies and case series. In a small group of patients with explant features at high risk of tumor recurrence, adjuvant therapy with sorafenib did not halt the risk of postoperative tumor recurrence nor improve postoperative survival[136]. The lack of benefit with sorafenib after LT mirrors what was found in patients at high risk for recurrence after resection or ablation receiving adjuvant sorafenib[137]. A meta-analysis including three prospective and five retrospective studies (including not only sorafenib but different oncological treatments) did not show any benefit in terms of HCC recurrence rate[138].
Lenvatinib has not been prospectively tested in the adjuvant setting and only few small retrospective studies and case series are available[139-141]. A small case series showed acceptable drug safety and patient tolerance but did not show any significant reduction in HCC recurrence[141]. Guo et al. demonstrated that in patients transplanted beyond the Milan criteria, adjuvant lenvatinib was an independent protective factor for tumor recurrence and reduced the rate of early recurrence (< 2 years) after LT (15.8% vs. 33.3%; P = 0.04), but in patients receiving the adjuvant treatment, the OS was comparable to that of the control group[139].
Recently, immune-checkpoint inhibitors (ICIs) became the standard of care treatment in unresectable HCC and the combination of atezolizumab and bevacizumab has been tested in the adjuvant setting for patients at high risk of recurrence after surgery and ablation, demonstrating potential benefit[142]. Currently, no prospective studies have investigated in depth the potential adjuvant role of ICIs after transplantation. However, the risk of acute rejection and potential graft loss raises concerns about the safety of these drugs in transplanted patients, in case of overt cancer recurrence and even more in the adjuvant setting[143].
MANAGEMENT OF POST-TRANSPLANT RECURRENCE
The detailed analysis of all possible treatments for patients with post-transplant HCC recurrence goes beyond the scope of this review. However, it is useful to provide some insights into therapeutic strategies. The first aspect concerns the patient’s clinical conditions and performance status, which allow a clear distinction between the choice of therapeutic options and palliative care. Secondly, the location of the recurrence (intra- vs. extrahepatic, single vs. multisite) represents essential elements for choosing the correct therapeutic option.
In patients with a single nodule or oligometastatic intrahepatic recurrence, surgery or interventional radiology procedures can be considered. Surgery can include both resection and ablation, depending on the location and number of lesions and the functionality of the transplanted liver. Few studies have demonstrated a significant increase in median survival in those who underwent surgery compared to those receiving non-surgical therapy and those who received best supportive care[17,144]. Therefore, whenever feasible, surgery should be pursued.
One small, single-center retrospective study comparing patients who underwent resection vs. ablation demonstrated similar outcomes in terms of RFS[145]. It should be noted that the laparoscopic approach is challenging in such cases and that immunosuppression may delay wound repair and increase the risk of postoperative surgical site infection. Trans-arterial chemoembolization can be considered an option in patients with multinodular disease, especially those with bilobar (i.e., unresectable) involvement, similar to what is usually proposed in pre-LT patients. There are few data available on the efficacy of this technique and it may face greater technical difficulties compared to the pre-transplant phase, especially in the case of complex arterial reconstructions at the time of transplant.
Regarding extrahepatic metastases, few data are available on surgical treatment for lung metastases. A recent series from South Korea showed good outcomes after lung surgery (mainly wedge resection) in 52 patients, with a median of 1.7 years of RFS after metastasectomy. Notably, more than half received adjuvant chemotherapy and experienced further recurrence after lung surgery[146].
Patients with multiple metastases, deemed not resectable, both inside and outside the liver, may receive systemic therapy. This option should be weighed against possible side effects, patient performance status, and comorbidities. Moreover, patients’ and family members’ expectations should be considered in the decision-making process. Few data are available for sorafenib as a first-line treatment[147,148], lenvatinib as a first-line treatment (median OS of 14.5 months)[149], and regorafenib as a second-line treatment after sorafenib (median OS of 12.9 months and 38.4 months for the sorafenib initiation)[150].
These data suggest that OS is acceptable, even in the second line, and that there are no significant safety concerns. However, it is possible that these studies, often with retrospective design, consider highly selected patients with excellent performance status and relatively favorable baseline characteristics. Few data have already investigated ICIs in post-transplant HCC recurrence, with the aforementioned concerns. A recently published individual patient data meta-analysis examining the impact of pre-LT ICIs on the subsequent risk of rejection showed a 26% rejection rate after transplant, suggesting that a washout period between chemotherapy and transplant may be necessary[151]. Therefore, this rate is expected to be even higher when immunotherapy is applied in the postoperative setting. Determining which patients may safely receive immunotherapy post-LT, and where this therapy should be placed (first- vs. second-line therapy)[152] remain gray areas to date. Therefore, these drugs should not be used outside of well-designed controlled studies[153]. A possible future development in the treatment of post-LT recurrence is the use of target T cell therapy against HCC cells. In particular, some preliminary and exploratory studies evaluated the treatment of patients with HBV-related HCC recurrences with HBV-specific T cell receptor-redirected T cells; these cells demonstrated the ability to target extrahepatic metastases[154]. The use of immunosuppressive drug-resistant T cells for the immune therapy of post-LT recurrences can improve the efficacy of these treatments[155]. Beyond being complex in its delivery, the efficacy and safety of this therapeutic option will require to be tested in large randomized clinical trials.
CONCLUSIONS
The recurrence of HCC remains a concern in the LT setting despite significant improvements in patient selection and downstaging treatments. There is still much work to be done in this area.
Multiple models with good accuracy have been proposed for stratifying the risk of post-transplant recurrence, and they deserve universal application within various transplant programs. Specifically, the ability to stratify risk based on clinical and histological factors should allow clinicians to create tailored surveillance programs and guide the choice of the most appropriate immunosuppression regimen. However, the long-term benefits of these surveillance programs are still to be understood, though they have been proven to be cost-effective, especially within the first five years post-transplant.
The second ambitious goal is to significantly increase survival in patients with post-transplant HCC recurrence, which currently averages around 24 months from diagnosis. Achieving this requires new, preferably prospective, studies comparing multimodal therapeutic strategies, especially in light of new oncological treatments.
A multidisciplinary approach should be pursued after every diagnosis of HCC recurrence. A thorough discussion within the local/oncological transplant board can ensure the best surgical and oncological care based on disease presentation, graft function, and patient performance status. This approach can pave the way for innovative oncotherapies being tested in such patients, involve dedicated surgeons to treat metastases in specific body areas, and provide comprehensive counseling and psychological support to patients and their families.
DECLARATIONS
Acknowledgments
Graphical abstract created with BioRender.com.
Authors’ contributions
Conceptualized and designed the review: Pelizzaro F, Ferrarese A, Burra P
Wrote, reviewed, and edited the manuscript: Pelizzaro F, Ferrarese A, Burra P
Reviewed the manuscript for intellectual content: Gambato M, Zanetto A, Russo FP, Germani G, Senzolo M, Rizzato MD, Soldà C, Vitale A, Gringeri E, Cillo U
Approved the final version for submission: All authors
Availability of data and materials
Not applicable.
Financial support and sponsorship
None.
Conflicts of interest
Burra P is an Associate Chief Editor of Hepatoma Research, Cillo U and Vitale A are Editorial Board members of Hepatoma Research, Zanetto A, Ferrarese A, and Pelizzaro F are Junior Editorial Board members of Hepatoma Research. The other authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
REFERENCES
1. Ivanics T, Abreu P, De Martin E, Sapisochin G. Changing trends in liver transplantation: challenges and solutions. Transplantation 2021;105:743-56.
2. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9.
3. Mehta N, Bhangui P, Yao FY, et al. Liver transplantation for hepatocellular carcinoma. working group report from the ILTS transplant oncology consensus conference. Transplantation 2020;104:1136-42.
4. Tschuor C, Ferrarese A, Kuemmerli C, Dutkowski P, Burra P, Clavien PA; Liver Allocation Study Group. Allocation of liver grafts worldwide - is there a best system? J Hepatol 2019;71:707-18.
5. Vitale A, Farinati F, Pawlik TM, et al. The concept of therapeutic hierarchy for patients with hepatocellular carcinoma: a multicenter cohort study. Liver Int 2019;39:1478-89.
6. de'Angelis N, Landi F, Carra MC, Azoulay D. Managements of recurrent hepatocellular carcinoma after liver transplantation: a systematic review. World J Gastroenterol 2015;21:11185-98.
7. Bzeizi KI, Abdullah M, Vidyasagar K, Alqahthani SA, Broering D. Hepatocellular carcinoma recurrence and mortality rate post liver transplantation: meta-analysis and systematic review of real-world evidence. Cancers (Basel) 2022;14:5114.
8. Al-Ameri A, Yu X, Zheng S. Predictors of post-recurrence survival in hepatocellular carcinoma patients following liver transplantation: systematic review and meta-analysis. Transplant Rev (Orlando) 2022;36:100676.
9. Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011;17 Suppl 2:S44-57.
10. Escartin A, Sapisochin G, Bilbao I, et al. Recurrence of hepatocellular carcinoma after liver transplantation. Transplant Proc 2007;39:2308-10.
11. Plessier A, Codes L, Consigny Y, et al. Underestimation of the influence of satellite nodules as a risk factor for post-transplantation recurrence in patients with small hepatocellular carcinoma. Liver Transpl 2004;10:S86-90.
12. Valdivieso A, Bustamante J, Gastaca M, et al. Management of hepatocellular carcinoma recurrence after liver transplantation. Transplant Proc 2010;42:660-2.
13. Sharma P, Welch K, Hussain H, et al. Incidence and risk factors of hepatocellular carcinoma recurrence after liver transplantation in the MELD era. Dig Dis Sci 2012;57:806-12.
14. Maccali C, Chagas AL, Boin I, et al. Recurrence of hepatocellular carcinoma after liver transplantation: prognostic and predictive factors of survival in a Latin American cohort. Liver Int 2021;41:851-62.
15. Mazzaferro V, Llovet JM, Miceli R, et al; Metroticket Investigator Study Group. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35-43.
16. Bodzin AS, Lunsford KE, Markovic D, Harlander-Locke MP, Busuttil RW, Agopian VG. Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics. Ann Surg 2017;266:118-25.
17. Pelizzaro F, Gambato M, Gringeri E, et al. Management of hepatocellular carcinoma recurrence after liver transplantation. Cancers (Basel) 2021;13:4882.
18. Ekpanyapong S, Philips N, Loza BL, et al. Predictors, presentation, and treatment outcomes of recurrent hepatocellular carcinoma after liver transplantation: a large single center experience. J Clin Exp Hepatol 2020;10:304-15.
19. Agopian VG, Harlander-Locke M, Zarrinpar A, et al. A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: analysis of 865 consecutive liver transplant recipients. J Am Coll Surg 2015;220:416-27.
20. Sapisochin G, Goldaracena N, Astete S, et al. Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large Euro-American series. Ann Surg Oncol 2015;22:2286-94.
21. Invernizzi F, Iavarone M, Zavaglia C, et al. Experience with early sorafenib treatment with mTOR inhibitors in hepatocellular carcinoma recurring after liver transplantation. Transplantation 2020;104:568-74.
22. Guerrini GP, Berretta M, Tarantino G, et al. Multimodal oncological approach in patients affected by recurrent hepatocellular carcinoma after liver transplantation. Eur Rev Med Pharmacol Sci 2017;21:3421-35.
23. Cillo U, Vitale A, Polacco M, Fasolo E. Liver transplantation for hepatocellular carcinoma through the lens of transplant benefit. Hepatology 2017;65:1741-8.
24. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394-403.
25. Yao FY, Xiao L, Bass NM, Kerlan R, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant 2007;7:2587-96.
26. Cillo U, Vitale A, Bassanello M, et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004;239:150-9.
27. Cillo U, Vitale A, Grigoletto F, et al. Intention-to-treat analysis of liver transplantation in selected, aggressively treated HCC patients exceeding the Milan criteria. Am J Transplant 2007;7:972-81.
28. Yang SH, Suh KS, Lee HW, et al. A revised scoring system utilizing serum alphafetoprotein levels to expand candidates for living donor transplantation in hepatocellular carcinoma. Surgery 2007;141:598-609.
29. Kwon CH, Kim DJ, Han YS, et al. HCC in living donor liver transplantation: can we expand the Milan criteria? Dig Dis 2007;25:313-9.
30. Duvoux C, Roudot-Thoraval F, Decaens T, et al; Liver Transplantation French Study Group. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143:986-94.e3.
31. Lai Q, Avolio AW, Manzia TM, et al. Combination of biological and morphological parameters for the selection of patients with hepatocellular carcinoma waiting for liver transplantation. Clin Transplant 2012;26:E125-31.
32. Toso C, Meeberg G, Hernandez-Alejandro R, et al. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: a prospective validation. Hepatology 2015;62:158-65.
33. Lai Q, Nicolini D, Inostroza Nunez M, et al. A novel prognostic index in patients with hepatocellular cancer waiting for liver transplantation: time-radiological-response-alpha-fetoprotein-INflammation (TRAIN) score. Ann Surg 2016;264:787-96.
34. Sapisochin G, Goldaracena N, Laurence JM, et al. The extended toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology 2016;64:2077-88.
35. Halazun KJ, Najjar M, Abdelmessih RM, et al. Recurrence after liver transplantation for hepatocellular carcinoma: a new MORAL to the story. Ann Surg 2017;265:557-64.
36. Lai Q, Vitale A, Iesari S, et al; European Hepatocellular Cancer Liver Transplant Study Group. Intention-to-treat survival benefit of liver transplantation in patients with hepatocellular cancer. Hepatology 2017;66:1910-9.
37. Sasaki K, Firl DJ, Hashimoto K, et al. Development and validation of the HALT-HCC score to predict mortality in liver transplant recipients with hepatocellular carcinoma: a retrospective cohort analysis. Lancet Gastroenterol Hepatol 2017;2:595-603.
38. Halazun KJ, Tabrizian P, Najjar M, et al. Is it time to abandon the milan criteria? Ann Surg 2018;268:690-9.
39. Mazzaferro V, Sposito C, Zhou J, et al. Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma. Gastroenterology 2018;154:128-39.
40. Parfitt JR, Marotta P, Alghamdi M, et al. Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence. Liver Transpl 2007;13:543-51.
41. Aziz S, Sey M, Marotta P, et al. Recurrent hepatocellular carcinoma after liver transplantation: validation of a pathologic risk score on explanted livers to predict recurrence. Transplant Proc 2021;53:1975-9.
42. Cullaro G, Rubin J, Mehta N, Yao F, Verna EC, Lai JC. Sex-based disparities in hepatocellular carcinoma recurrence after liver transplantation. Transplantation 2021;105:2420-6.
43. Orci LA, Combescure C, Fink M, et al. Predicting recurrence of hepatocellular carcinoma after liver transplantation using a novel model that incorporates tumor and donor-related factors. Transpl Int 2021;34:2875-86.
44. Ferrarese A, Sartori G, Orrù G, et al. Machine learning in liver transplantation: a tool for some unsolved questions? Transpl Int 2021;34:398-411.
45. Marsh JW, Finkelstein SD, Demetris AJ, et al. Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. Liver Transpl 2003;9:664-71.
46. Rodriguez-Luna H, Vargas HE, Byrne T, Rakela J. Artificial neural network and tissue genotyping of hepatocellular carcinoma in liver-transplant recipients: prediction of recurrence. Transplantation 2005;79:1737-40.
47. Jonas S, Bechstein WO, Steinmüller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080-6.
48. Lozanovski VJ, Ramouz A, Aminizadeh E, et al. Prognostic role of selection criteria for liver transplantation in patients with hepatocellular carcinoma: a network meta-analysis. BJS Open 2022:6.
49. Pommergaard HC, Rostved AA, Adam R, et al; European Liver and Intestine Transplant Association (ELITA). Vascular invasion and survival after liver transplantation for hepatocellular carcinoma: a study from the European liver transplant registry. HPB (Oxford) 2018;20:768-75.
50. Yao FY, Mehta N, Flemming J, et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology 2015;61:1968-77.
51. Tabrizian P, Holzner ML, Mehta N, et al. Ten-year outcomes of liver transplant and downstaging for hepatocellular carcinoma. JAMA Surg 2022;157:779-88.
52. Mazzaferro V, Citterio D, Bhoori S, et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol 2020;21:947-56.
53. Otto G, Herber S, Heise M, et al. Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma. Liver Transpl 2006;12:1260-7.
54. Millonig G, Graziadei IW, Freund MC, et al. Response to preoperative chemoembolization correlates with outcome after liver transplantation in patients with hepatocellular carcinoma. Liver Transpl 2007;13:272-9.
55. Lai Q, Avolio AW, Graziadei I, et al; European Hepatocellular Cancer Liver Transplant Study Group. Alpha-fetoprotein and modified response evaluation criteria in solid tumors progression after locoregional therapy as predictors of hepatocellular cancer recurrence and death after transplantation. Liver Transpl 2013;19:1108-18.
56. Biolato M, Galasso T, Marrone G, Miele L, Grieco A. Upper limits of downstaging for hepatocellular carcinoma in liver transplantation. Cancers (Basel) 2021;13:6337.
57. Cillo U, Vitale A, Volk ML, et al. The survival benefit of liver transplantation in hepatocellular carcinoma patients. Dig Liver Dis 2010;42:642-9.
58. Giannini EG, Aglitti A, Borzio M, et al; Associazione Italiana per lo Studio del Fegato (AISF) HCC Special Interest Group. Overview of immune checkpoint inhibitors therapy for hepatocellular carcinoma, and the ITA.LI.CA cohort derived estimate of amenability rate to immune checkpoint inhibitors in clinical practice. Cancers (Basel) 2019;11:1689.
59. Harper AM, Edwards E, Washburn WK, Heimbach J. An early look at the organ procurement and transplantation network explant pathology form data. Liver Transpl 2016;22:757-64.
60. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 2005;25:181-200.
61. Schwartz ME. Liver transplantation for hepatocellular carcinoma: the best treatment, but for which patient? Hepatology 1996;24:1539-41.
62. Shetty K, Timmins K, Brensinger C, et al. Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 2004;10:911-8.
63. Freeman RB, Mithoefer A, Ruthazer R, et al. Optimizing staging for hepatocellular carcinoma before liver transplantation: a retrospective analysis of the UNOS/OPTN database. Liver Transpl 2006;12:1504-11.
64. Mehta N, Dodge JL, Roberts JP, Hirose R, Yao FY. Misdiagnosis of hepatocellular carcinoma in patients receiving no local-regional therapy prior to liver transplant: an analysis of the organ procurement and transplantation network explant pathology form. Clin Transplant 2017:31.
65. Mehta N, Heimbach J, Harnois DM, et al. Validation of a risk estimation of tumor recurrence after transplant (RETREAT) score for hepatocellular carcinoma recurrence after liver transplant. JAMA Oncol 2017;3:493-500.
66. Mehta N, Dodge JL, Roberts JP, Yao FY. Validation of the prognostic power of the RETREAT score for hepatocellular carcinoma recurrence using the UNOS database. Am J Transplant 2018;18:1206-13.
67. Berry K, Ioannou GN. Serum alpha-fetoprotein level independently predicts posttransplant survival in patients with hepatocellular carcinoma. Liver Transpl 2013;19:634-45.
68. Levi DM, Tzakis AG, Martin P, et al. Liver transplantation for hepatocellular carcinoma in the model for end-stage liver disease era. J Am Coll Surg 2010;210:727-34, 735.
69. Grąt M, Krasnodębski M, Patkowski W, et al. Relevance of pre-transplant α-fetoprotein dynamics in liver transplantation for hepatocellular cancer. Ann Transplant 2016;21:115-24.
70. Hong G, Suh KS, Suh SW, et al. Alpha-fetoprotein and (18)F-FDG positron emission tomography predict tumor recurrence better than Milan criteria in living donor liver transplantation. J Hepatol 2016;64:852-9.
71. Toso C, Asthana S, Bigam DL, Shapiro AM, Kneteman NM. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the scientific registry of transplant recipients database. Hepatology 2009;49:832-8.
72. Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant 2008;8:2547-57.
73. Hameed B, Mehta N, Sapisochin G, Roberts JP, Yao FY. Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl 2014;20:945-51.
74. Decaens T, Roudot-Thoraval F, Badran H, et al. Impact of tumour differentiation to select patients before liver transplantation for hepatocellular carcinoma. Liver Int 2011;31:792-801.
75. Costentin C, Piñero F, Degroote H, et al; French-Italian-Belgium and Latin American collaborative group for HCC and liver transplantation. R3-AFP score is a new composite tool to refine prediction of hepatocellular carcinoma recurrence after liver transplantation. JHEP Rep 2022;4:100445.
76. Tran BV, Moris D, Markovic D, et al. Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: analysis of the US multicenter HCC transplant consortium. Liver Transpl 2023;29:683-97.
77. Halazun KJ, Hardy MA, Rana AA, et al. Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma. Ann Surg 2009;250:141-51.
78. Chaiteerakij R, Zhang X, Addissie BD, et al. Combinations of biomarkers and Milan criteria for predicting hepatocellular carcinoma recurrence after liver transplantation. Liver Transpl 2015;21:599-606.
79. Norman JS, Li PJ, Kotwani P, Shui AM, Yao F, Mehta N. AFP-L3 and DCP strongly predict early hepatocellular carcinoma recurrence after liver transplantation. J Hepatol 2023;79:1469-77.
80. Welling TH, Eddinger K, Carrier K, et al. Multicenter study of staging and therapeutic predictors of hepatocellular carcinoma recurrence following transplantation. Liver Transpl 2018;24:1233-42.
81. Pawlik TM, Delman KA, Vauthey JN, et al. Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl 2005;11:1086-92.
82. Gouw AS, Balabaud C, Kusano H, Todo S, Ichida T, Kojiro M. Markers for microvascular invasion in hepatocellular carcinoma: where do we stand? Liver Transpl 2011;17 Suppl 2:S72-80.
83. Kornberg A, Freesmeyer M, Bärthel E, et al. 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver transplant patients. Am J Transplant 2009;9:592-600.
84. Verna EC, Patel YA, Aggarwal A, et al. Liver transplantation for hepatocellular carcinoma: management after the transplant. Am J Transplant 2020;20:333-47.
85. Pawlik TM, Gleisner AL, Anders RA, Assumpcao L, Maley W, Choti MA. Preoperative assessment of hepatocellular carcinoma tumor grade using needle biopsy: implications for transplant eligibility. Ann Surg 2007;245:435-42.
86. Young RS, Aldiwani M, Hakeem AR, et al. Pre-liver transplant biopsy in hepatocellular carcinoma: a potential criterion for exclusion from transplantation? HPB (Oxford) 2013;15:418-27.
87. Kornberg A, Küpper B, Tannapfel A, et al. Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables. Eur J Surg Oncol 2010;36:275-80.
88. Fernandez-Sevilla E, Allard MA, Selten J, et al. Recurrence of hepatocellular carcinoma after liver transplantation: is there a place for resection? Liver Transpl 2017;23:440-7.
89. Kneuertz PJ, Cosgrove DP, Cameron AM, et al. Multidisciplinary management of recurrent hepatocellular carcinoma following liver transplantation. J Gastrointest Surg 2012;16:874-81.
90. Alshahrani AA, Ha SM, Hwang S, et al. Clinical features and surveillance of very late hepatocellular carcinoma recurrence after liver transplantation. Ann Transplant 2018;23:659-65.
91. Cescon M, Ravaioli M, Grazi GL, et al. Prognostic factors for tumor recurrence after a 12-year, single-center experience of liver transplantations in patients with hepatocellular carcinoma. J Transplant 2010;2010:1-8.
92. Lee DD, Sapisochin G, Mehta N, et al. Surveillance for HCC after liver transplantation: increased monitoring may yield aggressive treatment options and improved postrecurrence survival. Transplantation 2020;104:2105-12.
93. European Association for the Study of the Liver. EASL clinical practice guidelines: liver transplantation. J Hepatol 2016;64:433-85.
94. Lucey MR, Terrault N, Ojo L, et al. Long-term management of the successful adult liver transplant: 2012 practice guideline by the American association for the study of liver diseases and the american society of transplantation. Liver Transpl 2013;19:3-26.
95. Berenguer M, Burra P, Ghobrial M, et al. Posttransplant management of recipients undergoing liver transplantation for hepatocellular carcinoma. Working group report from the Ilts transplant oncology consensus conference. Transplantation 2020;104:1143-9.
96. Aggarwal A, Te HS, Verna EC, Desai AP. A national survey of hepatocellular carcinoma surveillance practices following liver transplantation. Transplant Direct 2021;7:e638.
97. Notarpaolo A, Layese R, Magistri P, et al. Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC. J Hepatol 2017;66:552-9.
98. Nörthen A, Asendorf T, Walson PD, Oellerich M. Diagnostic value of alpha-1-fetoprotein (AFP) as a biomarker for hepatocellular carcinoma recurrence after liver transplantation. Clin Biochem 2018;52:20-5.
99. Liu D, Chan AC, Fong DY, Lo CM, Khong PL. Evidence-based surveillance imaging schedule after liver transplantation for hepatocellular carcinoma recurrence. Transplantation 2017;101:107-11.
100. Hoffman D, Mehta N. Recurrence of hepatocellular carcinoma following liver transplantation. Expert Rev Gastroenterol Hepatol 2021;15:91-102.
101. Åberg F, Abrahamsson J, Schult A, Bennet W, Rizell M, Sternby-Eilard M. The RETREAT score provides valid predictions regarding hepatocellular carcinoma recurrence after liver transplantation. Transpl Int 2021;34:2869-74.
102. Reddy SHS, Mehta N, Dodge JL, et al. Liver transplantation for HCC: validation of prognostic power of the RETREAT score for recurrence in a UK cohort. HPB (Oxford) 2022;24:596-605.
103. Ivanics T, Nelson W, Patel MS, et al. The toronto postliver transplantation hepatocellular carcinoma recurrence calculator: a machine learning approach. Liver Transpl 2022;28:593-602.
104. Liu S, Nalesnik MA, Singhi A, et al. Transcriptome and exome analyses of hepatocellular carcinoma reveal patterns to predict cancer recurrence in liver transplant patients. Hepatol Commun 2022;6:710-27.
105. Lai Q, De Stefano C, Emond J, et al; EurHeCaLT and the West-East LT Study Group. Development and validation of an artificial intelligence model for predicting post-transplant hepatocellular cancer recurrence. Cancer Commun (Lond) 2023;43:1381-5.
106. Liu Z, Liu Y, Zhang W, et al. Deep learning for prediction of hepatocellular carcinoma recurrence after resection or liver transplantation: a discovery and validation study. Hepatol Int 2022;16:577-89.
107. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999;397:530-4.
108. Maluccio M, Sharma V, Lagman M, et al. Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression. Transplantation 2003;76:597-602.
109. Yokoyama I, Carr B, Saitsu H, Iwatsuki S, Starzl TE. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer 1991;68:2095-100.
110. Rodríguez-Perálvarez M, Tsochatzis E, Naveas MC, et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J Hepatol 2013;59:1193-9.
111. Vivarelli M, Cucchetti A, Piscaglia F, et al. Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl 2005;11:497-503.
112. Vivarelli M, Cucchetti A, La Barba G, et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence. Ann Surg 2008;248:857-62.
113. Rodríguez-Perálvarez M, Colmenero J, González A, et al; Chronic immunosuppression, cancer Spanish consortium. Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation. Cancer Commun (Lond) 2022;22:1671-82.
114. Zhou J, Wang Z, Wu ZQ, et al. Sirolimus-based immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria. Transplant Proc 2008;40:3548-53.
115. Kneteman NM, Oberholzer J, Al Saghier M, et al. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004;10:1301-11.
116. Zimmerman MA, Trotter JF, Wachs M, et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl 2008;14:633-8.
117. Toso C, Merani S, Bigam DL, Shapiro AM, Kneteman NM. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 2010;51:1237-43.
118. Yanik EL, Chinnakotla S, Gustafson SK, et al. Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma. Liver Transpl 2016;22:627-34.
119. Menon KV, Hakeem AR, Heaton ND. Meta-analysis: recurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma. Aliment Pharmacol Ther 2013;37:411-9.
120. Liang W, Wang D, Ling X, et al. Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl 2012;18:62-9.
121. Cholongitas E, Mamou C, Rodríguez-Castro KI, Burra P. Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review. Transpl Int 2014;27:1039-49.
122. Grigg SE, Sarri GL, Gow PJ, Yeomans ND. Systematic review with meta-analysis: sirolimus- or everolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Aliment Pharmacol Ther 2019;49:1260-73.
123. Yan X, Huang S, Yang Y, et al. Sirolimus or everolimus improves survival after liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Liver Transpl 2022;28:1063-77.
124. Geissler EK, Schnitzbauer AA, Zülke C, et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial. Transplantation 2016;100:116-25.
125. Schnitzbauer AA, Filmann N, Adam R, et al. mTOR inhibition is most beneficial after liver transplantation for hepatocellular carcinoma in patients with active tumors. Ann Surg 2020;272:855-62.
126. Rodríguez-Perálvarez M, Guerrero M, Barrera L, et al. Impact of early initiated everolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Transplantation 2018;102:2056-64.
127. Kang I, Lee JG, Choi SH, et al. Impact of everolimus on survival after liver transplantation for hepatocellular carcinoma. Clin Mol Hepatol 2021;27:589-602.
128. De Simone P, Precisi A, Lai Q, et al. Everolimus mitigates the risk of hepatocellular carcinoma recurrence after liver transplantation. Cancers (Basel) 2024;16:1243.
129. Lee SG, Jeng LB, Saliba F, et al. Efficacy and safety of everolimus with reduced tacrolimus in liver transplant recipients: 24-month results from the pooled analysis of 2 randomized controlled trials. Transplantation 2021;105:1564-75.
130. Safety and efficacy of everolimus treatment in liver transplantation for liver cancer. Available from: https://clinicaltrials.gov/study/NCT02081755?cond=transplantation%20for%20liver%20cancer&intr=everolimus&rank=1. [Last accessed on 25 Oct 2024].
131. Cholongitas E, Burra P, Vourli G, Papatheodoridis GV. Safety and efficacy of everolimus initiation from the first month after liver transplantation: a systematic review and meta-analysis. Clin Transplant 2023;37:e14957.
132. Charlton M, Levitsky J, Aqel B, et al. International liver transplantation society consensus statement on immunosuppression in liver transplant recipients. Transplantation 2018;102:727-43.
133. De Simone P, Fagiuoli S, Cescon M, et al; Consensus Panel. Use of everolimus in liver transplantation: recommendations from a working group. Transplantation 2017;101:239-51.
134. Cillo U, Carraro A, Avolio AW, et al; Italian Board of Experts in Liver Transplantation (I-BELT). Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT). Updates Surg 2024;76:725-41.
135. Siegel AB, El-Khoueiry AB, Finn RS, et al. Phase I trial of sorafenib following liver transplantation in patients with high-risk hepatocellular carcinoma. Liver Cancer 2015;4:115-25.
136. Satapathy SK, Das K, Kocak M, et al. No apparent benefit of preemptive sorafenib therapy in liver transplant recipients with advanced hepatocellular carcinoma on explant. Clin Transplant 2018;32:e13246.
137. Bruix J, Takayama T, Mazzaferro V, et al; STORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015;16:1344-54.
138. Lin HS, Wan RH, Gao LH, Li JF, Shan RF, Shi J. Adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma: a systematic review and a meta-analysis. Hepatobiliary Pancreat Dis Int 2015;14:236-45.
139. Guo DZ, Cheng JW, Yan JY, et al. Efficacy and safety of lenvatinib for preventing tumor recurrence after liver transplantation in hepatocellular carcinoma beyond the Milan criteria. Ann Transl Med 2022;10:1091.
140. Deng Y, Yang J, Chen Y, et al. Development of a risk classifier to predict tumor recurrence and lenvatinib benefits in hepatocellular carcinoma after liver transplantation. Transplant Proc 2023;55:153-63.
141. Han B, Ding H, Zhao S, et al. Potential role of adjuvant lenvatinib in improving disease-free survival for patients with high-risk hepatitis b virus-related hepatocellular carcinoma following liver transplantation: a retrospective, case control study. Front Oncol 2020;10:562103.
142. Qin S, Chen M, Cheng AL, et al; IMbrave050 investigators. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023;402:1835-47.
143. Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut 2021;70:204-14.
144. Yang Z, Wang S, Tian XY, et al. Impact of treatment modalities on patients with recurrent hepatocellular carcinoma after liver transplantation: preliminary experience. Hepatobiliary Pancreat Dis Int 2020;19:365-70.
145. Huang J, Yan L, Wu H, Yang J, Liao M, Zeng Y. Is radiofrequency ablation applicable for recurrent hepatocellular carcinoma after liver transplantation? J Surg Res 2016;200:122-30.
146. Jeong YH, Hwang S, Lee GD, et al. Surgical outcome of pulmonary metastasectomy for hepatocellular carcinoma recurrence in liver transplant patients. Ann Transplant 2021;26:e930383.
147. Sposito C, Mariani L, Germini A, et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol 2013;59:59-66.
148. Li BCW, Chiu J, Shing K, et al. The outcomes of systemic treatment in recurrent hepatocellular carcinomas following liver transplants. Adv Ther 2021;38:3900-10.
149. Bang K, Casadei-Gardini A, Yoo C, et al. Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation. Cancer Med 2023;12:2572-9.
150. Iavarone M, Invernizzi F, Czauderna C, et al. Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation. Am J Transplant 2019;19:3176-84.
151. Rezaee-Zavareh MS, Yeo YH, Wang T, et al. Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: a systematic review and individual patient data meta-analysis. J Hepatol 2024:Online ahead of print.
152. Di Marco L, Pivetti A, Foschi FG, et al. Feasibility, safety, and outcome of second-line nivolumab/bevacizumab in liver transplant patients with recurrent hepatocellular carcinoma. Liver Transpl 2023;29:559-63.
153. Tabrizian P, Abdelrahim M, Schwartz M. Immunotherapy and transplantation for hepatocellular carcinoma. J Hepatol 2024;80:822-5.
154. Tan AT, Yang N, Lee Krishnamoorthy T, et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy. Gastroenterology 2019;156:1862-1876.e9.
Cite This Article
Open Access
, ... Patrizia BurraHow to Cite
Pelizzaro, F.; Ferrarese A.; Gambato M.; Zanetto A.; Russo F. P.; Germani G.; Senzolo M.; Rizzato M. D.; Soldà C.; Vitale A.; Gringeri E.; Cillo U.; Burra P. Hepatocellular carcinoma recurrence after liver transplantation: risk factors, targeted surveillance and management options. Hepatoma. Res. 2024, 10, 44. http://dx.doi.org/10.20517/2394-5079.2024.107
Download Citation
Export Citation File:
Type of Import
Tips on Downloading Citation
Citation Manager File Format
Type of Import
Direct Import: When the Direct Import option is selected (the default state), a dialogue box will give you the option to Save or Open the downloaded citation data. Choosing Open will either launch your citation manager or give you a choice of applications with which to use the metadata. The Save option saves the file locally for later use.
Indirect Import: When the Indirect Import option is selected, the metadata is displayed and may be copied and pasted as needed.
About This Article
Copyright
Data & Comments
Data
0
Comments
Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.