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Simple Summary: Since their introduction in the 1990s, the Milan criteria have been the gold standard of indication for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Nevertheless, several institutions have reported wider indication criteria for LT with comparable survival outcomes. This paper summarizes the recent indications for LT for HCC through a literature review. Background/Objectives: Since their introduction in the 1990s, the Milan criteria have been the gold standard of indication for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Nevertheless, several institutions have reported wider indication criteria for LT with comparable survival outcomes. Methods: This paper summarizes the recent indications for LT for HCC through a literature review. Results: There are several criteria expanding the Milan criteria, which can be subdivided into the "based on tumor number and size only", "based on tumor number and size plus tumor markers", and "based on tumor differentiation" groups, with the outcomes being comparable to those of patients included within the Milan criteria. Besides the tumor size and number, which are included in the Milan criteria, recent criteria included biomarkers and tumor differentiation. Several retrospective studies have reported microvascular invasion (MVI) as a significant risk factor for postoperative recurrence, highlighting the importance of preoperatively predicting MVI. Several studies attempted to identify preoperative predictive factors for MVI using tumor markers or preoperative imaging findings. Patients with HCC who are LT candidates are often treated while on the waiting list to prevent the progression of HCC or to reduce the measurable disease burden of HCC. The expanding repertoire of chemotherapeutic regiments suitable for patients with HCC should be further investigated. Conclusions: There are several criteria expanding Milan criteria, with the outcomes being comparable to those of patients included within the Milan criteria. [ABSTRACT FROM AUTHOR]

Background: The appropriateness of ablation for liver cancer patients meeting the Milan criteria remains controversial. Purpose: This study aims to evaluate the long-term outcomes of MR-guided thermal ablation for HCC patients meeting the Milan criteria and develop a nomogram for predicting survival rates. Methods: A retrospective analysis was conducted from January 2009 to December 2021 at a single institution. Patients underwent MR-guided thermal ablation. Factors influencing progression-free survival (PFS) and overall survival (OS) were identified using univariate and multivariate Cox regression and stepwise regression. A nomogram was developed for survival prediction, followed by risk stratification and internal validation. Adverse events (AEs) were also analyzed. Results: A total of 181 patients were included, with a mean follow-up of 73.8 ± 31.7 months. The cumulative local tumor progression rates at 1, 3, and 5 years were 0.80%, 1.27%, and 1.86%, respectively. The 1-, 3-, and 5-year PFS rates were 81.8%, 57.4%, and 38.1%, and OS rates were 98.3%, 87.8%, and 62.9%. Poorer outcomes were associated with age ≤ 60 years, tumor size > 2 cm, multiple tumors, cirrhosis, proximity to major vessels, and narrow ablation margins (P < 0.05). The nomogram accurately predicted 3- and 5-year survival, and internal validation confirmed the results. AEs occurred in 33.7% of patients, with pain being the most common. Conclusion: MR-guided ablation is effective for HCC patients within the Milan criteria, especially for those with smaller tumors and better liver function. The nomogram and risk stratification model are valuable tools for predicting patient outcomes and guiding treatment. [ABSTRACT FROM AUTHOR]

Background: Minimally invasive techniques have significantly gained popularity for hepatocellular carcinoma (HCC) based on the Milan criteria. However, whether or not laparoscopic liver resection (LLR) or radiofrequency ablation (RFA) is a better treatment option remains debatable. We conducted a meta-analysis to review the published data comparing LLR and RFA for HCC through Milan criteria depending on tumor recurrence risk and survival. Methods: PubMed, OvidSP, Web of Science, and Cochrane Library databases were searched from inception to December 31, 2023. The studies comparing the outcomes and methods between LLR and RFA for HCC within the Milan criteria were included. Results: We recruited 19 cohort studies with 2532 patients. The postoperative complication rate was low, and hospital stays were shorter in the RFA group than in the LLR group. The total tumor recurrence, the local tumor recurrence rate, and the intrahepatic tumor recurrence rate were lower within the LLR group than in the RFA group. There was no significant difference in the extrahepatic recurrence rate between the two groups. Moreover, no significant differences were observed between the groups concerning 1-, 3-, and 5-year overall survival (OS) and 1-year recurrence-free survival (RFS). However, 3-year and 5-year RFS were better within the LLR group than among the RFA group. Conclusions: The treatment of HCC within the Milan criteria is moving toward multidisciplinary and minimally invasive approaches. Our meta-analysis identified a lower postoperative complication rate and higher recurrence rate for RFA than LLR. RFA could be an alternative treatment due to its comparable long-term efficacy with LLR. [ABSTRACT FROM AUTHOR]

Our study included 41 patients fulfilling the Milan criteria preoperatively and aimed to identify individuals at high risk of post-resection HCC relapse, which occurred in 18 out of 41 patients (43.9%), retrospectively. We analyzed whole slide images of CD8 immunohistochemistry with automated segmentation of tissue classes and detection of CD8+ lymphocytes. The image analysis outputs were subsampled using a hexagonal grid-based method to assess spatial distribution of CD8+ lymphocytes with regards to the epithelial edges. The CD8+ lymphocyte density indicators, along with clinical, radiological, post-surgical and pathological variables, were tested to predict HCC relapse. Low standard deviation of CD8+ density along the tumor edge and R1 resection emerged as independent predictors of shorter recurrence-free survival (RFS). In particular, patients presenting with both adverse predictors exhibited 100% risk of relapse within 200 days. Our results highlight the potential utility of integrating CD8+ density variability and surgical margin to identify a high relapse-risk group among Milan criteria-fulfilling HCC patients. Validation in cohorts with core biopsy could provide CD8+ distribution data preoperatively and guide preoperative decisions, potentially prioritizing liver transplantation for patients at risk of incomplete resection (R1) and thereby improving overall treatment outcomes significantly.

Simple Summary: Liver transplantation is one of the most effective treatments for hepatocellular carcinoma, but only when specific transplantation criteria are met. Local therapies may be used to prevent the tumor from exceeding the transplantation criteria (i.e., so-called bridging therapy). However, the impact of bridging therapy on transplantation outcomes and its predictive value are still not known. We performed a systematic review on both radiological and histopathological responses as prognostic indicators of transplantation outcomes. Five studies were included. The overall risk of bias was serious across the studies. If the tumor showed a good radiological response to bridging therapy, there was a greater chance of better transplantation outcomes. Complete tumor necrosis was not associated with better transplantation outcomes. Future predictive models should include radiological, pathological, histological, cellular, and molecular tumor features. Liver transplantation (LT) is one of the most effective treatments for hepatocellular carcinoma (HCC) in cirrhotic livers. Neoadjuvant bridging treatment in patients qualifying and listed for LT is advised but is still debatable owing to the low level of evidence. The aim of this study was to perform a systematic review to assess the prognostic value of bridging therapy, in terms of radiological and histopathological examination outcomes, for survival after LT. The systematic review was performed according to the PRISMA 2020 guidelines. The MEDLINE and Web of Science databases were searched. In total, five studies were included. An evaluation with the ROBINS-I resulted in studies classified as the following: moderate risk of bias (n = 1) and serious risk of bias (n = 4). The results of the analysis indicated that favorable LT outcomes were most common with complete response or partial radiological response. Poor radiological response or progressive disease during bridging treatment was generally associated with worse overall LT survival. There were not enough data to support the use of this approach to achieve a complete pathologic response. Radiological, pathological, histological, cellular, and molecular tumor features should be included in future LT qualification models. [ABSTRACT FROM AUTHOR]

Our study included 41 patients fulfilling the Milan criteria preoperatively and aimed to identify individuals at high risk of post-resection HCC relapse, which occurred in 18 out of 41 patients (43.9%), retrospectively. We analyzed whole slide images of CD8 immunohistochemistry with automated segmentation of tissue classes and detection of CD8+ lymphocytes. The image analysis outputs were subsampled using a hexagonal grid-based method to assess spatial distribution of CD8+ lymphocytes with regards to the epithelial edges. The CD8+ lymphocyte density indicators, along with clinical, radiological, post-surgical and pathological variables, were tested to predict HCC relapse. Low standard deviation of CD8+ density along the tumor edge and R1 resection emerged as independent predictors of shorter recurrence-free survival (RFS). In particular, patients presenting with both adverse predictors exhibited 100% risk of relapse within 200 days. Our results highlight the potential utility of integrating CD8+ density variability and surgical margin to identify a high relapse-risk group among Milan criteria-fulfilling HCC patients. Validation in cohorts with core biopsy could provide CD8+ distribution data preoperatively and guide preoperative decisions, potentially prioritizing liver transplantation for patients at risk of incomplete resection (R1) and thereby improving overall treatment outcomes significantly. [ABSTRACT FROM AUTHOR]

Background This study compared long-term outcomes between patients with initial hepatocellular carcinoma (IHCC) and those with recurrent HCC (RHCC) treated with microwave ablation (MWA).Methods This retrospective study included 425 patients with HCCs (294 IHCCs and 131 RHCCs) within the Milan criteria who were treated with ultrasound-guided percutaneous MWA between January 2008 and November 2021. All patients with RHCC had previously undergone MWA for initial HCC. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the IHCC and RHCC groups before and after propensity score matching (PSM).Results Before matching, the 1-, 3-, 5-, and 10-year OS rates in the IHCC group were 95.9%, 78.5%, 60.2%, and 42.5%, respectively, which were significantly higher than those in the RHCC group (93.8%, 70.0%, 42.0%, and 6.6%, respectively). This difference remained significant after PSM. However, subgroup analyses suggested that there were no significant differences in OS rates between IHCC and RHCC in patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or Albumin-Bilirubin (ALBI) grade 1. RFS was significantly higher in IHCC than in RHCC before and after PSM, as well as in subgroup analyses. ALBI grade (hazard ratio (HR), 2.38; 95% CI: 1.46–3.86; p

Background Validating the expanded criteria for living donor liver transplantation for hepatocellular carcinoma using national data is highly significant. The aim of this study was to evaluate the validity of the new Japanese criteria for living donor liver transplantation for hepatocellular carcinoma patients and identify factors associated with a poor prognosis using the Japanese national data set. Methods The study population comprised patients who underwent living donor liver transplantation for hepatocellular carcinoma at 37 centres in Japan between 2010 and 2018. In a nationwide survey, the overall survival and recurrence-free survival rates were evaluated based on the new Japanese criteria for applying the 5-5-500 rule when extending the indication beyond the Milan criteria. Prognostic factors within the Japanese criteria were determined using the Cox proportional hazards model. Results Patients within (485 patients) and beyond (31 patients) the Japanese criteria exhibited 5-year overall survival rates of 81% and 58% and 5-year recurrence-free survival rates of 77% and 48% respectively. Patients who met the Milan criteria, but not the 5-5-500 rule, had poorer outcomes. Multivariate analysis for 474 patients identified a neutrophil-to-lymphocyte ratio greater than or equal to 5 and a history of hepatectomy as independent risk factors. Conclusion This nationwide survey confirms the validity of the Japanese criteria. The poor prognostic factors within the Japanese criteria include a neutrophil-to-lymphocyte ratio greater than or equal to 5 and previous hepatectomy. [ABSTRACT FROM AUTHOR]

Aim: The Japanese indication criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC) have been updated based on living donor LT data to include either the Milan criteria (MC) or the 5‐5‐500 rule, which requires a nodule size of ≤5 cm, ≤5 nodules, and an alpha‐fetoprotein (AFP) level ≤500 ng/mL. We aimed to validate the 5‐5‐500 rule and the MC for deceased donor LT (DDLT). Methods: Using national registry data from the United States from 2010 to 2014, we separated DDLT patients into four groups based on the MC and the 5‐5‐500 rule. The AFP values were stratified into categories: ≤100, 101–300, 301–500, and >500 ng/mL. Results: The 5‐year survival rate was significantly lower for patients in the groups within MC/beyond 5‐5‐500 (56.3%) or beyond MC/5‐5‐500 (60.7%) than for patients in the groups within MC/5‐5‐500 (76.2%) and beyond MC/within 5‐5‐500 (72.3%) (p < 0.01). Hepatocellular carcinoma recurrence at 5 years was highest for the within MC/beyond 5‐5‐500 (25.4%) group, followed by the beyond MC/within 5‐5‐500 (13.1%), beyond MC/5‐5‐500 (9.6%), and within MC/5‐5‐500 (7.4%) groups. The stratified 5‐year survival rates after DDLT were 76.5%, 72.4%, 58.4%, and 55.6% in the AFP ≤100, 101–300, 301–500, and >500 categories, respectively (p < 0.01). Conclusion: The 5‐5‐500 rule guides the appropriate selection of patients with HCC for DDLT. Patients with AFP levels from 300 to 500 ng/mL had inferior outcomes even when they met the 5‐5‐500 rule, so further investigation is needed to guide their treatment. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is widely recognized as the predominant type of primary liver malignancy. Orthotopic liver transplantation (OLT) has emerged as a highly effective treatment option for unresectable HCC. Immunotherapies as neoadjuvant options are now being actively investigated in the transplant oncology era to enhance outcomes in patients with HCC. Here, we report our experience with patients with HCC who had received Immune Checkpoint Inhibitors (ICPI) prior to curative OLT. Methods: This was a retrospective cohort that included patients with HCC who received ICPI prior to OLT at a single institution from January 2019 to August 2023. Graft rejection was assessed and reported along with the type of ICPI, malignancy treated, and the timing of ICPI in association with OLT. Results: During this cohort period, six patients with HCC underwent OLT after neoadjuvant ICPI. All patients were male with a median age of 61 (interquartile range: 59–64) years at OLT. Etiology associated with HCC was viral (N = 4) or Non-alcoholic steatohepatitis, NASH (N = 2). Tumor focality was multifocal (N = 4) and unifocal (N = 2). Lymphovascular invasion was identified in four patients. No perineural invasion was identified in any of the patients. All patients received ICPI including atezolizumab/bevacizumab (N = 4), nivolumab/ipilimumab (N = 1), and nivolumab as monotherapy (N = 1). All patients received either single or combined liver-directed/locoregional therapy, including transarterial chemoembolization (TACE), Yttrium-90 (Y90), stereotactic body radiotherapy (SBRT), and radiofrequency ablation (RFA). The median washout period was 5 months. All patients responded to ICPI and achieved a safe and successful OLT. All patients received tacrolimus plus mycophenolate as immunosuppressant (IS) therapy post-OLT and one patient received prednisone as additional IS. No patient had clinical evidence of rejection. Conclusions: This cohort emphasizes the success of tumor downstaging by ICPI for OLT when employed as the neoadjuvant therapy strategy. In addition, this study illustrated the importance of timing for the administration of ICPI before OLT. Given the lack of conclusive evidence in this therapeutic area, we believe that our study lays the groundwork for prospective trials to further examine the impact of ICPI prior to OLT. [ABSTRACT FROM AUTHOR]

Purpose: Liver transplantation is curative for hepatocellular carcinoma (HCC). Checkpoint inhibitor therapy (CPIT) has been used in unresectable HCC, but recent advances have demonstrated CPIT as an innovative method of downstaging advanced HCC with the caveat that CPIT prior to transplantation has risks including irreversible graft rejection. We report the outcomes of Mayo Clinic Arizona patients who underwent downstaging with CPIT. Methods: This retrospective chart review was conducted for Mayo Clinic Arizona patients who were diagnosed with HCC who underwent downstaging with CPIT with the goal of meeting criteria for transplantation. Results: We present nine cases with HCC outside Milan who underwent CPIT. Four received a transplant; one was delisted due to his exceptional therapeutic response. All received liver-directed therapy. Peak alpha-fetoprotein pre-CPIT ranged from 8–29,523 ng/mL, which decreased to 2.2–19.6 ng/mL on CPIT. CPIT included atezolizumab/bevacizumab, ipilimumab/nivolumab, nivolumab, and pembrolizumab; one patient received two regimens. CPIT was held prior to transplant at a median of 3 months. Three patients received methylprednisolone for immunosuppression induction; one received thymoglobulin. One patient developed acute cellular rejection at 5 weeks, 9 weeks, and 5 months post-transplant; given the late onset, these were not attributed to CPIT and were successfully treated. During an average follow-up of 16.5 months, no tumor recurrence has occurred. Conclusion: We describe nine patients with HCC outside Milan with inadequate response with liver-directed therapy, who achieved marked responses with CPIT, allowing for consideration of successful liver transplantation. Our case series supports the consideration of locoregional therapies and CPIT for downstaging to within transplant criteria. [ABSTRACT FROM AUTHOR]

BackgroundMinimally invasive techniques have significantly gained popularity for hepatocellular carcinoma (HCC) based on the Milan criteria. However, whether or not laparoscopic liver resection (LLR) or radiofrequency ablation (RFA) is a better treatment option remains debatable. We conducted a meta-analysis to review the published data comparing LLR and RFA for HCC through Milan criteria depending on tumor recurrence risk and survival.MethodsPubMed, OvidSP, Web of Science, and Cochrane Library databases were searched from inception to December 31, 2023. The studies comparing the outcomes and methods between LLR and RFA for HCC within the Milan criteria were included.ResultsWe recruited 19 cohort studies with 2532 patients. The postoperative complication rate was low, and hospital stays were shorter in the RFA group than in the LLR group. The total tumor recurrence, the local tumor recurrence rate, and the intrahepatic tumor recurrence rate were lower within the LLR group than in the RFA group. There was no significant difference in the extrahepatic recurrence rate between the two groups. Moreover, no significant differences were observed between the groups concerning 1-, 3-, and 5-year overall survival (OS) and 1-year recurrence-free survival (RFS). However, 3-year and 5-year RFS were better within the LLR group than among the RFA group.ConclusionsThe treatment of HCC within the Milan criteria is moving toward multidisciplinary and minimally invasive approaches. Our meta-analysis identified a lower postoperative complication rate and higher recurrence rate for RFA than LLR. RFA could be an alternative treatment due to its comparable long-term efficacy with LLR.

Background/objective: The aim of this study was to evaluate tumor progression and recurrence patterns of radiofrequency ablation (RFA) with or without transarterial chemoembolization (TACE) for treating hepatocellular carcinoma (HCC) that meets Milan criteria. Methods: This retrospective study included consecutive HCC patients meeting Milan criteria who underwent percutaneous RFA with or without TACE as initial treatment at a tertiary academic center between December 2017 and 2022. Technical success rate, local recurrence-free survival (LRFS), progression-free survival (PFS) and recurrence patterns were recorded. Results: A total of 135 HCC patients (109 male [80.7%]) with a mean age of 62 years and 147 target lesions were retrospectively enrolled. The technical success rate was 99.3%. The median LRFS was 60 months, and the cumulative 1-, 3-, and 5-year LRFS were 88.9%, 70.1%, and 30.0%, respectively. Additionally, the median PFS was 23 months, with cumulative 1-, 3-, and 5-year PFS of 74%, 30%, and 0%, respectively. Multivariate analysis confirmed that age > 60, alpha-fetoprotein (AFP) (> 10), and albumin were associated with PFS (2.34, p = 0.004; 1.96, p = 0.021; 0.94, p = 0.007, respectively). Six recurrence patterns were identified: local tumor progression (LTP) alone (n = 15, 25.0%), intrahepatic distant recurrence (IDR) alone (n = 34, 56.7%), extrahepatic recurrence (ER) alone (n = 2, 3.3%), IDR + ER (n = 2, 3.3%), LTP + IDR (n = 5, 8.8%), and LTP + IDR + ER (n = 2, 3.3%). IDR occurred most frequently as a sign of good local treatment. Conclusions: RFA in combination with TACE does not appear to provide an advantage over RFA alone in improving tumor progression in patients with HCC meeting the Milan criteria. However, further prospective studies are needed to confirm these findings and to determine the optimal treatment approach for this patient population. [ABSTRACT FROM AUTHOR]

Simple Summary: This research delves into better treatment options for patients with liver cancer (HCC) who fall outside the eligibility criteria of traditional Milan guidelines for liver transplants. By reviewing patient data from Jena University spanning from 2007 to 2023, the study explores whether new patient classification systems and the use of living donor liver transplantation (LDLT) could extend life-saving options to those previously considered unsuitable. Findings indicate that patients not meeting the Milan criteria still benefit significantly from transplantation, showcasing similar survival rates between those undergoing standard transplants and LDLT. Key factors such as tumour grade and vascular invasion emerged as predictors for cancer recurrence, highlighting the importance of pre-transplant treatments in enhancing survival outcomes. The study underscores LDLT as a feasible alternative, particularly for patients undergoing successful bridging therapies, thereby broadening the scope of liver transplantation for liver cancer and offering new therapeutic approaches for advanced liver tumours. Purpose: This study was designed to elucidate the various new classifications and the use of LDLT and bridging therapy for HCC in this context beyond the Milan criteria (MC). Methods: The clinical data of patients with HCC outside the MC who underwent LT at Jena University between January 2007 and August 2023 were retrospectively analysed. Eligible patients were classified according to various classification systems. Clinicopathological features, overall and disease-free survival rates were compared between LT and LDLT within the context of bridging therapy. The Results: Among the 245 patients analysed, 120 patients did not meet the MC, and 125 patients met the MC. Moreover, there were comparable overall survival rates between patients outside the MC for LT versus LDLT (OS 44.3 months vs. 28.3 months; 5-year survival, 56.4% vs. 40%; p = 0.84). G3 tumour differentiation, the presence of angioinvasion and lack of bridging were statistically significant risk factors for tumour recurrence according to univariate and multivariate analyses (HR 6.34; p = 0.0002; HR 8.21; p < 0.0001; HR 7.50; p = 0.0001). Bridging therapy before transplantation provided a significant survival advantage regardless of the transplant procedure (OS: p = 0.008; DFS: p < 0.001). Conclusions: Patients with HCC outside the MC who underwent LT or LDLT had worse outcomes compared to those of patients who met the MC but still had a survival advantage compared to patients without transplantation. Nevertheless, such patients remain disadvantaged on the waiting list, which is why LDLT represents a safe alternative to LT and should be considered in bridged HCC patients because of differences in tumour differentiation, size and tumour marker dynamics. [ABSTRACT FROM AUTHOR]

In the presented case, after liver transplantation (LT) for hepatocellular cancer (HCC), the disease progressed in the graft, left lung and bronchopulmonary lymph nodes after 16 months, according to the Milan criteria. Against the background of combined treatment – hepatic artery chemoembolization (HAC), systemic targeted therapy and stereotactic radiotherapy for metastatic node of the left lung – HCC in the extrahepatic foci was stabilized. In this situation, we considered resection of the liver transplant as the only therapeutic option that provides a chance for significant prolongation of the patient’s life. However, extensive resection of the right liver lobe seemed unsafe due to a number of limiting factors – borderline functional residual capacity of the remaining liver: future liver remnant (FLR), 599 cm3 (32%); plasma disappearance rate (PDR), 12.3%/min; tumor invasion of the middle hepatic vein basin. In this case, right portal vein branch (RPVB) embolization could promote vicarious hypertrophy of the remaining part of the liver, but the waiting period usually exceeds three to four weeks, and the RPVB was already partially blocked by the tumor at that time. The only option for surgical intervention was, in our opinion, two-stage hepatectomy according to the Associated Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS) procedure, despite the absence of literature data on the performance of such operations on a liver transplant. On postoperative day 5 from the first stage, a 799 cm3 FLR hypertrophy was achieved, which allowed to perform the second stage of intervention relatively safely. Competent tactics regarding medication in the intensive care unit (ICU) and renal replacement therapy allowed to cope with sepsis and acute renal failure – the prevailing postoperative complications.

Background: Hepatocellular carcinoma (HCC) accounts for 75% of primary liver tumors. Controlling risk factors associated with its development and implementing screenings in risk populations does not seem sufficient to improve the prognosis of these patients at diagnosis. The development of a predictive prognostic model for mortality at the diagnosis of HCC is proposed. Methods: In this retrospective multicenter study, the analysis of data from 191 HCC patients was conducted using machine learning (ML) techniques to analyze the prognostic factors of mortality that are significant at the time of diagnosis. Clinical and analytical data of interest in patients with HCC were gathered. Results: Meeting Milan criteria, Barcelona Clinic Liver Cancer (BCLC) classification and albumin levels were the variables with the greatest impact on the prognosis of HCC patients. The ML algorithm that achieved the best results was random forest (RF). Conclusions: The development of a predictive prognostic model at the diagnosis is a valuable tool for patients with HCC and for application in clinical practice. RF is useful and reliable in the analysis of prognostic factors in the diagnosis of HCC. The search for new prognostic factors is still necessary in patients with HCC. [ABSTRACT FROM AUTHOR]

Background: Black patients have higher hepatocellular carcinoma (HCC)‐related mortality than White patients and more often develop HCC in non‐cirrhotic liver. HCC surveillance is primarily directed toward cirrhotic patients. We aimed to characterize HCC in non‐cirrhotic patients and to identify factors associated with HCC beyond Milan criteria. Methods: Demographic, imaging, laboratory, and pathology data of HCC patients at our institution, 2003–2018, were reviewed, retrospectively. Race/ethnicity were self‐reported. Cirrhosis was defined as a Fibrosis‐4 score ≥3.25. Results: Compared to 1146 cirrhotic patients, 411 non‐cirrhotic patients had larger tumors (median 4.7 cm vs. 3.1 cm, p < 0.01) and were less likely to be within Milan criteria (42.6% vs. 57.7%, p < 0.01). Among non‐cirrhotic patients, Black patients had larger tumors (4.9 cm vs. 4.3 cm, p < 0.01) and a higher percentage of poorly differentiated tumors (39.4% vs. 23.1%, p = 0.02). Among cirrhotic patients, Black patients had larger tumors (3.3 cm vs. 3.0 cm, p = 0.03) and were less likely to be within Milan criteria (52.3% vs. 83.2%, p < 0.01). In multivariable analysis, lack of commercial insurance (OR 1.45 [CI 95% 1.19–1.83], p < 0.01), male sex (OR 1.34 [CI 95% 1.05–1.70], p < 0.01), absence of cirrhosis (OR 1.58 [CI 95% 1.27–1.98], p < 0.01) and Black race/ethnicity (OR 1.34 [CI 95% 1.09–1.66], p = 0.01) were associated with HCC beyond Milan criteria. Black patients had lower survival rates than other patients (p < 0.01). Conclusions: Non‐cirrhotic patients had more advanced HCC than cirrhotic patients. Black patients (with or without cirrhosis) had more advanced HCC than comparable non‐Black patients and higher mortality rates. Improved access to healthcare (commercial insurance) may increase early diagnosis (within Milan criteria) and reduce disparities. [ABSTRACT FROM AUTHOR]

Background: This study compared long-term outcomes between patients with initial hepatocellular carcinoma (IHCC) and those with recurrent HCC (RHCC) treated with microwave ablation (MWA). Methods: This retrospective study included 425 patients with HCCs (294 IHCCs and 131 RHCCs) within the Milan criteria who were treated with ultrasound-guided percutaneous MWA between January 2008 and November 2021. All patients with RHCC had previously undergone MWA for initial HCC. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the IHCC and RHCC groups before and after propensity score matching (PSM). Results: Before matching, the 1-, 3-, 5-, and 10-year OS rates in the IHCC group were 95.9%, 78.5%, 60.2%, and 42.5%, respectively, which were significantly higher than those in the RHCC group (93.8%, 70.0%, 42.0%, and 6.6%, respectively). This difference remained significant after PSM. However, subgroup analyses suggested that there were no significant differences in OS rates between IHCC and RHCC in patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or Albumin-Bilirubin (ALBI) grade 1. RFS was significantly higher in IHCC than in RHCC before and after PSM, as well as in subgroup analyses. ALBI grade (hazard ratio (HR), 2.38; 95% CI: 1.46–3.86; p < 0.001), serum AFP level (HR, 2.07; 95% CI: 1.19–3.62; p = 0.010) and ablative margins (HR, 0.18; 95% CI: 0.06-0.59; p = 0.005) were independent prognostic factors for OS of RHCC. Serum AFP(HR, 1.29; 95% CI: 1.02–1.63, p = 0.036) level was the only factor associated with RFS in RHCC. Conclusions: MWA yielded comparable OS in IHCC and RHCC patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or ALBI grade 1. [ABSTRACT FROM AUTHOR]

We aimed to assess changes in the composition of the waiting list for liver transplantation (LT) after expanding from Milan to "up-to-seven" criteria in patients with hepatocellular carcinoma (HCC). A consecutive cohort of 255 LT candidates was stratified in a pre-expansion era (2016–2018; n = 149) and a post-expansion era (2019–2021; n = 106). The most frequent indication for LT was HCC in both groups (47.7% vs. 43.4%; p = 0.5). The proportion of patients exceeding the Milan criteria in the explanted liver was nearly doubled after expansion (12.5% vs. 21.1%; p = 0.25). Expanding criteria had no effect in drop-out (12.3% vs. 20.4%; p = 0.23) or microvascular invasion rates (37.8% vs. 38.7%; p = 0.93). The length on the waiting list did not increase after the expansion (172 days [IQR 74–282] vs. 118 days [IQR 67–251]; p = 0.135) and was even shortened in the post-expansion HCC subcohort (181 days [IQR 125–232] vs. 116 days [IQR 74–224]; p = 0.04). Tumor recurrence rates were reduced in the post-expansion cohort (15.4% vs. 0%; p = 0.012). In conclusion, expanding from Milan to up-to-seven criteria for LT in patients with HCC had no meaningful impact on the waiting list length and composition, thus offering the opportunity for the adoption of more liberal policies in the future. [ABSTRACT FROM AUTHOR]

Background: Fine needle aspiration cytology (FNAC) is an integral part of the preoperative work-up of parotid tumours. Aim: To determine the rate of concordance between FNAC and histology following parotidectomy. Methods: A review of records of patients who had parotidectomy which was preceded FNAC was done. Data collected included patients' demography, presenting symptoms and clinical signs; cytology and post-operative histology results. Results: Seventy-seven records were found and 14 were excluded. Forty-five (71%: 45/63) of the tumours were benign, 21% (13/63) malignant and 8% (5/63) inflammatory lesions. Forty-one (91.1%: 41/45) of the benign tumours had concordance between FNAC and final histology. Seven (63.6%: 7/11) of FNAC diagnosed malignancies were confirmed on histology. Conclusion: Around 71% of parotid masses were benign. Painful masses are more likely to be malignant and FNAC is more reliable for the diagnosis of pleomorphic adenoma than rare benign and malignant tumours of the parotid gland. [ABSTRACT FROM AUTHOR]

Background: The suitability of hepatectomy among patients with multinodular hepatocellular carcinoma (MHCC) beyond the Milan criteria remains controversial. There is a need for a reliable risk stratification tool among these patients for the selection of ideal candidates of curative resection. Purpose: To determine the clinicoradiological prognostic factors for patients with MHCC beyond the Milan criteria to further develop a stratification system. Study Type: Retrospective. Subjects: 176 patients with pathologically confirmed MHCC beyond the Milan criteria. Field Strength/Sequence: The 1.5 T scanner, including T1‐, T2‐, diffusion‐weighted imaging, in/out‐phase imaging, and dynamic contrast‐enhanced imaging. Assessment: Conventional MRI features and preoperative laboratory data including aspartate aminotransferase (AST) and α‐fetoprotein (AFP) were collected and analyzed. Two nomograms incorporating clinicoradiological variables were independently constructed to predict recurrence‐free survival (RFS) and overall survival (OS) with Cox regression analyses and verified with 5‐fold cross validation. Based on the nomograms, two prognostic stratification systems for RFS and OS were further developed. Statistical Tests: The Cohen's kappa/intraclass correlation coefficient, C‐index, calibration curve, Kaplan–Meier curve, log‐rank test. A P value <0.05 was considered statistically significant. Results: AST > 40 U/L, increased tumor burden score, radiological liver cirrhosis and nonsmooth tumor margin were independent predictors for poor RFS, while AST > 40 U/L, AFP > 400 ng/mL and radiological liver cirrhosis were independent predictors for poor OS. The two nomograms demonstrated good discrimination performance with C‐index of 0.653 (95% confidence interval [CI], 0.602–0.794) and 0.685 (95% CI, 0.623–0.747) for RFS and OS, respectively. The 5‐fold cross validation further validated the discrimination capability of the nomograms. Based on the nomogram models, MHCC patients beyond the Milan criteria were stratified into low−/medium−/high‐risk groups with significantly different RFS and OS. Data Conclusion: The proposed MRI‐based prognostic stratification system facilitates the refinement and further subclassification of patients with MHCC beyond the Milan criteria. Evidence Level: 4. Technical Efficacy: 2. [ABSTRACT FROM AUTHOR]

Simple Summary: Image-guided interventional treatments play an important role in treating HCC. Percutaneous thermal ablation is suitable for early-stage HCC, and transarterial therapies are recommended for intermediate-stage HCC. Several studies evaluated the combination therapy of TACE and RFA, in comparison to monotherapy of RFA or TACE alone, but there is still a lack of studies that investigated the combination therapy of bland embolization (without the application of chemotherapeutics) with thermal ablation. This study aims to compare the combination therapy of lipiodol-based TAE and MWA with MWA alone for primary HCC. A comparison of the combination therapy consisting of microwave ablation (MWA) after bland lipiodol-based transarterial embolization (TAE) with MWA alone in the treatment of hepatocellular carcinoma (HCC) within the Milan criteria. Forty-nine patients in the TAE-MWA group (12 women and 37 men; mean age: 63.3 ± 9.6 years) with 55 tumors and 63 patients in the MWA group (18 women and 45 men; mean age: 65.9 ± 10.5 years) with 67 tumors were retrospectively enrolled in this study. For the investigation of treatment protocols based upon both safety and efficacy, patients' cases were analyzed with regard to complications, local tumor progression (LTP), intrahepatic distant recurrence (IDR), overall survival (OS), and progression-free survival (PFS). There were no cases of major complications in either group. The LTP rate was 5.5% in the MWA-TAE group and 7.5% in the MWA group (p = 0.73). The rate of IDR was 42.9% in the MWA-TAE group and 52.4% in the MWA group (p = 0.42). The 12-, 24-, and 36-month OS rates starting at the date of tumor diagnosis were 97.7%, 85.1%, and 78.8% in the TAE-MWA group, and 91.9%, 71.4%, and 59.8% in the MWA group, respectively (p = 0.004). The 6-, 12-, and 24-month PFS rates were 76.5%, 55%, and 44.6% in the TAE-MWA group, and 74.6%, 49.2%, and 29.6% in the MWA group, respectively (p = 0.18). The combination therapy of TAE-MWA was significantly superior to MWA monotherapy according to OS in treating HCC within the Milan criteria. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) is a curative treatment for early-stage hepatocellular carcinoma (HCC) unsuitable for surgical resection. However, tumor recurrence (TR) rates range from 8% to 20% despite strict selection criteria. The validation of new prognostic tools, such as pre-MORAL or RETREAT risks, is necessary to improve recurrence prediction. A retrospective study was conducted at Marqués de Valdecilla University Hospital in Cantabria, Spain, between 2010 and 2019 to determine the rate of TR in LT patients and identify associated factors. Patients with liver-kidney transplantation, re-transplantation, HIV infection, survival less than 90 days, or incidental HCC were excluded. Data on demographic, liver disease-related, LT, and tumor-related variables, as well as follow-up records, including TR and death, were collected. TR was analyzed using the Log-Rank test, and a multivariate Cox regression analysis was performed. The study was approved by the IRB of Cantabria. TR occurred in 13.6% of LT patients (95% CI = 7.3–23.9), primarily as extrahepatic recurrence (67%) within the first 5 years (75%). Increased TR was significantly associated with higher Body Mass Index (BMI) (HR = 1.3 [95% CI = 1.1–1.5]), vascular micro-invasion (HR = 8.8 [1.6–48.0]), and medium (HR = 20.4 [3.0–140.4]) and high pre-MORAL risk (HR = 30.2 [1.6–568.6]). TR also showed a significant correlation with increased mortality. Conclusions: LT for HCC results in a 13.6% rate of tumor recurrence. Factors such as BMI, vascular micro-invasion, and medium/high pre-MORAL risk are strongly associated with TR following LT. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims In patients with surgically unresectable early and intermediate stage hepatocellular carcinoma (HCC), only liver transplant (LT) offers a cure. Locoregional therapies, such as transarterial chemoembolization (TACE), are widely used to bridge patients waiting for an LT or downstage tumors beyond Milan Criteria (MC). However, there are no formal guidelines on the number of TACE procedures patients should receive. Our study explores the extent to which repeated TACE might offer diminishing gains toward LT. Approach We retrospectively analyzed 324 patients with BCLC stage A and B HCC who had received TACE with the intention of disease downstaging or bridging to LT. In addition to baseline demographics, we collected data on LT status, survival, and the number of TACE procedures. Overall survival (OS) rates were estimated using the Kaplan‐Meier method, and correlative studies were calculated using chi‐square or Fisher's exact test. Results Out of 324 patients, 126 (39%) received an LT, 32 (25%) of whom had responded favorably to TACE. LT significantly improved OS: HR 0.174 (0.094‐0.322, P

Abstract Background Liver transplantation (LT), resection (LR), and ablation (LA) are three curative‐intent treatment options for patients with early hepatocellular carcinoma (HCC). We aimed to develop a prognostic calculator to compare the long‐term outcomes following each of these therapies. Methods A total of 976 patients with HCC within the Milan criteria who underwent LT, LR, and LA between 2009 and 2019 from four institutions were evaluated. Multistate competing risks prediction models for recurrence‐free survival (RFS), recurrence within the Milan criteria (RWM), and HCC‐specific survival (HSS) were derived to develop a prognostic calculator. Results During a median follow‐up of 51 months, 420 (43%) patients developed recurrence. In the multivariate analysis, larger tumor size, multinodularity, older age, male, higher alpha‐fetoprotein (AFP), higher albumin‐bilirubin (ALBI) grade, and the presence of portal hypertension were significantly associated with higher recurrence and decreased survival rates. The RFS and HSS were both significantly higher among patients treated by LT than by LR or LA and significantly higher between patients treated by LR than by LA (all p

The United Network for Organ Sharing (UNOS) grants priority listing for liver transplant for patients with hepatocellular carcinoma after successful down-staging to Milan criteria. We evaluated the national experience on down-staging by comparing 2 down-staging groups: tumor burden meeting UNOS down-staging (UNOS-DS) inclusion criteria, and all-comers (AC)-DS with initial tumor burden beyond UNOS-DS criteria vs patients always within Milan criteria. We performed a retrospective analysis of the UNOS database of 23,398 patients listed for liver transplant who had submitted a hepatocellular carcinoma Model for End-Stage Liver Disease exception application from 2010 to 2019, classified as always within Milan (n = 20,579), UNOS-DS (n = 2151), and AC-DS (n = 668). The 2-year cumulative probabilities of dropout were 19% for Milan, 25% for UNOS-DS (P <.001), and 30% for AC-DS (P <.001). In multivariate analysis of the down-staging groups, factors predicting dropout included Model for End-Stage Liver Disease at listing (hazard ratio [HR], 1.06; P <.001) and initial total tumor diameter (HR, 1.04; P =.002). Compared with α-fetoprotein (AFP) level ≤20 ng/mL, AFP levels of 21 to 100, 101 to 1000, and greater than 1000 ng/mL were associated with a higher risk of dropout (HRs, 1.63, 2.06, and 4.58, respectively; P <.001). A subset of all-comers with AFP levels greater than 100 ng/mL had a 2-year probability of dropout of 52% vs 26% for all others beyond Milan criteria (P <.001). All-comers had a significantly higher risk for waitlist dropout compared with the UNOS-DS and Milan groups after initial successful down-staging to Milan criteria. In particular, the subgroup of AC-DS with an AFP level greater than 100 ng/mL had a greater than 50% probability of dropout in the next 2 years. These observations suggest a high likelihood of failure when expanding the indications for down-staging. [ABSTRACT FROM AUTHOR]

Abstract Objectives To compare the diagnostic performance of international hepatocellular carcinoma (HCC) guidelines with gadoxetic acid-enhanced MRI (EOB-MRI) and contrast-enhanced Computed tomography (CECT) and their impact on liver transplant (LT) allocation in cirrhotic patients with explant histopathology correlation. Methods In this prospective single-centre ethics-approved study, 101 cirrhotic patients were consecutively enrolled with informed consent from the pre-LT clinic. They underwent CECT and EOB-MRI alternately at three monthly intervals until LT or removal from LT list. Two abdominal radiologists, blinded to explant histopathology, independently recorded liver lesions visible on CECT and EOB-MRI. Imaging-based HCC scores were assigned to non-treated liver lesions utilizing Liver Imaging Reporting and Data System (LI-RADS), European Association for the Study of the Liver (EASL), Asian-Pacific Association for the Study of the Liver (APASL) and Korean Liver Cancer Association-National Cancer Center (KLCA) guidelines. Liver explant histopathology was the reference standard. Simulated LT eligibility was assessed as per Milan criteria (MC) in reference to explant histopathology. Results One hundred and three non-treated HCC and 12 non-HCC malignancy were identified at explant histopathology in 34 patients (29 men, 5 women, age 55–73 years). Higher HCC sensitivities of statistical significance were observed with EOB-MRI for LI-RADS 4 + 5, APASL and KLCA compared to LI-RADS 5 and EASL with greatest sensitivity obtained for LIRADS 4 + 5 lesions. HCC sensitivities by all guidelines with both EOB-MRI and CECT were significantly lower if all histopathology-detected HCCs were included in the analysis, compared to imaging-visible lesions only. A significantly greater variation in HCC sensitivity was noted across the guidelines with EOB-MRI compared to CECT. No significant differences in simulated LT eligibility based on MC were observed across the HCC scoring guidelines with EOB-MRI or CECT. Conclusion HCC sensitivities are variable depending on scoring guideline, lesion size and imaging modality utilised. Prior studies that included only lesions visible on pre-operative imaging overestimate the diagnostic performance of HCC scoring guidelines. Per-lesion differences in HCC diagnosis across these guidelines did not impact patient-level LT eligibility based on MC.

Objective To evaluate the role of preoperative serological indexes in predicting long-term survival and tumor recurrence of hepatocellular carcinoma (HCC) patients after liver transplantation, aiming to explore its significance in expanding the Milan criteria. Methods Clinical data of 669 recipients undergoing liver transplantation for HCC were retrospectively analyzed. The optimal cut-off value was calculated by the receiver operating characteristic (ROC) curve. The risk factors affecting the overall survival and recurrence-free survival rates of HCC patients after liver transplantation were identified by univariate and multivariate regression analyses. The correlation between preoperative serum liver enzymes and pathological characteristics in HCC patients was analyzed. The predictive values of alpha-fetoprotein (AFP) combined with γ -glutamyl transferase (GGT) and different liver transplant criteria for the survival and recurrence of HCC patients after liver transplantation were compared. Results Exceeded Milan criteria, total tumor diameter (TTD)> 8 cm, AFP>200 ng/mL and GGT>84 U/L were the independent risk factors for the overall survival and recurrence-free survival rates of HCC patients after liver transplantation (all P<0.05). Correlation analysis showed that preoperative serum GGT level was correlated with TTD, number of tumor, venous invasion, microsatellite lesions, capsular invasion, tumor, node, metastasis (TNM) stage, Child-Pugh score and exceeded Milan criteria (all P<0.05). Milan-AFP-GGT-TTD (M-AGT) criteria were proposed by combining Milan criteria, TTD with serum liver enzyme indexes (AFP and GGT). The 5-year overall survival and recurrence-free survival rates of HCC recipients who met the M-AGT criteria (111 cases of exceeded Milan criteria) were significantly higher than those who met Hangzhou criteria (both P<0.05), whereas had no significant difference from their counterparts who met the University of California at San Francisco (UCSF) criteria (both P>0.05). Conclusions Preoperative serological indexes of AFP and GGT could effectively predict the long-term survival and tumor recurrence of HCC patients after liver transplantation. Establishing the M-AGT criteria based on serological indexes contributes to expanding the Milan criteria, which is convenient and feasible. [ABSTRACT FROM AUTHOR]

Background and Aims: In patients with surgically unresectable early and intermediate stage hepatocellular carcinoma (HCC), only liver transplant (LT) offers a cure. Locoregional therapies, such as transarterial chemoembolization (TACE), are widely used to bridge patients waiting for an LT or downstage tumors beyond Milan Criteria (MC). However, there are no formal guidelines on the number of TACE procedures patients should receive. Our study explores the extent to which repeated TACE might offer diminishing gains toward LT. Approach: We retrospectively analyzed 324 patients with BCLC stage A and B HCC who had received TACE with the intention of disease downstaging or bridging to LT. In addition to baseline demographics, we collected data on LT status, survival, and the number of TACE procedures. Overall survival (OS) rates were estimated using the Kaplan‐Meier method, and correlative studies were calculated using chi‐square or Fisher's exact test. Results: Out of 324 patients, 126 (39%) received an LT, 32 (25%) of whom had responded favorably to TACE. LT significantly improved OS: HR 0.174 (0.094‐0.322, P <.001). However, the LT rate significantly decreased if patients received ≥3 vs < 3 TACE procedures (21.6% vs 48.6%, P <.001). If their cancer was beyond MC after the third TACE, the LT rate was 3.7%. Conclusions: An increased number of TACE procedures may have diminishing returns in preparing patients for LT. Our study suggests that alternatives to LT, such as novel systemic therapies, should be considered for patients whose cancers are beyond MC after three TACE procedures. [ABSTRACT FROM AUTHOR]

Abstract Background Previous studies have reported the surgical resection (SR) and radiofrequency ablation (RFA) could achieve comparable recurrence-to-death survival (RTDS). However, the impact of primary tumor burden on RTDS of patients with recurrent hepatocellular carcinoma (HCC) following SR or RFA has not been clarified. Methods From January 2009 to March 2015, 171 patients who underwent initial hepatectomy and second curative treatments in West China Hospital were retrospectively analyzed. Survival analysis was performed by the Kaplan–Meier method. Risk factors were identified using the Cox proportional hazard model. Results At initial hepatectomy, 96 patients (56.1%) were diagnosed with HCC within the Milan criteria (MC), and 75 patients (43.9%) were HCC beyond the MC. The clinicopathological features and re-treatment methods of recurrent HCC were similar between patients with primary HCC within or beyond the MC. Patients with primary HCC within the MC had longer recurrence time (31.4 ± 24.2 months vs. 20.2 ± 16 months, P 400 ng/mL at the time of recurrence were associated with RTDS. Conclusions The primary tumor burden had no impact on RTDS, but had an impact on recurrence time. The recurrence time had an impact on RTDS and might be a good index to reflect the biology of recurrent HCC.

Background: Hepatectomy is the recommended option for radical treatment of BCLC stage A/B hepatocellular carcinoma (HCC) that has progressed beyond the Milan criteria. This study evaluated the efficacy and safety of preoperative neoadjuvant transcatheter arterial chemoembolization (TACE) for these patients. Methods: In this prospective, randomized, open-label clinical study, BCLC stage A/B HCC patients beyond the Milan criteria were randomly assigned (1:1) to receive either neoadjuvant TACE prior to hepatectomy (NT group) or hepatectomy alone (OP group). The primary outcome was overall survival (OS), while the secondary outcomes were progression-free survival (PFS) and adverse events (AEs). Results: Of 249 patients screened, 164 meeting the inclusion criteria were randomly assigned to either the NT group (n = 82) or OP group (n = 82) and completed follow-up requirements. Overall survival was significantly greater in the NT group compared to the OP group at 1 year (97.2% vs. 82.4%), two years (88.4% vs. 60.4%), and three years (71.6% vs. 45.7%) (p = 0.0011) post-treatment. Similarly, PFS was significantly longer in the NT group than the OP group at 1 year (60.1% vs. 39.9%), 2 years (53.4% vs. 24.5%), and 3 years (42.2% vs. 24.5%) (p = 0.0003). No patients reported adverse events of grade 3 or above in either group. Conclusions: Neoadjuvant TACE prolongs the survival of BCLC stage A/B HCC patients beyond the Milan criteria without increasing severe adverse events frequency. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation (LT), resection (LR), and ablation (LA) are three curative‐intent treatment options for patients with early hepatocellular carcinoma (HCC). We aimed to develop a prognostic calculator to compare the long‐term outcomes following each of these therapies. Methods: A total of 976 patients with HCC within the Milan criteria who underwent LT, LR, and LA between 2009 and 2019 from four institutions were evaluated. Multistate competing risks prediction models for recurrence‐free survival (RFS), recurrence within the Milan criteria (RWM), and HCC‐specific survival (HSS) were derived to develop a prognostic calculator. Results: During a median follow‐up of 51 months, 420 (43%) patients developed recurrence. In the multivariate analysis, larger tumor size, multinodularity, older age, male, higher alpha‐fetoprotein (AFP), higher albumin‐bilirubin (ALBI) grade, and the presence of portal hypertension were significantly associated with higher recurrence and decreased survival rates. The RFS and HSS were both significantly higher among patients treated by LT than by LR or LA and significantly higher between patients treated by LR than by LA (all p < 0.001). For multinodular HCC ≤3 cm, although LT had better RFS and HSS than LR or LA, LA was noninferior to LR. An online prognostic calculator was then developed based on the preoperative clinical factors that were independently associated with outcomes to evaluate RFS, RWM, and HSS at different time intervals for all three treatment options. Conclusions: Although LT resulted in the best recurrence and survival outcomes, LR and LA also offered durable long‐term alternatives. This prognostic calculator is a useful tool for clinicians to guide an informed and personalized discussion with patients based on their tumor biology and liver function. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate the optimal radiologic method to determine Milan criteria (MC) for the prediction of recurrence in patients who underwent locoregional treatment (LRT) for hepatocellular carcinoma (HCC) and subsequent liver transplantation (LT). Methods: This retrospective study included 121 HCC patients who underwent LRT and had both liver dynamic CT and MRI. They were classified with MC using four cross combinations of two imaging modalities (CT and MRI) and two diagnostic criteria (modified Response Evaluation Criteria in Solid Tumors [mRECIST] and Liver Imaging Reporting and Data System treatment response algorithm [LI-RADS TRA]). Competing risk regression was performed to analyze the time to recurrence after LT. The predictive abilities of the four methods for recurrence were evaluated using the time-dependent area under the curve (AUC). Results: Competing risk regression analyses found that beyond MC determined by MRI with mRECIST was independently associated with recurrence (hazard ratio, 6.926; p = 0.001). With mRECIST, MRI showed significantly higher AUCs than CT at 3 years and 5 years after LT (0.597 vs. 0.756, p = 0.012 at 3 years; and 0.588 vs. 0.733, p = 0.024 at 5 years). Using the pathologic reference standard, MRI with LI-RADS TRA showed higher sensitivity (61.5%) than CT with LI-RADS TRA (30.8%, p < 0.001) or MRI with mRECIST (38.5%, p < 0.001). Conclusions: MRI with mRECIST was the optimal radiologic method to determine MC for the prediction of post-LT recurrence in HCC patients with prior LRT. Key Points: • MRI with modified RECIST (mRECIST) is the optimal preoperative method to determine Milan criteria for the prediction of post-transplant HCC recurrence in patients with prior locoregional treatment. • With mRECIST, MRI was better than CT for the prediction of post-transplant recurrence. [ABSTRACT FROM AUTHOR]

Hepatic resection has long been considered the preferred treatment for hepatocellular carcinoma (HCC) when feasible, but its role, as well as the outcomes is evolving rapidly. This article explores the impact of the changing demographics of HCC, reviews current criteria for resection, considers the roles of liver transplantation and nonsurgical locoregional therapies vis-a-vis resection, highlights the potential of new systemic therapies (particularly immune checkpoint inhibitors) to improve outcomes, details the common complications associated with resection, and discusses recurrence of HCC after resection and its management., Competing Interests: Disclosure None of the authors has any commercial or financial conflict related to the content of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Malignant biological behaviors such as microvascular invasion (MVI), satellite nodule formation and poor differentiation can appear in the postoperative pathology of early hepatocellular carcinoma (HCC), which often indicates that it has entered the stage of malignant evolution earlier. This study aimed to evaluate tumor recurrence in HCC patients meeting the Milan criteria who underwent postoperative adjuvant transarterial chemoembolization (PA-TACE) based on postoperative pathological indices., Methods: A retrospective study was conducted on 790 HCC patients within the Milan criteria who underwent hepatectomy across four medical centers, comprising 366 patients treated with PA-TACE and 424 patients without PA-TACE. To reduce selection bias, propensity score matching (PSM) at a 1:1 ratio was applied, achieving balanced clinical characteristics between the two groups., Results: Patients receiving PA-TACE did not experience more severe adverse events or toxicity-related deaths. After PSM of each subgroup, it was found that patients with MVI (Median time: 37 months vs 17 months, p = 0.010), satellite nodules (Median time: NA vs 14 months, p = 0.018), and Edmondson-Steiner grade III-IV (Median time: NA vs 13 months, p = 0.004) who received PA-TACE had higher recurrence-free survival (RFS). However, patients who were MVI-negative, satellite nodule-negative, and Edmondson-Steiner grade I-II did not benefit from PA-TACE in terms of RFS (All p > 0.05). Patients who received PA-TACE were more likely to undergo liver transplantation, re-hepatectomy, and local ablation after tumor recurrence, whereas patients who did not receive PA-TACE were more likely to receive TACE, chemoradiotherapy, and immunotargeted therapy after tumor recurrence (All p < 0.05)., Conclusion: Postoperative pathological indicators can guide the selection of PA-TACE for patients with HCC within the Milan criteria. Patients with MVI, satellite nodules, and Edmondson-Steiner grade III-IV are more suitable for receiving PA-TACE to improve RFS. PA-TACE may alter the recurrence pattern of tumors, rendering them more localized., (Copyright © 2025. Published by Elsevier Inc.)

Background: Among primary liver tumors, hepatocellular carcinoma (HCC) is considered the most common hepatic tumor. Liver transplantation is one of the curative treatment options for HCC. However, the risk of HCC recurrence after liver transplantation varies and is influenced by various factors. Microvascular invasion (MVI) is a major factor associated with HCC recurrence after a liver transplant (LT). The study assessed the pre-transplant factors to predict MVI on explant liver specimens., Methods: The retrospective study included adult LT recipients with HCC on explant specimens to identify pre-transplant predictors of MVI. Univariate analyses, including Mann-Whitney U tests and chi-square tests, were conducted to assess associations between variables and MVI. Logistic regression was employed for multivariate analysis, including variables significant in univariate analysis. Pearson or Spearman correlation coefficients were calculated to examine correlations between continuous variables. Cohen's kappa coefficient was used to measure inter-rater reliability., Results: Out of 523 LT recipients, 136 (26%) were diagnosed with HCC based on pre-transplant imaging and histopathological analysis of the explanted liver. Descriptive data showed an average age of 54.06 ± 8.16 years (range: 15-70), with a majority being male (76.47%). Hepatitis C (HCV) was the leading etiology (72.8%). Most patients had moderately differentiated grade-II tumors (75.7%) and met the Milan criteria (74.3%). Mean pre-operative alpha-fetoprotein (pre-op AFP) levels were 104.42 ± 308.38 ng/ml. 74.3% were within the Milan criteria. MVI was present in 28.7%. The frequency of MVI among HCCs within vs. outside Milan criteria was not statistically significant (26.73% vs. 34.28% (p = 0.395)). Univariate analysis revealed that pre-op AFP levels (p = 0.001), Child-Turcotte Pugh class (p=0.05), and body mass index (p=0.02) were significantly associated with MVI. Multivariate logistic regression analysis showed that pre-op AFP was the only independent predictor of MVI (OR: 1.006, 95% CI: 1.003-1.008, p < 0.001)., Conclusion: This study not only reinforces the clinical significance of pre-op AFP levels as a simple pre-transplant predictor of MVI in patients with HCC but also advocates for the safety of liver transplantation beyond conventional Milan criteria, promoting extended LT protocols., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Review Board of Pakistan Kidney and Liver Institute & Research Center issued approval PKLI-IRB/AP/170. This study was conducted following the Declaration of Helsinki and approved by the Institutional Review Board of Pakistan Kidney and Liver Institute & Research Center (Approval No. [PKLI-IRB/AP/170]). Given the study's retrospective nature, informed consent was waived by the Institutional Review Board, and all data were anonymized before analysis to protect the privacy and confidentiality of the participants. No animals or prisoners were included in the study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Aujla et al.)

Objective We aimed to develop and validate a nomogram for preoperatively estimating the risk of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) within the Milan criteria. Methods The clinical data of 312 HCC patients who underwent liver surgery at the xxx from Jan 2017 to Dec 2019 were retrospectively collected. Then, the study population was categorized into the training and validation group based on the date of surgery. To identify risk factors related to MVI, we conducted a series of logistic regression analyses. By combining these risk factors, a nomogram was then established. We further clarified the usability of our model through the area under the ROC curve (AUC), decision curve analysis (DCA), and calibration curve. Results Pathological examination revealed MVI in 108 patients with HCC (34.6%). Three independent predictors were identified: level of alpha-fetoprotein (AFP) exceeds 194 ng/mL (OR = 2.20, 95% CI: 1.13-4.31, p = 0.021), size of tumor (OR = 1.59; 95% CI: 1.18-2.12; P

Purpose: To establish and validate a nomogram model incorporating both liver imaging reporting and data system (LI-RADS) features and contrast enhanced magnetic resonance imaging (CEMRI)-based radiomics for predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC) falling the Milan criteria. Methods: In total, 161 patients with 165 HCCs diagnosed with MVI (n = 99) or without MVI (n = 66) were assigned to a training and a test group. MRI LI-RADS characteristics and radiomics features selected by the LASSO algorithm were used to establish the MRI and Rad-score models, respectively, and the independent features were integrated to develop the nomogram model. The predictive ability of the nomogram was evaluated with receiver operating characteristic (ROC) curves. Results: The risk factors associated with MVI (P

Increasing incidence of hepatocellular carcinoma (HCC) in India is a matter of concern and need for adequate profiling and streamlining management strategies cannot be over-emphasized. This is a prospective multi-centric observational cohort study comprising of an oncology center, one university tertiary hospital with specialized hepatology service, one public hospital with gastroenterology service, and a private liver transplant center located within a 3-km radius. The demographic and clinical parameters were recorded on a prospectively maintained database. The clinical profile, demographics, characteristics of HCC and the allocated treatment were noted and compared among the four centers. In total, 672 patients were enrolled from June 2016 till January 2020. Abdominal pain (64.3%) and weight loss (47.3%) were the most common symptoms. Most common identified etiology was hepatitis B (39%). The cancer center received lesser patients with hepatitis C and those with advanced stage of HCC. The private transplant center reported the highest proportion of NASH, which was also significantly higher in those belonging to higher socioeconomic strata, and lowest proportion of alcoholic cirrhosis. Metastasis was seen in almost one-fifth (19%) cases at diagnosis. Portal vein thrombosis was evident in 40%. Adherence to treatment guidelines was seen in three-fourth cases (76%). Hepatitis B is the most common underlying cause for HCC, whereas other causes like NASH are on the rise. Etiologic profile may vary with selective specialization of centers catering to patients with HCC. Adherence to guideline while allocating treatment was high among all centers with highest non-adherence in BCLC A. [ABSTRACT FROM AUTHOR]

Simple Summary: This is a systematic and meta-analysis study that looked at the hepatocellular carcinoma recurrence rate and its risk factors after liver transplantation. The recurrence rate, overall survival rate, and mortality rates in HCC patients post-liver transplantation remain relatively high. Significant regional differences exist in the prevalence of the recurrence, overall survival, and mortality rates. These findings will be of valuable guidance both for clinicians considering patients for an LT, and for providing tailored post-transplant HCC recurrence counselling to different populations with different risk levels. Background: liver transplantation (LT) is the best curative option for eligible patients with hepatocellular carcinoma (HCC), however recurrence remains a major concern. This meta-analysis aimed to investigate the prevalence and risk factors of HCC recurrence. Methods: studies were selected using PubMed, Epistemonikas, and Google Scholar databases published from inception to 15 May 2022 and a meta-analysis of the proportions was conducted. Observational studies reporting the prevalence of recurrent HCC after an LT were included, with the analysis being stratified by an adherence to the Milan criteria (MC), geographical region, AFP levels, and donor type. Results: out of 4081 articles, 125 were included in the study. The prevalence of recurrent HCC was 17% (CI: 15–19). Patients beyond the MC were more likely to recur than patients within the MC. Asian populations had the greatest prevalence of HCC recurrence (21%; CI: 18–24), whereas North American populations had the lowest recurrence (10%; CI: 7–12). The mortality rate after HCC recurrence was 9%; CI: 8–11. North American populations had the greatest prevalence of mortality with 11% (CI: 5–17). Conclusions: the recurrence, overall survival, and mortality rates among patients with HCC post-LT remains high, with substantial differences between regions. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to evaluate the predictive value of the combined prognostic nutritional index (PNI) and GGT/ALT for the postoperative prognosis of patients with hepatocellular carcinoma (HCC) within Milan criteria undergoing radical hepatectomy. Methods: This single-center retrospective study included 283 patients with HCC within the Milan criteria who underwent hepatectomy. The receiver operating characteristic (ROC) curve was used to calculate the optimal PNI and GGT/ALT cut-off values. Pre-treatment PNI, GGT/ALT, and PNI-GGT/ALT grades were calculated. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method, and multivariate analysis was used to identify prognostic factors. Results: Multivariate Cox regression analysis identified that the PNI, GGT/ALT, tumor number were significant prognostic markers for OS, and that the GGT/ALT, tumor number were significant prognostic markers for OS. The survival curves showed that low PNI, high GGT/ALT ratio, and high PNI-GGT/ALT grade were associated with poorer OS and DFS. With an area under the curve (AUC) of 0.690, PNI-GGT/ALT outperformed each individual score. Conclusion: PNI-GGT/ALT, a new prognostic scoring model, qualifies as a novel prognostic predictor for patients with HCC within the Milan criteria after curative resection. [ABSTRACT FROM AUTHOR]

Background: Radiofrequency ablation (RFA) is considered as a convenient treatment with mild damage in treating recurrent hepatocellular carcinoma (RHCC). However, for patients with high risk of progression after RFA still needs new strategies to decrease the repeat recurrence.Methods: A total of 460 patients with RHCC within Milan criteria in four institutions were enrolled. 174 pairs were enrolled after propensity score matching (PSM). Overall survival (OS) and tumor-free survival (TFS) were compared between the two groups. A quantitative score system was established to screen out the beneficial population from RFA-sorafenib treatment.Results: The 1-, 3-, and 5-year OS rates were 97.7%, 83.7%, 54.7% for RFA-sorafenib group, and 93.1%, 61.3%, 30.9% for RFA group after PSM, respectively. Compared with the RFA group, the RFA-sorafenib group had significantly better OS (P < 0.001). The 1-, 3-, and 5-year TFS rates were 90.8%, 49.0%, 20.4% for RFA-sorafenib group, and 67.8%, 28.0%, 14.5% for RFA group after PSM. The difference was observed significantly between RFA-sorafenib group and RFA group (P < 0.001). A quantitative risk score system was established to precisely screen out the beneficial population from RFA-sorafenib treatment.Conclusions: Adjuvant sorafenib after RFA was superior to RFA alone in improving survival outcomes in patients with recurrent HCC within Milan criteria after initial hepatectomy. Subgroup analyses concluded that patients with high risk score had significantly longer survival from sorafenib administration. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor burden score (TBS) has been recently introduced to assess the tumor burden in hepatocellular carcinoma (HCC), but its prognostic role in patients with early-stage HCC is unclear. We confirm that TBS is an independent prognostic predictor in HCC patients within the Milan criteria undergoing radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). TACE may be an effective treatment alternative for these patients. Among patients with low TBS, RFA should be considered the priority treatment modality. Tumor burden score (TBS), estimated by the diameter and number of tumor nodules, was recently proposed to assess the tumor burden in hepatocellular carcinoma (HCC). We aimed to evaluate the prognostic impact of TBS on HCC patients within the Milan criteria undergoing radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). A total of 883 patients undergoing RFA and TACE were included. The multivariate Cox proportional hazards model was used to determine independent prognostic predictors in different patient cohorts. The TACE group had significantly higher TBS compared with the RFA group. The RFA group had better long-term survival than the TACE group in patients within the Milan criteria in univariate survival analysis. In the Cox model, serum α-fetoprotein (AFP) > 20 ng/mL, performance status 1–2, medium and high TBS, albumin–bilirubin (ALBI) grade 2 and grade 3 were independent predictors linked with mortality (all p < 0.001). Overall, TACE was not an independent predictor; among patients with low TBS, TACE was independently associated with decreased survival compared with RFA (p = 0.034). Conclusions: TBS is a feasible prognostic marker for HCC patients within the Milan criteria. TACE may be an effective treatment alternative for these patients. Among patients with low TBS, RFA should be considered the priority treatment modality. [ABSTRACT FROM AUTHOR]

Hui-Zhou Li,1 Jie Tan,1 Tian Tang,2 Tian-Zhi An,3 Jun-Xiang Li,4 Yu-Dong Xiao1 1Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, 410011, People’s Republic of China; 2Department of Interventional Radiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China; 3Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550002, People’s Republic of China; 4Department of Interventional Radiology, Guizhou Medical University Affiliated Cancer Hospital, Guiyang, 550004, People’s Republic of ChinaCorrespondence: Yu-Dong XiaoDepartment of Radiology, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, People’s Republic of ChinaTel +86 13637403027Fax +86 731-85292116Email xiaoyudong222@csu.edu.cnPurpose: Transarterial chemoembolization (TACE) is recommended in patients with unresectable HCC beyond the Milan criteria (MC). However, the long-term efficacy of TACE remains unsatisfactory. Percutaneous microwave ablation (MWA) is a curative therapy for early-stage HCC that provides better local tumor control than TACE; however, MWA is limited for large or multifocal lesions. We aimed to compare treatment efficacy and downstaging rate following combined TACE-MWA and TACE alone in patients with unresectable HCC beyond the MC.Patients and Methods: Patients with unresectable HCC beyond the MC who underwent either TACE-MWA (n=91) or TACE alone (n=140) at four medical institutions were included. Potential influencing factors on overall survival (OS) and progression-free survival (PFS) were included in the Cox regression analysis. Propensity-score matching of patients treated with TACE-MWA and TACE alone was performed. Differences in OS and PFS were compared with the Log rank test. Patients who met the University of California, San Francisco criteria were eligible for assessment of the probability of downstaging within the MC. Downstaging rate was compared between the two groups.Results: In multivariate analysis, treatment with TACE alone was an independent predictor of poor PFS (P=0.011) and OS (P< 0.001). Both PFS (P=0.043) and OS (P=0.002) were significantly higher in patients treated with TACE-MWA than those treated with TACE alone. The downstaging rate was higher in patients treated with TACE-MWA than those treated with TACE alone (P=0.039).Conclusion: Compared with TACE alone, TACE-MWA may offer a survival benefit in terms of OS and PFS in HCC patients beyond the MC. Additionally, TACE-MWA may provide higher probability of downstaging within the MC than TACE alone, thereby increasing the possibility of liver transplantation.Keywords: microwave ablation, transarterial chemoembolization, survival, propensity score-matching, Milan criteria

Abstract Background The controlling nutritional status (CONUT) score has been widely used to evaluate the nutritional and immunological status. Clinical value of postoperative CONUT (PoCONUT) score in hepatocellular carcinoma (HCC) remains unknown. This study assessed whether PoCONUT score could serve as a useful predictor of survival for patients with small HCC. Methods 547 consecutive patients with small HCC who underwent liver resection between February 2007 and December 2015 were included in this retrospective case-control study. Patients were categorized into two groups: low PoCONUT group (PoCONUT score ≤ 2, n = 382) and high PoCONUT group (PoCONUT score ≥ 3, n = 165). Propensity score matching (PSM) analysis was applied to balance the bias in baseline characteristics. A cumulative survival curve was established by the Kaplan–Meier method, and differences in OS and RFS among CONUT score groups were determined by the log rank test. Cox proportional hazard regression analysis was used to evaluate the association of PoCONUT score and overall survival (OS) and recurrence-free survival (RFS), with calculation of hazard ratios (HRs) and 95 % confidence intervals (95 % CIs). Results Cox proportional hazard regression analysis suggested that the PoCONUT score was an independent risk factor for both OS and RFS in patients with small HCC before and after PSM. Conclusions High PoCONUT score helps to predict worse OS and RFS in patients with small HCC who underwent liver resection.