Background: Examinations of procalcitonin (PCT) and Ki-67 expression levels in hepatocellular carcinoma (HCC) patients who have undergone liver transplantation (LT) through immunohistochemical analyses of tumor tissue may reveal the biological characteristics of the tumor, thus informing the selection of HCC patients for LT. Methods: Hepatectomy specimens from 86 HCC patients who underwent LT were obtained and analyzed immunohistochemically for the expression of PCT and Ki-67. The percentage and intensity of PCT staining, as well as the percentage of Ki-67 expression, were assessed for each patient. The impacts of PCT and Ki-67 expression on disease-free survival, overall survival, and the recurrence rate were studied, as well as their correlations with other clinicopathological features. Results: The recurrent HCC group showed a higher Ki-67 level (p < 0.001), larger maximum dominant tumor diameter (p < 0.001), and higher rate of vascular invasion (p = 0.001). The pre-transplant AFP (p = 0.001), maximum dominant tumor diameter (p < 0.001), number of tumor nodules (p < 0.001), rate of vascular invasion (p = 0.001), and Ki-67 level (p = 0.044) were higher in patients beyond the Milan criteria. Similarly, the pre-transplant AFP (p < 0.001); maximum dominant tumor diameter (p < 0.001); number of tumor nodules (p < 0.001); rates of portal vein tumor thrombus (p = 0.002), poor differentiation (p = 0.021), and vascular invasion (p < 0.001); and Ki-67 level (p = 0.010) were higher in patients beyond the expanded Malatya criteria. The maximum dominant tumor diameter (p = 0.006); Ki-67 level (p = 0.003); rates of vascular invasion (p < 0.001), cases beyond the Milan criteria (p = 0.042) and the expanded Malatya criteria (p = 0.027), and portal vein tumor thrombus (p = 0.020); and presence of recurrence (p < 0.001) were higher in HCC patients with mortality. The Kaplan-Meier estimates indicated that Ki-67 levels exceeding 5% significantly affected DFS and OS. Although the Kaplan-Meier estimates indicated that a PCT staining percentage of ≥25% did not have a statistically significant effect on DFS or OS, the outcomes may be considered clinically significant. Conclusions: This study demonstrated that the Ki-67 proliferation index can be used as a predictive biomarker of the biological behavior of HCC. Furthermore, we claim that PCT expression over a particular threshold might impact recurrence and survival, and we believe that further multicenter prospective studies focused on standardized PCT antibody staining are crucial in order to determine its potential as a biomarker for HCC.

Intrahepatic cholangiocarcinoma (iCC) is the liver's second most common neoplasm. Until now, surgery is the only curative option, but only 35% of the cases are considered resectable at the diagnosis, with a post-resection survival of around 30%. Advancements in surgical techniques and perioperative care related to liver transplantation (LT) have facilitated the expansion of indications for hepatic neoplasms.

This study is a comprehensive review of the global experience in living donor LT (LDLT) for treating iCC and describes our first case of LDLT for an unresectable iCC.

While exploring LT for intrahepatic cholangiocarcinoma dates to the 1990s, the initial outcomes were discouraging, marked by poor survival and high recurrence rates. Nevertheless, contemporary perspectives underscore a reinvigorated emphasis on extending the frontiers of LT indications within the context of the "oncologic era." The insights gleaned from examining explants, wherein incidental iCC was categorized as hepatocellular carcinoma in the preoperative period, have demonstrated comparable survival rates to small hepatocellular carcinoma. These findings substantiate the potential viability of LT as a curative alternative for iCC. Another investigated scenario pertains to "unresectable tumors with favorable biological behavior," LT presents a theoretical advantage by providing free margins without the concern of a small future liver remnant. The constraint of organ shortage persists, particularly in nations with low donation rates. LDLT emerges as a viable and secure alternative for treating iCC.

LDLT is an excellent option for augmenting the graft pool, particularly in carefully selected patients.

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.

The outcome of liver transplantation (LT) for hepatocarcinoma (HCC) is strongly influenced by HCC staging, which is based on radiological examinations in a pre-LT setting; concordance between pre-LT radiological and definitive pathological staging remains controversial. To address this issue, we retrospectively analyzed our LT series to assess concordance between radiology and pathology and to explore the factors associated with poor concordance and outcomes. We included all LTs with an HCC diagnosis performed between 2013 and 2018. Concordance (Co group) was defined as a comparable tumor burden in preoperative imaging and post-transplant pathology; otherwise, non-concordance was diagnosed (nCo group). Concordance between radiology and pathology was observed in 32/134 patients (Co group, 24%). The number and diameter of the nodules were higher when nCo was diagnosed, as was the number of pre-LT treatments. Although concordance did not affect survival, more than three pre-LT treatments led to a lower disease-free survival. Patients who met the Milan Criteria (Milan-in patients) were more likely to receive ≥three prior treatments, leading to a lower survival in multi-treated Milan-in patients than in other Milan-in patients. In conclusion, the concordance rate between the pre-LT imaging and histopathological results was low in patients with a high number of nodules. Multiple bridging therapies reduce the accuracy of pre-LT imaging in predicting HCC stages and negatively affect outcomes after LT.

Immunogenic cell death (ICD) has emerged as a promising strategy to activate the adaptive immune response, modulate the tumor microenvironment (TME) and enhance the efficacy of immune therapy. However, the relationship between ICD and TME reprogramming in hepatocellular carcinoma (HCC) remains poorly understood.

Transcriptional profiles and clinical spectrum of 486 HCC patients were obtained from TCGA and GEO databases. We utilized consensus clustering analysis to construct two distinct molecular subtypes and established an ICD-based scoring system (named ICD score) via WGCNA and LASSO Cox regression to predict the prognosis of the HCC cohort. Then we employed CIBERSORT and ESTIMATE methods to analyze the immune landscape of ICD score in HCC. Subsequently, the immunophenoscore (IPS) and tumor immune dysfunction and rejection (TIDE) analyses were performed to determine whether the ICD score could influence the immune therapeutic effect. Based on the ICD scoring system, a novel nomogram was generated to provide a numerical probability of HCC patients' overall survival (OS).

We identified two independent ICD clusters (cluster A/B), and cluster B possessed a worse prognosis and higher immune cell infiltration. Using ICD scoring system, the HCC patients were divided into high- and low-ICD-score groups. Through integrative analyses, the high-ICD cohort owned advanced TNM stage, high pathologic grade and increased suppressive immune cell enrichment. We developed a nomogram containing the ICD score, demonstrating a high predictive accuracy with a C-index of 0.703. We further discovered that PSMD2 and PSMD14 could serve as ICD-associated prognostic biomarkers and therapeutic targets in HCC.

The ICD score exhibits a high degree of reliability for predicting prognosis and may provide valuable guidance for the selection of immunotherapy for HCC patients. This novel scoring system enables the estimation of clinical immunotherapy response for HCC patients, offering new opportunities for personalized immunotherapy.

Hepatocellular carcinoma (HCC) patients with clinically significant portal hypertension (CSPH) and beyond the Milan criteria undergoing hepatectomy were previously considered to be at high risk and to have a poor prognosis, especially for major hepatectomy. The aim of this study was to investigate the safety and efficacy of hepatectomy in those patients.

Data were collected on HCC patients with CSPH treated at a single centre from January 2010 to October 2021. Propensity score-matched (PSM) analysis was used to balance the bias between groups.

Of the included patients, 556 underwent hepatectomy and 172 underwent transcatheter arterial chemoembolization (TACE). Comparison of patients beyond the Milan criteria and those with Milan criteria underwent hepatectomy, the 90-day mortality and complication rates were similar in the two groups. However, the overall survival (OS) and recurrence-free survival (RFS) of patients within the Milan criteria were significantly better than those beyond the Milan criteria (p < 0.001). In HCC patients beyond the Milan criteria, OS of performing hepatectomy was significantly longer than TACE (p < 0.001). Within HCC patients beyond the Milan criteria underwent hepatectomy, there was no significant difference in 90-day mortality and complications between minor and major hepatectomy in patients beyond the Milan criteria and no significant difference in RFS and OS after PSM.

Hepatectomy for HCC patients with CSPH and beyond the Milan criteria is safe and feasible, with an acceptable prognosis and no significant difference between minor and major hepatectomy.

Liver transplantation (LT) is a good therapeutic decision, cures hepatocellular carcinoma (HCC) and promotes survival of cases with unrespectable HCC based on the Milan criteria. HCC still recur after LT. Identifying high risk tissue markers that predict recurrence becomes important for LT decision-making. Little is known regarding use of tissue expression of epithelial cell adhesion molecule (EpCAM) to predict HCC recurrence. This study investigates the role of EpCAM, Ki67, and endothelial-cell-specific molecule-1 (ESM1) as immunohistochemical markers to predict HCC recurrence after LT. It included 52 explanted HCC tissues from Egyptian patients who had undergone LT for HCC according to Milan criteria. Immunohistochemical staining was done on paraffin-embedded formalin-fixed tissue sections. HCC recurrence occurred in 13.5% cases. Positive EpCAM expression in HCC, was significantly associated with HCC recurrence, ( P =0.011), achieving 71.43% sensitivity, 84.44% specificity and 78.8% accuracy in predicting recurrence. High Ki67 percentage was significantly associated with HCC recurrence, ( P =0.005), achieving 57.14% sensitivity, 86.67% specificity and 82.69% accuracy in predicting HCC recurrence. ESM1 showed significant association with HCC recurrence ( P =0.041), with 71.43% sensitivity, 71.11% specificity and 71.15% accuracy in predicting HCC recurrence. EpCAM score and Ki67 percentage showed positive correlation. In conclusion, it is suggested that large tumor size (≥3 cm), advanced pathologic staging and Ki67 could be stratified as high risk predictors of HCC recurrence after LT. Although higher classes of Child-Turcotte-Pugh classification, high serum alpha-fetoprotein, microvascular invasion, positive EpCAM and ESM1 are stratified as lower risk predictors of HCC recurrence after LT.

Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people.

Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer.

The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

Several breakthroughs in hepatocellular carcinoma (HCC) therapy across tumor stages provide hope to improve its dismal prognosis. Although surgical and local ablative therapies have few significant changes in technique, an improved understanding of tumor biology has facilitated increase numbers of patients who are now eligible to undergo curative-intent procedures. Most notably, acceptable post-transplant outcomes can be achieved in well selected patients whose tumors are downstaged into Milan Criteria. Adjuvant therapy in patients at high risk of recurrence also significantly improves recurrence-free survival after resection or ablation. For patients with liver-localized disease who are not eligible for curative-intent procedures, transarterial chemoembolization (TACE) was historically the treatment modality of choice, regardless of tumor burden; however, there is now increased recognition of patients who are "TACE unsuitable" and may be better treated with systemic therapy. The greatest evolution in HCC treatment options has occurred with systemic therapy, where several new agents are now available in the first- and second-line setting, including immune checkpoint inhibitor combinations. Objective responses are observed in approximately 30% of patients and median survival is approaching 2 years. The availability of immune checkpoint inhibitors has renewed interest in combination therapies for earlier tumor stages, with several phase III trials ongoing. Considering increasing complexities of HCC care, requiring decisions between therapies delivered by different providers, multidisciplinary care is critical and is associated with improved clinical outcomes. In this review, we detail major breakthroughs in HCC therapy, how these breakthroughs can be applied in clinical practice, and remaining areas in need of further research.

In this debate, the authors consider whether patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis are candidates for liver transplantation (LT). The argument for LT in this context is based on the premise that, following successful downstaging treatment, LT confers a much greater clinical benefit in terms of survival outcomes than the available alternative (palliative systemic therapy). A major argument against relates to limitations in the quality of evidence for LT in this setting - in relation to study design, as well as heterogeneity in patient characteristics and downstaging protocols. While acknowledging the superior outcomes offered by LT for patients with portal vein tumour thrombosis, the counterargument is that expected survival in such patients is still below accepted thresholds for LT and, indeed, the levels achieved for other patients who receive transplants beyond the Milan criteria. Based on the available evidence, it seems too early for consensus guidelines to recommend such an approach, however, it is hoped that with higher quality evidence and standardised downstaging protocols, LT may soon be more widely indicated, including for this population with high unmet clinical need.

We aimed to identify new, more accurate risk factors of liver transplantation for liver cancer through using the Surveillance, Epidemiology, and End Results (SEER) database.

Using the SEER database, we identified patients that had undergone surgical resection for non-metastatic hepatocellular carcinoma (HCC) and subsequent liver transplantation between 2010 and 2017. Overall survival (OS) was estimated using Kaplan-Meier plotter. Cox proportional hazards regression modelling was used to identify factors independently associated with recurrent disease [presented as adjusted hazard ratios (HR) with 95% CIs].

Totally, 1530 eligible patients were included in the analysis. There were significant differences in ethnicity (P=0.04), cancer stage (P<0.001), vascular invasion (P<0.001) and gall bladder involvement (P<0.001) between the groups that survived, died due to cancer, or died due to other causes. In the Cox regression model, there were no significant differences in OS at 5 years with different operative strategies (autotransplantation versus allotransplantation), nor at survival at 1 year with neoadjuvant radiotherapy. However, neoadjuvant radiotherapy did appear to improve survival at both 3 years (HR: 0.540, 95% CI: 0.326-0.896, P=0.017) and 5 years (HR: 0.338, 95% CI: 0.153-0.747, P=0.007) from diagnosis.

This study demonstrated differences in patient characteristics between prognostic groups after liver resection and transplantation for HCC. These criteria can be used to inform patient selection and consent in this setting. Preoperative radiotherapy may improve long-term survival post-transplantation.

Interest in anonymous nondirected living organ donation is increasing in the United States and a small number of transplantation centers are accumulating an experience regarding nondirected donation in living donor liver transplantation. Herein, we review current transplant policy, discuss emerging data, draw parallels from nondirected kidney donation, and examine relevant considerations in nondirected living liver donation. We aim to provide a consensus guidance to ensure safe evaluation and selection of nondirected living liver donors and a schema for just allocation of nondirected grafts.

Defining optimum management of patients progressing beyond Milan criteria on the waiting list is a controversial topic. Our aim was to determine whether the policy of allowing a limited progression beyond enlistment criteria permits acceptable post-transplant outcomes in terms of survival and recurrence.

Patients with hepatocellular carcinoma included on the waiting list for orthotopic liver transplantation (OLT) between January 1989 and December 2016 were analysed. Tumour features were assessed at inclusion on the waiting list, before OLT and at explant pathology. Patients were retained on the waiting list despite exceeding enlistment criteria if not presenting with macrovascular invasion, extrahepatic spread or cancer-related symptoms.

A total of 495 patients constituted the target population. Comparison between the Milan-in (n = 434) and Milan-out (n = 61) groups showed statistically significant differences in: largest tumour size; BCLC stage; patients treated before OLT; alpha-fetoprotein, and time on the waiting list. Milan-out patients showed a significantly higher number of poorly differentiated nodules, satellitosis and microscopic vascular invasion. The 1-, 3-, 5- and 10-year survival rate was 89.6%, 82.5%, 75%, and 55.5%, vs. 83.6%, 70.5%, 65.5%, and 53.9% for Milan-in/Milan-out patients, respectively. Recurrence rates at 1, 3, 5 and 10 years were 1.2%, 3.3%, 5.5%, and 10.8% vs. 7.1% 14.5%, 23%, and 23% for Milan-in and Milan-out patients, respectively (p <0.01).

This study shows that although limited tumour progression without reaching major adverse predictors (vascular invasion, extrahepatic spread, cancer symptoms) has an expected impact on recurrence rate, overall survival remains above the minimum proposed benchmark of 65% at 5 years. The clinically relevant increase in tumour recurrence must be considered when analysing the benefit of this approach in the face of limited organ supply.

When considering orthotopic liver transplantation for patients with hepatocellular carcinoma, optimum results are achieved when transplanting patients within the Milan criteria. However, the most appropriate strategy for patients who progress beyond these criteria while on the waiting list is still unclear. Herein, we show that transplantation is associated with acceptable overall survival in select patients who progress beyond the Milan criteria, although recurrence rates were notably higher. Therefore, the assessment of transplantation viability in these patients must consider the availability of organs and the impact on other patient categories.

The incidence of hepatocellular carcinoma (HCC) is increasing, despite effective antiviral treatment for hepatitis B (HBV) and C virus infection and the application of preventive measures such as vaccination at birth against HBV infection. This is mainly due to the increase in metabolic syndrome and its hepatic components, nonalcoholic fatty liver disease and steatohepatitis. Liver resection and transplantation are the main treatment options, offering long-term survival and potential cure. In this review, the recent advances in the surgical management of HCC are presented. More specifically, the role of liver resection in the intermediate and advanced stages, according to the Barcelona Clinic Liver Cancer classification, is analyzed. In addition, the roles of minimally invasive surgery and of living-related liver transplantation in the management of patients with HCC are discussed. Finally, recent data on the role of molecular markers in the early diagnosis and recurrence of HCC are presented. The management of HCC is complex, as there are several options for each stage of the disease. In order for, each patient to get the maximum benefit, an individualized approach is suggested, in specialized liver units, where cases are discussed in multidisciplinary tumor boards.

Liver transplantation is the definitive treatment modality of the patients having an end-stage liver disease with hepatocellular carcinoma.

The number of living donor liver transplantations has been increased because of the deceased donor organ shortage, especially in Asian countries.

Reports of different clinics about the postoperative course and tumor recurrence rates comparing living donor versus deceased donor liver transplantations, besides patient selection criteria, are reviewed along with our clinic's experiences.

Liver transplantation remains the main curative treatment method for hepatocellular carcinoma. There are several criteria for hepatocellular carcinoma to be eligible for liver transplantation, and it depends on main transplantation centers worldwide. Locoregional treatments and downstaging protocols are used for either to achieve these criteria or to prevent drop outs on the transplant waiting lists. But who can benefit from these bridging therapies effectively for the main purpose of curative treatment? Main contraindications are known for locoregional treatments like cirrhosis or low hepatic function, total main portal vein occlusion, and extrahepatic metastasis. HCCs, which are confined to liver but have high tumor burden, remains the main controversial issue.

On this aspect, we reviewed the literature for downstaging protocols for hepatocellular carcinoma with their effect on survival and recurrence rates after liver transplantation.

Although candidates for downstaging is still controversial, with the absence of main contraindications, LRT can be applied to selected HCCs, which have a certain degree of tumor burden.

Hepatocellular carcinoma prognosis depends on both liver and tumor determinants, especially on maximum tumor diameter, multifocality, and presence of portal vein thrombosis, despite apparently complete tumor removal by resection or liver transplantation.

To examine parameters of hepatocellular carcinoma aggressiveness as tumor size increases.

A large hepatocellular carcinoma database was examined for trends in serum alpha-fetoprotein and the percentage of patients with macroscopic portal vein thrombosis or tumor multifocality.

A total of 13,016 hepatocellular carcinoma patients were identified having full tumor and survival data. Of these, 76.56% were male and 23.44% were female, with a median age of 64.4 years. We found that as the maximum tumor diameter increased, there was a significant trend for increased alpha-fetoprotein levels (P<0.001) and an increased percentage of patients with either portal vein thrombosis or tumor multifocality, each P<0.0001. Furthermore, the increases of both alpha-fetoprotein and portal vein thrombosis were proportionately greater than the related maximum tumor diameter increases. These trends of increased alpha-fetoprotein, portal vein thrombosis, and multifocality with increasing maximum tumor diameter had non-linear patterns. Within alpha-fetoprotein and multifocality trends, there were identifiable sub-trends associated with specific maximum tumor diameter ranges.

The greater fold-increases in alpha-fetoprotein and portal vein thrombosis compared with increases in maximum tumor diameter imply that hepatocellular carcinoma characteristics may change with increasing size to a more aggressive phenotype, suggesting that follow-up tumor sampling might be useful, in addition to baseline tumor sampling, for optimal therapeutic choices to be made.

Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people.

Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2017 Edition) in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition (2019 Edition) was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years.

Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People's Republic of China in December 2019.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths and the 7th most common cancer. It has two characteristic features: being advanced stage at diagnosis and association with liver cirrhosis. Liver transplantation (LT) offers the only curative option to treat both components of the disease. The Milan criteria have been extensively used for selecting patients with HCC for LT. However, using Milan criteria, we can only transplant 30% of the patients. The aim of the present review is to evaluate the role of LT in HCC beyond the Milan criteria.

We evaluated the studies that have introduced extended criteria to select patients with HCC beyond the Milan criteria. We evaluated the outcomes in terms of disease-free survival rates and HCC recurrences.

There are patients with tumors that are beyond Milan criteria that could benefit from LT. Selection of these patients has paramount importance in the era of living donor liver transplantation. Current expanded criteria depend on either the bulk of the tumor or the additional surrogate markers of tumor biology such as alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP).

There is no ideal marker or an extended criterion for selecting patients with HCC beyond the Milan criteria and it needs further research to find an effective biomarker that has prognostic significance to select patients with advanced tumors.

The evolution of locoregional therapies in the last decade has been refined with improved patient selection and a development of a more personalized approach. In doing so, there has been associated improved outcomes and less toxicity. With the rapidly changing landscape of systemic therapy, the role of locoregional therapies alone or in combination for downstaging and curative intent will continue to evolve.

The prognosis of HCC depends in large measure on maximum tumor diameter (MTD).

To examine characteristics of tumor aggressiveness over an MTD range of < 2 to 8 cm.

A large HCC database was examined retrospectively for trends in serum alpha-fetoprotein (AFP), and percent of patients with macroscopic portal vein thrombosis (PVT) or tumor multifocality.

There was a significant trend to increased serum AFP levels and percent of patients with PVT, for each, p < 0.001. Within those trends, there were clearly identifiable sub-trends for variations of AFP or percent PVT patients, associated with specific MTD ranges. Calculation of the fold increase for either AFP or percent PVT patients over distinct MTD ranges showed a greater increase of AFP or percent PVT patients compared with the related MTD increase. Interestingly, the increase in percent PVT was mainly independent of AFP.

Patterns of AFP and PVT increase can be discerned with increasing MTD, which are nonlinear. The greater fold increase in tumor aggressiveness factors compared with MTD suggests that HCCs may change with increasing size to a more aggressive phenotype. Baseline HCC biopsies might therefore be insufficient in future rational HCC management, and repeated liquid biopsies have potential in following HCC evolution and thus choices of therapies.

Survival was examined from a Turkish liver transplant center of patients with HCC, to identify prognostic factors. Data from 215 patients who underwent predominantly live donor liver transplant for HCC at our institute over 12 years were included in the study and prospectively recorded. They were 152 patients within and 63 patients beyond Milan criteria. Patients beyond Milan criteria were divided into two groups according to presence or absence of tumor recurrence. Recurrence-associated factors were analyzed. These factors were then applied to the total cohort for survival analysis. We identified four factors, using multivariate analysis, that were significantly associated with tumor recurrence. These were maximum tumor diameter, degree of tumor differentiation, and serum AFP and GGT levels. A model that included all four of these factors was constructed, the 'Malatya criteria.' Using these Malatya criteria, we estimated DFS and cumulative survival, for patients within and beyond these criteria, and found statistically significant differences with improved survival in patients within Malatya criteria of 1, 5, and 10-year overall survival rates of 90.1%, 79.7%, and 72.8% respectively, which compared favorably with other extra-Milan extended criteria. Survival of our patients within the newly defined Malatya criteria compared favorably with other extra-Milan extended criteria and highlight the usefulness of serum AFP and GGT levels in decision-making.

The Milan criteria have been the cornerstone of selection policies for patients with hepatocellular carcinoma (HCC) awaiting liver transplantation (LT) globally for over two decades. Many groups have proposed the transplantation of patients with larger and more numerous tumors achieving comparable results. Many of these use radiologic morphometric criteria as surrogates for explant pathology to predict outcomes. Several other indices have been developed both within and beyond Milan incorporating biological indices as well as dynamic markers of response to pre-transplant locoregional treatments and waiting time. These have allowed for successful expansion of transplant selection criteria without compromising outcomes with limited organ supplies. In this review we will discuss the predictors of outcome in patients beyond Milan criteria.

To assess the potential influence of replacing Milan criteria with simple risk scores on outcomes of hepatocellular carcinoma (HCC) patients undergoing liver transplantation.

Several risk scores combining morphological and biological features were recently proposed for precise selection of HCC patients for transplantation.

This retrospective study included 282 HCC liver transplant recipients. Recurrence-free survival (RFS), the primary outcome measure, was evaluated according to Metroticket 2.0 model and French AFP model with Milan criteria serving as benchmark.

Patients were well stratified with respect to RFS by Milan criteria, Metroticket 2.0 criteria, and AFP model cut-off ≤2 points (all P < 0.001) with c-statistics of 0.680, 0.695, and 0.681, respectively. Neither Metroticket 2.0 criteria (0.014, Z = 0.023; P = 0.509) nor AFP model (-0.014, Z = -0.021; P = 0.492) provided significant net reclassification improvement. Both patients within the Metroticket 2.0 criteria and AFP model ≤2 points exhibited heterogeneous recurrence risk, dependent upon alpha-fetoprotein (P = 0.026) and tumor number (P = 0.024), respectively. RFS of patients beyond Milan but within Metroticket 2.0 criteria (75.3%) or with AFP model ≤2 points (74.1%) was inferior to that observed for patients within Milan criteria (87.1%; P = 0.067 and P = 0.045, respectively). Corresponding microvascular invasion rates were 37.2% and 50.0%, compared with 13.6% in patients within Milan criteria (both P < 0.001). Moreover, Milan-out status was associated with significantly higher recurrence risk in subgroups within Metroticket 2.0 criteria (P = 0.021) or AFP model ≤2 points (P = 0.014).

Utilization of simple risk scores for liver transplant eligibility assessment leads to selection of patients at higher risk of posttransplant HCC recurrence.

Background: Improving surgical outcomes in hepatocellular carcinoma (HCC) patients would greatly benefit from biomarkers. Angiogenesis and inflammation are hallmarks of HCC progression and therapeutic targets. Methods: We retrospectively evaluated preoperative clinical variables and circulating (plasma) biomarkers of angiogenesis and inflammation in a cohort of HCC patients who underwent liver resection (LR) or transplantation (LT). Biomarker correlation with outcomes-freedom of liver recurrence (FLR), disease-free survival (DFS) and overall survival (OS)-was tested using univariate and multivariate Cox regression analyses. Results: Survival outcomes associated with sVEGFR1, VEGF and VEGF-C in LT patients and with IL-10 in LR patients. Moreover, in LT patients within Milan criteria, higher plasma VEGF and sVEGFR1 were associated with worse outcomes, while in those outside Milan criteria lower plasma VEGF-C associated with better outcomes. Multivariate analysis indicated that adding plasma VEGF or VEGF-C to a predictive model including Milan criteria and AFP improved prediction of DFS and OS (all p < 0.05). Conclusion: Survival outcomes after LR or LT differentially associated with angiogenic and inflammatory biomarkers. High plasma VEGF correlated with poorer prognosis within Milan criteria while low plasma VEGF-C associated with better prognosis outside Milan criteria. These candidate biomarkers should be further validated to improve patient stratification.

This article analyzes the ethical soundness of living donor liver transplantation (LDLT) in situations where the transplant team does not consider deceased donor liver transplantation (DDLT) a clinical or timely option. Given that patients with end-stage liver disease have a high risk of death without DDLT, the option of LDLT becomes compelling and may save lives. We present 3 representative cases from our center that raise concerns over social behavior, limited time constraints for decision making, and high potential for disease recurrence that render DDLT an unlikely option. Thereafter, we discuss ethical issues for each patient, which predominantly pertain to compromises to the living donor informed consent process and the feasibility of LDLT. We conclude with recommendations regarding whether LDLT is an acceptable ethical option for those patients, which may inform clinical practice in the broader transplant community.

As experience grows, living donor liver transplantation (LDLT) has become an effective treatment option to overcome the deceased donor organ shortage.

Donor safety is the highest priority in LDLT. Strict donor selection according to structured protocols and center experience are the main factors that determine donor safety. However, with increased experience, many centers have explored increasing organ availability within living donation by means of ABO incompatible LDLT, dual graft LDLT, and anonymous living donation. Also, this growing experience in LDLT has allowed the transplant community to cautiously explore the role of liver transplantation for hepatocellular carcinoma outside of Milan criteria and patients with unresectable colorectal liver metastases.

LDLT has become established as a viable strategy to ameliorate the organ shortage experienced by centers around the world. Improved understanding of this technique has allowed the improved utilization of live donor graft resources, without compromising donor safety. Moreover, LDLT may offer some advantages over deceased donor liver transplantation and a unique opportunity to assess the broader applicability of liver transplantation.

Multiple systemic agents have recently been approved in the first- and second-line setting for hepatocellular carcinoma (HCC), increasing the therapeutic options for patients and treating physicians. The randomised controlled trials that led to these approvals were predominantly conducted in a population comprised of patients with advanced HCC. However, these trials also included a subset of patients who had progressed after locoregional therapies (LRTs), mostly transarterial chemoembolisation. With a greater number of systemic agents available, the role of LRTs has become a topic of debate, specifically regarding when to transition to systemic therapy in unresectable HCC and the potential opportunities for combining locoregional and systemic therapies. Trials of immuno-oncology agents (notably T cell checkpoint inhibitors) are ongoing in the advanced disease setting and these agents also present opportunities for combination therapies, both with other systemic agents and with LRTs in earlier stage disease. This article will review strategies to guide patient selection for LRT as well as the development of locoregional-systemic combinations based on scientific rationale and the challenges of clinical trial design in this setting.

The Barcelona Clinic Liver Cancer (BCLC) staging system is commonly used to classify hepatocellular carcinoma (HCC) patients. However, other staging classification schemes have been proposed. We aimed to compare the prognostic accuracy of the Hong Kong Liver Cancer Staging (HKLC), the Model to Estimate Survival for HCC (MESH), and the BCLC staging systems using a Western cohort of HCC patients.

We retrospectively analyzed 918 patients diagnosed with HCC treated at the University Medical Center of Mainz between 2005 and 2014. We compared the predictive power of survival time of the BCLC, HKLC, and MESH. Predictive ability was tested using the integrated Brier score (IBS) and Harrell's C index.

Kaplan-Meier analyses showed significant differences in survival between stages defined by the BCLC, HKLC, and MESH. The HKLC classification demonstrated a more robust classification concordance and lower prediction error compared to the BCLC and MESH. In addition, we found that the BCLC offers superior predictive ability to the MESH in the first four years, whereas the MESH is superior for long-term predictions.

Our analyses confirm the prognostic value of three different HCC scoring systems. When compared, the HKLC provides superior prognostication ability.

Patients with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma are a heterogeneous population, and the classifications available could not predict the prognosis accurately. Herein, we proposed a new substage classification method, Scoring Method for Intermediate Stage, for precise classification and clinical guidance in hepatocellular carcinoma patients within Barcelona Clinic Liver Cancer stage B.

A total of 1026 stage B patients of hepatocellular carcinoma who underwent transcatheter arterial chemoembolization as a first-line treatment in Liver Cancer Institute, Zhongshan Hospital, Fudan University were retrospectively enrolled. The prognostic evaluation ability of the new substage classification criteria was analyzed, in comparison with the existing substage classification criteria.

Using Scoring Method for Intermediate Stage, 1026 stage B patients were subclassified into three subgroups, based on Child-Pugh score and up-to-7 grade, as B1 (scoring 2), B2 (scoring 3 or 4), and B3 (scoring 5 or 6). The median survival time of the three substages was 29 (95% confidence interval [CI]: 25-36), 19 (95% CI: 16-21), and 10 (95% CI: 8-12) months, respectively. More favorable discrimination efficacy was identified by the new criteria in comparison with the existing substage classification criteria, including Bolondi, Kinki, MICAN, and Kim's criteria. Moreover, multivariate analyses indicated that the novel classification was highly associated with prognosis (Hazard ratio(s) = 1.63, 95% CI: 1.43-1.86, P < 0.001).

Scoring Method for Intermediate Stage demonstrates satisfying capacity in classifying patients with stage B hepatocellular carcinoma and predicting prognosis.

Patients with hepatocellular carcinoma (HCC) within the University of California, San Francisco down-staging (UCSF-DS) criteria (one lesion > 5 cm and ≤ 8 cm; two to three lesions each ≤ 5 cm; or four to five lesions each ≤ 3 cm with total tumor diameter ≤ 8 cm) who achieved successful down-staging (DS) to Milan criteria had similar outcomes after liver transplantation (LT) compared with HCC initially meeting the Milan criteria. Nevertheless, little is known about the outcome of DS in patients with initial tumor burden exceeding the UCSF-DS criteria, defined as "all-comers" (AC). We compared the intention-to-treat (ITT) outcomes of DS in 74 patients in the AC group and 133 patients in the UCSF-DS group. Successful DS to Milan was observed in 64.8% of the AC group versus 84.2% of the UCSF-DS group (P < 0.001). The sum of tumor number and largest tumor diameter was significantly associated with successful DS (hazard ratio [HR] 0.87, P < 0.05). The cumulative probability of dropout within 1 year and 3 years was 53.5% and 80.0%, respectively, for AC versus 25.0% and 36.1%, respectively, for UCSF-DS (P < 0.0001). Factors predicting dropout included sum of tumor number and largest tumor diameter greater than 8 (HR 1.79, P = 0.049) and Child class B and C (HR 2.54, P = 0.001). The AC group also had a significantly lower liver transplant (LT) rate (13.5% versus 59.0%, P < 0.001). ITT survival at 1 year and 5 years was 77.4% and 21.1%, respectively, in AC versus 85.5% and 56.0%, respectively, in UCSF-DS (P < 0.001). Three of 10 patients in the AC group who underwent LT developed HCC recurrence. Conclusion: We observed a significantly lower LT probability and inferior ITT survival with DS in the AC group versus the UCSF-DS group. Our results suggest that an upper limit in tumor burden exists beyond which successful LT after DS becomes an unrealistic goal.