The spatial structure of various cell types in the tumour microenvironment (TME) can provide valuable insights into disease progression. However, identifying the spatial organization of diverse cell types that significantly correlates with patient prognosis remains challenging. In this study, enabled by deep learning-based cell segmentation and recognition, we developed a computational pipeline to systematically quantify the spatial distribution features of tumour cells, stromal cells, and lymphocytes in haematoxylin and eosin (H&E)-stained pathological images of hepatocellular carcinoma (HCC). We identified six cellular spatial features that consistently and significantly correlated with the overall survival of patients in two independent HCC patient cohorts, The Cancer Genome Atlas Program cohort and the Beijing Hospital cohort. Each threshold for patient stratification was the same for both cohorts, and the six features independently served as prognostic indicators when individually analysed alongside clinical variables. Furthermore, the combination of features such as the mean value of cellular diversity around stromal cells (StrDiv-M), the median distance between all cells (CellDis-MED), and the median value of variation coefficient of the distance around stromal cells and their neighbours (CvStrDis-MED) could further stratify the patient prognosis. In addition, incorporating cell spatial features with another clinical feature, microvascular invasion improved prognostic stratification efficacy for patients from both cohorts. In conclusion, by quantifying the cellular spatial organization features in the HCC TME, we discovered novel biomarkers for evaluating tumour prognosis. These findings could promote mechanistic studies of the cellular spatial organization within the HCC TME and potentially guide future clinical treatment.

Among patients with hepatocellular carcinoma(HCC), late recurrence-defined as recurrence occurring two or more years after treatment-has often been treated as a singular, uniform event, despite being inherently heterogeneous and driven by diverse biological mechanisms. We sought to identify prognostic factors associated with recurrence among long-term HCC survivors post-treatment with particular emphasis on the role of underlying liver fibrosis and intrinsic tumor aggressiveness.

Patients who underwent hepatectomy for HCC between 2000 and 2021 were identified from an international database. Prognostic factors for recurrence-free survival(RFS) were evaluated using multivariable Cox regression. Recurrence timing patterns were assessed with kernel density plots.

Among 769 patients, 166(21.6%) developed late recurrence. Patients who experienced late recurrence had a higher FIB-4 index(median2.31vs.2.09;p=0.002) and tended to have microvascular invasion more often(19.3%vs.13.6%;p=0.089). Both a high FIB-4 index(HR1.090[1.011-1.174];p=0.024) and the presence of microvascular invasion(HR2.064[1.260-3.383];p=0.004) were independently associated with worse RFS. Patients were stratified into low-/intermediate-/high-risk groups based on these factors relative to RFS(p=0.027). The hazard of recurrence at 5-years was two-fold higher among high-risk patients (HR 2.07[1.20-3.59]) and 34% higher among patients categorized as intermediate-risk (HR 1.34[0.93-1.95]) (both p<0.05). Kernel density plots demonstrated that microvascular invasion was associated with a peak in recurrence risk at around 3-years, while a high FIB-4 index demonstrated a more gradual and sustained risk, peaking at approximately 4-years that persisted beyond 5-years.

High FIB-4 index and microvascular invasion were independent predictors of late recurrence. Distinct temporal risk patterns emphasize the need for tailored, risk-based postoperative surveillance to enhance detection and early intervention of HCC recurrence.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, the sixth most common cancer worldwide, and the third leading cause of cancer-related death. Cirrhosis is the predominant risk factor for HCC, driven by major etiologies including hepatitis B and C, excessive alcohol consumption, and metabolic dysfunction-associated steatotic liver disease (MASLD). While approximately 80% of HCC cases occur in patients with cirrhosis, its incidence among individuals without cirrhosis has significantly increased, particularly in developed countries, driven by the rising prevalence of MASLD. The prevalence of patients with non-cirrhotic HCC varies geographically, yet data on this subgroup remain limited. Consequently, screening and clinical management guidelines for patients with non-cirrhotic HCC are underdeveloped. Current surveillance is typically not recommended for non-cirrhotic populations, except for individuals with hepatitis B, and diagnostic criteria like Liver Imaging Reporting and Data System are designed explicitly for cirrhotic or hepatitis B-associated HCC. Furthermore, treatment strategies for non-cirrhotic HCC are often extrapolated from studies focused on patients with cirrhosis, leading to gaps in knowledge regarding treatment efficacy, survival outcomes, and etiological variability in non-cirrhotic cohorts. Thus, emerging evidence must be reviewed to guide the development of enhanced diagnostic and therapeutic strategies for patients with non-cirrhotic HCC. To address these gaps, we comprehensively reviewed the epidemiology, clinical and genetic characteristics, diagnostic modalities, and therapeutic approaches for patients with non-cirrhotic HCC.

In patients with hepatocellular carcinoma (HCC), undergoing liver transplantation (LT), cytomegalovirus reactivation (CMVr) may modulate the immune system to prevent tumor recurrence. In this multicenter retrospective study (2010-2015) involving 15 institutions, we assessed the effect of early CMVr in tumor recurrence rates among 771-LT HCC patients with tacrolimus-based immunosuppression (88% men, mean age 58 years). CMV prophylaxis was implemented for 19.7% of patients, while the rest were managed with preemptive therapy. The Milan criteria were met by 88% of patients. Microvascular invasion was present in 12.7% of explanted livers. The serum AFP level before transplantation was 5.1 (3-15) ng/mL. After a median follow-up of 7.4 years, 101 patients (13%) experienced HCC recurrence. CMVr occurred in 235 patients (30.5%) at a median of 41.5 days post-LT and 42 patients (5.6%) had CMV disease. Cumulative exposure to tacrolimus within the first 3 months after LT was similar among patients with and without CMVr. In a multivariate Cox regression analysis, factors associated with an increased rate of HCC recurrence included microvascular invasion [HR:2.82, CI95%:1.55-5.14; p 0.0001], donation after circulatory determination of death [HR:4.43,CI95%:1.52-12.9; p 0.006) and diameter of the main nodule at explant [HR:1.04, CI95%:1.02-1.06; p < 0.001]. Meanwhile CMVr [HR:0.46, CI95%:0.23-0.93, p 0.031] and MELD [HR:0.93, CI95%:0.87-0.99; p0.017] exhibited protective effects. In conclusion, early CMVr may protect against HCC recurrence. The underlying immune mechanisms warrant further investigation.

This study aimed to develop and validate a novel prognostic index, the Weighted Alpha-Fetoprotein Tumor Burden Score (WATS), for predicting outcomes in hepatocellular carcinoma (HCC) patients undergoing resection.

A total of 772 resected HCC patients were included. WATS was developed and validated using an 8:2 cohort split. The score was derived from multivariate Cox regression, resulting in the formula: WATS = 0.73 × tumor number +0.17 × tumor size +0.1 × ln AFP. The time-dependent ROC curve assessed the score's predictive ability, while restricted cubic splines evaluated the dose-response relationship between WATS and prognostic outcomes. Kaplan-Meier curves and multivariate Cox regression further validated the prognostic accuracy.

In the training cohort, AUCs for progression-free survival (PFS) at 1, 2, 3, 4, and 5 years were 0.683, 0.664, 0.661, 0.633, and 0.620, respectively; for overall survival (OS), they were 0.757, 0.732, 0.703, 0.672, and 0.670, respectively. In the validation cohort, AUCs for PFS were 0.711, 0.654, 0.671, 0.662, and 0.684, respectively; for OS, they were 0.724, 0.688, 0.642, 0.698, and 0.721, respectively. WATS outperformed other complex indicators and staging systems. RCS analysis showed a linear relationship between WATS and outcomes. The nomogram based on WATS demonstrated excellent discrimination, calibration, and clinical benefit.

WATS is a novel, reliable prognostic tool for HCC post-resection, offering enhanced patient stratification and risk assessment, thereby improving clinical management.

In this expert opinion, we provide the rationale for concluding that radiation segmentectomy (using the RADSEG method) - a technique involving the transarterial delivery of an ablative, complete necrosis-inducing dose of yttrium-90 radiotherapy - is curative in limited-disease burden hepatocellular carcinoma (HCC). Currently, curative options for early stage and other carefully selected HCC cases include transplantation, resection, and ablation. Because of issues with organ availability, co-morbidities preventing resection, and tumour size and location limiting ablation, other treatments are necessary for this selected patient population. The RADSEG method has evolved into an intra-arterial approach in this setting, with long-term outcomes comparable to ablation, resection, and transplantation. It is proposed that yttrium-90 radioembolisation, applying the RADSEG technique, be formally recognised as curative for early HCC.

Investigative work in the treatment of hepatocellular carcinoma is rapidly growing with the advent of immunotherapy. Nonetheless, trial endpoints and, more importantly, clinically meaningful endpoints need to be accurately chosen depending on the phase of trial and the patient population studied. We provide a scoping review focusing on trial endpoints on the use of immunotherapy in hepatocellular carcinoma.

We searched PubMed and Google Scholar for prospective phase II and III trials using immunotherapy, whether in the neoadjuvant, adjuvant, bridging, downstaging, or palliative settings, while discussing the clinical implications of trial endpoints.

The field of immune oncology is rapidly progressing and has become the standard of care in advanced hepatocellular carcinoma. However, the role of immunotherapy in the treatment of early and intermediate stage hepatocellular carcinoma is yet to be defined. Prospective trials for all stages of disease must strive for endpoints that are not only statistically significant but also clinically consequential. Whereas overall response rate may be a reasonable trial endpoint in phase II trials, phase III trials should rather aim for the improvement of overall survival or quality of life to have clinically meaningful impacts.

Liver transplant (LT) for transplant oncology (TO) indications is being slowly adopted worldwide and has been recommended to be incorporated cautiously due to concerns about mid-long-term survival and its impact on the waiting list.

We conducted 4 systematic reviews of all series on TO indications (intrahepatic cholangiocarcinoma and perihilar cholangiocarcinoma [phCC]) and liver metastases from neuroendocrine tumors (NETs) and colorectal cancer (CRLM) and compared them using patient-level meta-analyses to data obtained from the United Network for Organ Sharing (UNOS) database considering conventional daily-practice indications. Secondary analyses were done for specific selection criteria (Mayo-like protocols for phCC, SECA-2 for CRLM, and Milan criteria for NET). A total of 112,014 LT were analyzed from 2005 to 2020 from the UNOS databases and compared with 345, 721, 494, and 103 patients obtained from meta-analyses on intrahepatic cholangiocarcinoma and phCC, and liver metastases from NET and CRLM, respectively. Five-year overall survival was 53.3%, 56.4%, 68.6%, and 53.8%, respectively. In Mantel-Cox one-to-one comparisons, survival of TO indications was superior to combined LT, second, and third LT and not statistically significantly different from LT in recipients >70 years and high BMI.

Liver transplantation for TO indications has adequate 5-year survival rates, mostly when performed under the selection criteria available in the literature (Mayo-like protocols for phCC, SECA-2 for CRLM, and Milan for NET). Despite concerns about its impact on the waiting list, some other LT indications are being performed with lower survival rates. These oncological patients should be given the opportunity to have a definitive curative therapy within validated criteria.

The RETREAT (Risk Estimation of Tumor Recurrence After Transplant) Score is a validated tool to predict post-transplant HCC recurrence risk. Alpha-fetoprotein (AFP) bound to Lens culinaris agglutinin (AFP-L3) and des-gamma-carboxyprothrombin (DCP) measured at transplant predict worse post-LT survival and may improve the RETREAT score. Our cohort comprised 284 patients transplanted for HCC who were within or downstaged to Milan, with 23 (8.1%) experiencing HCC recurrence. The modified RETREAT (mRETREAT) score assigns AFP-L3 ≥15% 2 points and DCP ≥7.5 ng/mL 3 points. Patients with a modified RETREAT score ≥4 showed a 3-year recurrence-free survival of 73.2% versus 97.8% recurrence-free survival if <4. In comparison, the original RETREAT score had a 3-year recurrence-free survival of 80.0% if ≥2 versus 98.0% if <2. mRETREAT demonstrated a superior AUC of 0.86, compared to the original RETREAT's 0.82, and enhanced calibration and accuracy with a lower Brier score (0.04). The integration of AFP-L3 and DCP into the RETREAT score appears to enhance the prediction of post-LT HCC recurrence. Given these promising results, further study in a larger multicenter cohort is warranted for empiric derivation and validation of a modified RETREAT score, including AFP-L3 and DCP.

Ultrasound is the primary imaging modality used for surveillance of patients at risk for HCC. In 2017, the American College of Radiology Liver Imaging Reporting and Data Systems (ACR LI-RADS) introduced US LI-RADS to standardize the performance, interpretation, and reporting of US for HCC surveillance, with the algorithm recently updated as LI-RADS US Surveillance v2024. The American Association for the Study of Liver Diseases (AASLD) recommends reporting both the examination-level LI-RADS US Category as well as the US Visualization Score. The US Category conveys the overall findings of the exam and primarily determines follow up recommendations. The US Visualization Score conveys the expected sensitivity of the test and stratifies patients into appropriate surveillance pathways. One of the goals of routine surveillance is the detection of HCC at an early, potentially curable stage. Therefore, optimizing US technique is of critical importance. Increasing North American and worldwide utilization of LI-RADS US Surveillance, which includes technical recommendations, through education and outreach will undoubtedly benefit patients undergoing US HCC surveillance.

Liver transplantation (LT) provides the best long-term survival outcomes for patients with liver cancer. As a result, the field of transplant oncology has grown greatly over the past few decades, and many centers have expanded their criteria to allow increased access to LT for liver malignancies. Center-level guidelines and practices in transplant oncology significantly vary across the world, leading to debate regarding the best course of treatment for this patient population. An international consensus conference was convened by the International Liver Transplantation Society and the International Liver Cancer Association on February 1-2, 2024, in Valencia, Spain to establish a more universal consensus regarding LT for oncologic indications. The conference followed the Delphi process, followed by an external expert review. Consensus statements were accepted regarding patient assessment and waitlisting criteria, pretransplant treatment (including immunotherapy) and downstaging, living donor LT, post-LT patient management, and patient- and caregiver-related outcomes. The multidisciplinary participants in the consensus conference provided up-to-date recommendations regarding the selection and management of patients with liver cancer being considered for LT. Although participants deferred to center protocols in many cases, there was great interest in safely expanding access to LT for patients with larger tumor burden and biologically amenable lesions.

Suitability for liver transplantation in patients with hepatocellular carcinoma (HCC) is based on Milan imaging criteria developed several decades ago. We sought to compare pre-transplant imaging with explant liver histopathology in a national retrospective observational study.

All patients who underwent liver transplantation for HCC at the Scottish Liver Transplant Unit (2015-2020) were included. Per-lesion sensitivity of imaging, proportion of patients transplanted outwith UK transplant criteria and two-year survival outcomes were analysed.

140 patients were included. Per-lesion sensitivity was 70 % (38 % for lesions <10 mm). Histopathology of 36 (26 %) patients were outwith UK transplant criteria. 19 (14 %) livers contained >5 HCCs, median lesion size was 9 mm. 9 (6 %) livers contained cholangiocarcinoma. Two-year survival rates: cholangiocarcinoma 100 %, combined HCC-cholangiocarcinoma 100 %, HCC within criteria 90.8 %, HCC outwith criteria 87.5 %, >5 HCCs 77.8 % (p = 0.010).

Current pre-operative imaging for liver transplantation has suboptimal sensitivity, particularly for sub-centimetre lesions. A quarter of transplanted patients are subsequently found to be outwith transplant criteria on explant histopathology, but most have good short-term survival (including cholangiocarcinoma), except for patients with multi-focal small HCCs. Further research is needed to better identify this cohort and to explore whether transplant criteria should be revised.

Hepatocellular carcinoma (HCC) recurrence following liver transplantation (LT) remains a major challenge. This study aimed to investigate the effect of adjuvant chemotherapy (ACT) with the modified FOLFOX-6 (mFOLFOX-6) regimen on the post-transplant prognosis of HCC patients.

HCC patients who underwent LT at our institution from June 2017 to December 2019 were enrolled. The cohort was divided into the ACT group (n = 57) and the non-ACT group (n = 93). The median post-transplant follow-up period was 54.0 months. The study endpoints were HCC recurrence and patient mortality following LT. The association between ACT and recurrence/mortality were evaluated through univariate and multivariate analyses utilizing a Cox proportional hazards model, propensity score adjustment, propensity score matching, and inverse probability of treatment weighting (IPTW) analyses. A stratification analysis was performed to determine the interaction effects.

The ACT group was younger and had worse tumor characteristics including tumor number, tumor size, portal vein tumor thrombosis, pathological differentiation and microvascular invasion (MVI). The ACT group also demonstrated a lower risk of mortality than the non-ACT group (hazard ratio = 0.36, P = 0.017). It was consistent across sensitivity analyses utilizing propensity score adjustment and matching. There was a significant stronger association between ACT and recurrence-free benefit in patients with grade M2 of MVI compared to patients with grade M0/1 (P for interaction = 0.002).

ACT with mFOLFOX-6 regimen decreased the recurrence and mortality risks following LT for HCC patients. ACT may be considered in HCC patients with high risk of recurrence and mortality after LT.

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer-related death worldwide. Contemporary advances in systemic and locoregional therapies have led to changes in peer-reviewed guidelines regarding systemic therapy as well as the possibility of downstaging disease that may enable some patients with advanced disease to ultimately undergo partial hepatectomy or transplantation with curative intent. This review focuses on all modalities of therapy for HCC, guided by modern-day practice-changing randomized data where available. The surgical management of HCC, including resection and transplantation, both of which have evolving criteria for what is considered biologically resectable and transplantable, as well as locoregional therapy (i.e., therapeutic embolization, ablation, radiation, and hepatic arterial infusion), are discussed. Historical and modern-day practice-changing trials evaluating immunotherapy with targeted therapies for advanced disease, as well as adjuvant systemic therapy, are also summarized. In addition, this article examines the critical dimension of toxicities and patient-oriented considerations to ensure a comprehensive and balanced discourse on treatment implications.

The clinical significance of occult HCC identified on explant pathology in liver transplantation (LT) remains unclear. Among recipients of LT, discordance between pre-LT radiographic assessment of HCC and explant tumor burden is common. Data regarding the association of incidental HCC (no pre-LT radiographic diagnosis) and occult multifocal hepatocellular carcinoma (omHCC, pre-LT radiology underestimates a number of explant tumors) with outcomes are scarce. Post-LT recurrence and survival were compared among recipients of LT (n=919, 2002-2019) with incidental HCC (n=129), omHCC (n=349), and non-omHCC (n=437). Multivariable analysis identified independent predictors of omHCC in the subset of patients with kHCC. Compared to kHCC, incidental HCC had similar 5-year overall (OS) and recurrence-free survival (RFS), lower post-LT recurrence (6.9% vs. 16.2%, p =0.0019), but higher non-HCC-related mortality (38.4% vs. 23.7%, p =0.0042). Of 790 kHCC, 349 (44.1%) had omHCC, who demonstrated greater radiographic number of lesions ( p =0.049) and locoregional treatments ( p <0.001) but similar maximum and pre-LT alphafetoprotein compared to non-omHCC. Compared to kHCC without omHCC, patients with omHCC had inferior 5-year OS (60.4% vs. 70.9%, p =0.010) and RFS (56.8% vs. 69.7%, p <0.001), higher recurrence (23.8% vs. 9.2%, p <0.001), and similar non-HCC-related mortality. These observations remained true within patients who remained within Milan throughout preoperative imaging (5-y OS: 62.1% vs. 72.6%, p =0.027; RFS: 58.6% vs. 71.7%, p =0.010; recurrence: 21.7% vs. 7.6%, p <0.001). Multivariable predictors of omHCC tumor included a number of pre-LT locoregional therapies (OR 1.62 for 2 treatments, 95% CI 1.15-2.28, p =0.005; OR 1.98 for 3+ treatments, 1.36-2.88, p <0.001). In patients with kHCC prior to LT, the presence of omHCC is common and associated with inferior post-LT survival and higher recurrence rates. The development of improved radiographic and serum biomarkers that more accurately reflect explant tumor burden may improve patient selection and post-LT outcomes.

Hepatocellular carcinoma (HCC) is one of the leading causes of liver transplant worldwide. While liver transplantation offers a survival advantage for early-stage HCC patients, post-transplant recurrence remains a significant concern, affecting up to 15% of recipients. We sought to conduct a comprehensive review related to HCC recurrence after liver transplant. Tumor-related factors such as poor differentiation, vascular invasion, and elevated tumor biomarkers like alpha-fetoprotein are key predictors of recurrence. Donor-related factors, including graft type and surgical procedures, can also influence outcomes, though their effects are less conclusive. Advancements in patient selection criteria and scoring systems, such as the Milan Criteria and RETREAT score, have improved risk stratification by incorporating tumor size, biomarkers, and response to pre-transplant treatment. Despite these measures, recurrent HCC after transplantation poses treatment challenges. Curative approaches such as resection are feasible for localized or oligometastatic recurrence and offer the best outcomes when applicable. Locoregional treatments, including ablation and transarterial chemoembolization, provide options for unresectable cases but have limited long-term efficacy. Systemic therapies, including targeted agents like sorafenib, regorafenib, and lenvatinib, have shown modest benefits in managing advanced recurrent HCC. Emerging immunotherapy approaches hold promise but face unique challenges due to the required immunosuppression in transplant recipients. Multidisciplinary evaluation remains essential for tailoring treatment plans. Future efforts should focus on refining predictive tools and exploring novel therapies to improve survival outcomes for patients with recurrent HCC after liver transplantation.

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria, liver transplantation (LT) is an effective therapy. This study aims to define the survival-related molecular biological features helping precisely identifying the patients with HCC beyond the Milan criteria who have acceptable outcomes. In the derivation cohort, integrated analyses of tumor tissues are conducted using RNA sequencing (RNA-seq), proteomic landscape, and transposase-accessible chromatin sequencing (ATAC-seq). Based on transcriptomics, three subgroups that significantly differ in overall survival were identified in the derivation cohort, and these findings are validated in an independent cohort. In-depth bioinformatics analysis using RNA-seq and proteomics reveals that the promotion of cancer stemness by cancer-associated fibroblasts (CAFs) can be responsible for the negative biological characteristics observed in high-risk HCC patients. The ATAC-seq identifies key factors regulating transcription, which may bridge CAF infiltration and stemness. Finally, we demonstrate that the CAF-derived CXCL12 sustains the stemness of HCC cells by promoting XRCC5 through CXCR4.

Liver transplantation for cancer indications has gained momentum in recent years. This review is intended to optimize the care setting of liver transplant candidates by highlighting current indications, technical aspects and barriers with available solutions to facilitate the guidance of available strategies for healthcare professionals in specialized centres.

A review of the most recent relevant literature was conducted for all the cancer indications of liver transplantation including colorectal cancer liver metastases, hilar cholangiocarcinoma, intrahepatic cholangiocarcinoma, neuroendocrine tumours, hepatocellular carcinoma and hepatic epitheloid haemangioendothelioma.

Transplant benefit from the best available evidence, including SECA I, SECA II, TRANSMET studies for colorectal liver metastases, various preoperative protocols for cholangiocarcinoma patients, standard, extended selection criteria for hepatocellular carcinoma and neuroendocrine tumours, are discussed. Innovative approaches to deal with organ shortages, including machine-perfused deceased grafts, living donor liver transplantation and RAPID procedures, are also explored.

Cancer indications for liver transplantation are here to stay, and the selection criteria among all cancer groups are likely to evolve further with improved prognostication of tumour biology using adjuncts such as radiomics, cancer genomics, and circulating DNA and RNA status. International prospective registry-based studies could overcome the limitations of smaller patient cohorts and lack of level 1 evidence.

To explore the emerging use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) patients eligible for liver transplantation (LT), particularly as bridging and downstaging therapies. This review also addresses the clinical challenges of integrating ICIs into transplant protocols, including graft rejection, immune-related toxicities, and gaps in evidence.

ICIs have shown potential as bridging and downstaging therapies before LT, with multicentric studies reporting 75.6% successful downstaging, 85% 3-year post-LT survival, and 7.2% rejection-related mortality. A washout interval >94 days and older age have been identified as protective factors against allograft rejection. Combining locoregional therapies with ICIs has proven effective in the EMERALD-1 and LEAP-012 trials, which demonstrated improved progression-free survival (15.0 and 14.6 months, respectively) with ICI-TACE combinations. Similarly, the STAR-FIT phase II trial, combining TACE, SBRT, and avelumab, showed a 42% complete response rate and 12% conversion to curative therapy. Toxicity and rejection risk remain major challenges.

ICIs represent a promising tool for expanding transplant eligibility in HCC, but their integration into LT pathways remains complex. Safety concerns, particularly regarding timing and immune modulation, require careful evaluation. Prospective studies and biomarker development are needed to guide clinical decision-making. Novel therapies such as CAR-T cells may offer more targeted approaches in the future.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Intermediate-stage HCC is often treated with either transcatheter arterial chemoembolisation (TACE) or transcatheter arterial embolisation (TAE). Integrating machine learning (ML) offers the possibility of improving treatment outcomes through enhanced patient selection. This systematic review evaluates the effectiveness of ML models in improving the precision and efficacy of both TACE and TAE for intermediate-stage HCC. A comprehensive search of PubMed, EMBASE, Web of Science, and Cochrane Library databases was conducted for studies applying ML models to TACE and TAE in patients with intermediate-stage HCC. Seven studies involving 4,017 patients were included. All included studies were from China. Various ML models, including deep learning and radiomics, were used to predict treatment response, yielding a high predictive accuracy (AUC 0.90). However, study heterogeneity limited comparisons. While ML shows potential in predicting treatment outcomes, further research with standardised protocols and larger, multi-centre trials is needed for clinical integration.

Despite the growing interest in liver transplantation for cholangiocarcinomas (CCA), conclusive evidence is lacking. We sought to evaluate the outcomes of liver transplantation for intrahepatic cholangiocarcinoma in Brazil.

Retrospective database analysis of patients undergoing liver transplantation for hepatocellular carcinoma (HCC) within Milan criteria in São Paulo, Brazil. Anatomopathological examination of the explanted liver with the presence of intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA) comprised the study group (50 patients). They were compared to a 1:3 HCC-matched cohort.

Study group had lower survival rates than HCC controls (survival at 1, 3, and 5 years, 70.0 %, 57.5 %, and 57.5 % versus 78.7 %, 71.4 %, and 66.6 %, p = 0.019). 5-year survival rates of the control group, cHCC-CCA, and iCCA group were 66.6 %, 59.6 %, and 50.0 % (p = 0.017). There was no statistically significant difference in survival for study group patients with tumors up to 3 cm compared to their controls (p = 0.086).

Patients with CCA had worse outcomes after liver transplantation than those with HCC. Interesting results were found in the more individualized analyses, but because of the limited number of patients, caution should be taken when analyzing them.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma are the primary hepatic malignancies with established pathways to transplantation and model for end-stage liver disease (MELD) exception points. Other tumors managed with liver transplantation (LT) include hepatic epithelioid hemangioendothelioma and fibrolamellar HCC. LT for metastatic neuroendocrine tumor has been established with patient selection criteria and a path to MELD exception points. Additionally, recent data on LT for patients with unresectable hepatic colorectal metastases demonstrate increasingly encouraging initial results.

Treatment options for hepatocellular carcinoma (HCC) vary according to known guidelines among liver resection (LR), liver transplantation (LT), radiofrequency ablation (RFA), and transarterial chemoembolization (TACE). This study aimed to compare the outcomes of initial treatment for patients with resectable HCC within Milan criteria (MC) via nationwide data.

Patients with resectable HCC (Child-Pugh class A; platelet count, ≥100,000/µL) within MC from the Korean Liver Cancer Association databank were analyzed, retrospectively. Outcomes according to initial treatment and subgroups according to tumor size and number were analyzed. Overall survival (OS) rates after initial treatment were compared.

A total of 3,241 patients who underwent LR (n = 1,371), LT (n = 12), RFA (n = 679), or TACE (n = 1,179) were included. The 5-year OS rates differed significantly between the groups (P < 0.05), except for LT (LR, 84.9%; LT, 82.5%; RFA, 76.2%; and TACE, 59.9%). For patients with a single tumor of any size, the 5-year OS rates of the LR group were significantly higher than RFA and TACE groups. For patients with multiple tumors, the 5-year OS rates were 78.2%, 100%, 74.3%, and 53.0% for the LR, LT, RFA, and TACE groups, respectively, but without significant difference between LR and RFA (P = 0.86).

For resectable HCC within MC, the LR had the highest OS rate for a single tumor of any size. LR and RFA showed no significant differences in OS rate for multiple tumors. LR has a much more optimistic outlook for HCC within MC.

Extreme surgery using the hypothermic perfusion technique is often the only treatment option to achieve R0 resection and long-term prognosis for abdominal tumours that are either conventionally unresectable or contraindicated to allotransplantation. We conducted a systematic review and meta-analysis to delineate the indications and outcomes of extreme surgery.

Human studies on extreme resection for abdominal malignant tumours were searched among five databases between January 1988 to March 2023. The Risk Of Bias In Non-randomised Studies - of Interventions tool was used to assess the risk of bias. A meta-analysis of proportions was performed, pooling 1-, 3- and 5-year overall survival and recurrence rates.

This study comprised 73 studies encompassing 333 patients who underwent extreme liver resection (in situ, n = 127; ante situm, n = 72; ex situ, n = 134). Additionally, 90 patients from 17 studies focusing on extreme resection of other (non-hepatic) organs were included. The pooled 90-day mortality and 1- and 5-year overall survival rates were 7.3 %, 72.3 % and 23.4 %, respectively. The 1- and 5-year recurrence rates were 38.7 % and 86.1 %, respectively. Patients aged <65 years had a significantly lower 90-day mortality (5.5 % vs. 29.6 %; P = 0.022) and a higher 5-year overall survival rate (23.9 % vs. 0 %; P < 0.001) than those aged ≥65 years. Additionally, non-epithelial tumours were associated with favourable prognosis compared with epithelial tumours.

Extreme surgery offers acceptable outcomes for younger patients with non-epithelial tumours that are either unresectable by conventional cancer surgery or contraindicated to allotransplantation.

People living with HIV (PLWH) carry a higher risk of developing chronic liver disease and hepatocellular carcinoma (HCC). This relates to shared transmission pathways of HIV and viral hepatitis and a plethora of direct and indirect effects of HIV in the progression of chronic liver disease and HCC. In absence of active cancer treatment, the prognosis of PLWH affected by HCC is worse compared to matched controls without HIV. Evolving evidence suggests that PLWH may receive curative therapies including liver transplantation, loco-regional and systemic anti-cancer therapy for HCC with comparable benefit than people without HIV, underscoring that well controlled HIV infection should not be a barrier to the delivery of cancer care. Nevertheless, PLWH have historically been excluded from interventional clinical trials, and most of the evidence supporting clinical decision making in this population comes from small retrospective studies, adding further challenges to the management of PLWH affected by HCC. Furthermore, whether the biology of the tumour and its microenvironment is influenced by HIV and affects response to treatment is incompletely understood. In this review we summarise the current understanding of pathophysiology, screening and management of HCC in PLWH and discuss the persisting challenges and disparities in care which may contribute to clinical outcome in PLWH.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Multiple treatment modalities are available for the management of HCC, depending on its stage as determined by the Barcelona Clinic Liver Cancer staging system. Because liver transplantation (LT) theoretically removes the cancer and replaces the organ at risk for future malignancy, LT is often considered the most definitive and one of the most efficacious treatment options for HCC. Nevertheless, the success and efficacy of liver transplantation depend on various tumor characteristics. As a result, multiple criteria have been developed to assess the appropriateness of a case of HCC for LT, with the pioneering Milan Criteria established in 1996. Over the past 20 to 30 years, these criteria have been critically evaluated, expanded, and often liberalized to make LT for patients with HCC a more universally applicable option. Furthermore, the development of other treatment modalities has enabled downstaging and bridging strategies for HCC prior to LT. In this narrative and comprehensive review, we provided an update on recent trends in the epidemiology of HCC, selection criteria for LT, implementation of LT across different regions, treatment modalities available as bridges, downstaging strategies, alternatives to LT, and, finally, post-LT surveillance.

The current noninvasive prognostic evaluation methods for hepatocellular carcinoma (HCC), which are largely reliant on radiographic imaging features and serum biomarkers such as alpha-fetoprotein (AFP), have limited effectiveness in discriminating patient outcomes. Identification of new prognostic biomarkers is a critical unmet need to improve treatment decision-making. Epigenetic changes in cell-free DNA (cfDNA) have shown promise in early cancer diagnosis and prognosis. Thus, we aim to evaluate the potential of cfDNA methylation as a noninvasive predictor for prognostication in patients with active, radiographically viable HCC.

Using Illumina HumanMethylation450 array data of 377 HCC tumors and 50 adjacent normal tissues obtained from The Cancer Genome Atlas (TCGA), we identified 158 HCC-related DNA methylation markers associated with overall survival (OS). This signature was further validated in 29 HCC tumor tissue samples. Subsequently, we applied the signature to an independent cohort of 52 patients with plasma cfDNA samples by calculating the cfDNA methylation-based risk score (methRisk) via random survival forest models with 10-fold cross-validation for the prognostication of OS.

The cfDNA-based methRisk showed strong discriminatory power when evaluated as a single predictor for OS (3-year AUC = 0.81, 95% CI: 0.68-0.94). Integrating the methRisk with existing risk indices like Barcelona clinic liver cancer (BCLC) staging significantly improved the noninvasive prognostic assessments for OS (3-year AUC = 0.91, 95% CI: 0.80-1), and methRisk remained an independent predictor of survival in the multivariate Cox model (P = 0.007).

Our study serves as a pilot study demonstrating that cfDNA methylation biomarkers assessed from a peripheral blood draw can stratify HCC patients into clinically meaningful risk groups. These findings indicate that cfDNA methylation is a promising noninvasive prognostic biomarker for HCC, providing a proof-of-concept for its potential clinical utility and laying the groundwork for broader applications.

Extrahepatic recurrence (EHR) is a significant negative prognostic factor in hepatocellular carcinoma (HCC). Although EHR is commonly observed in high-risk patients following HCC hepatectomy, its occurrence without concurrent intrahepatic HCC remains poorly understood. Therefore, this study aims to examine the clinical characteristics and risk factors associated with EHR in patients without intrahepatic HCC at diagnosis.

This study included 1066 treatment-naïve patients who underwent curative hepatectomy for HCC at four tertiary academic centers between January 2004 and December 2019. After excluding those with intrahepatic recurrence (IHR), concurrent EHR, or incomplete clinical records, 569 patients were included in the final analysis. Risk factors for EHR were assessed using multivariate Cox regression over a median follow-up period of 3.91 years.

Among the cohort, 38 patients developed EHR post-surgery without residual intrahepatic HCC, with a median follow-up of 1.04 years. These patients experienced earlier initial HCC recurrence than those without EHR (1.73 vs. 4.43 years). Multivariate analysis revealed significant associations between EHR and microvascular invasion (hazard ratio [HR]: 2.418, p = 0.020), tumor necrosis (HR: 2.592, p = 0.009), and initial tumor staging beyond the Milan criteria (HR: 3.008, p = 0.001). Moreover, Cox regression analysis revealed that EHR strongly correlated with decreased post-hepatectomy survival (HR: 14.044, p < 0.001). Cumulative EHR and survival rates were closely linked to the number of risk factors present.

EHR without detectable IHR is significant and warrants close monitoring in high-risk patients.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Due to the advanced stage in which HCC presents, most patients are only eligible for transarterial chemoembolization (TACE) or radioembolization (Y90). The purpose of this study is to examine the differences in survival and health-related quality of life (HRQOL) in patients diagnosed with HCC and treated with TACE or Y90.

Two hundred thirty-four patients with HCC were enrolled in studies examining HRQOL between 2003-2009. HRQOL was evaluated using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep). Between-group differences were examined using chi-square and ANOVA. Survival was assessed using Kaplan-Meier and Cox regression analyses.

Significant baseline differences between patients treated with TACE versus Y90 were found. Patients who received Y90 tended to be older (p < 0.001), female (p < 0.001), had fewer lesions (p = 0.03), had smaller tumors (p = 0.03), and were less likely to have vascular invasion (p = 0.04). After adjusting for demographic and disease-specific factors, no significant differences in HRQOL were observed at 3 months (p = 0.79) or 6 months (p = 0.75). Clinically meaningful differences were found, with the TACE group reporting greater physical, social, and emotional well-being at 3 and 6 months and greater overall HRQOL at 6 months. No significant differences in survival were found.

Treatment with TACE and Y90 was similar with regard to survival. However, TACE showed statistically and clinically meaningful benefits in physical, social/family, and emotional well-being. Further research is warranted to identify profiles of patients who may demonstrate a preferential response to either TACE or Y90.

Primary and secondary liver cancers are frequently unresectable at the time of diagnosis. Historically, these patients were treated with palliative therapy and no hope for curative resection. While liver transplant has been the standard of care for unresectable hepatocellular carcinoma (HCC), its indications have expanded to other oncologic indications based on promising data from select centers. This review focuses on the utilization of liver transplant for HCC, cholangiocarcinoma, and colorectal liver metastasis.

In the realm of HCC, immunotherapy is an emerging treatment that has the potential for use in the advanced and neoadjuvant setting. It can benefit patients by downstaging them to resectable or transplantable disease burden. Regarding cholangiocarcinoma, better molecular profiling and targeted therapies have benefited patients, and ongoing studies in the United States and internationally will help further delineate the patients with cholangiocarcinoma who benefit from transplantation. Finally, there is emerging evidence that liver transplant for colorectal liver metastases can be safe and effective. While there is promising data showing survival benefit of liver transplantation (LT) for CRLM, standardized guidelines and recommendations in coordination with multidisciplinary oncology teams will be essential for establishing best practices.

Similar to the evolution of LT becoming the standard of care for well selected patients with HCC, the evolution of the role for LT for other hepatobiliary malignancies is quickly progressing as centers in Europe, Asia, and North America gain experience and develop protocols for selected patients with favorable tumor biology. Optimal oncology treatment requires multidisciplinary tumor board and case-by-case approaches which are essential for providing these patients with the best chance at optimal survival.

Hepatocellular carcinoma arises in the setting of cirrhosis in most cases, requiring multidisciplinary input to define resectability. In this regard, more precise surgical management considers patient factors and anatomical states, including resection margins, tumour biology, and perioperative therapy. Together with advances in surgical techniques, this integrated approach has resulted in considerable improvements in patient morbidity and oncological outcomes. Despite this, recurrence rates in hepatocellular carcinoma remain high. As the systemic treatment landscape in hepatocellular carcinoma continues to evolve and locoregional options are increasingly used, we review current and future opportunities to individualise the surgical management of patients with hepatocellular carcinoma.

Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS.

In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.