Hepatocellular Carcinoma Recurrence Research Articles

Histopathological diagnosis of microvascular invasion in hepatocellular carcinoma: Is it reliable?

BACKGROUND Microvascular invasion (MVI) is a critical prognostic factor for postoperative hepatocellular carcinoma recurrence, but the reliability of its current pathological diagnosis remains uncertain. AIM To evaluate the accuracy of current 7-point sampling methods and propose an optimal pathological protocol using whole-mount slide imaging (WSI) for better MVI detection. METHODS We utilized 40 New Zealand white rabbits to establish VX2 liver tumor models. The entire tumor-containing liver lobe was subsequently obtained, following which five different sampling protocols (A-E) were employed to evaluate the detection rate, accuracy, quantity, and distribution of MVI, with the aim of identifying the optimal sampling method. RESULTS VX2 liver tumor models were successfully established in 37 rabbits, with an incidence of MVI of 81.1% (30/37). The detection rates [27% (10/37), 43% (16/37), 62% (23/37), 68% (25/37), and 93% (14/15)] and quantity (15, 36, 107, 125, and 395) of MVI increased significantly from protocols A to E. The distribution of MVI showed fewer MVIs farther away from the tumor, but the percentage of MVI detected quantity gradually increased from 6.7% to 48.3% in the distant nonneoplastic liver tissue from protocols A to E. Protocol C was identified as the optimal sampling method by comparing them in sequence. The sampling protocol of three consecutive interval WSIs at the tumor center (WSI3) was further screened to determine the optimal number of WSIs. Protocol A (7-point sampling method) exhibited only 46% accuracy and a high false-negative rate of 67%. Notably, the WSI3 protocol improved the accuracy to 78% and decreased the false-negative rate to 27%. CONCLUSION The current 7-point sampling method has a high false-negative rate in MVI detection. In contrast, the WSI3 protocol provides a practical and effective approach to improve MVI diagnostic accuracy, which is crucial for hepatocellular carcinoma diagnosis and treatment planning.

Recurrence and survival after robotic vs laparoscopic liver resection in very-early to early-stage (BCLC 0-A) hepatocellular carcinoma.

Robotic (RLR) and laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) provide similar short-term outcomes, but data focused on recurrence and survival are still lacking. We hypothesized non-inferior oncologic results of RLR compared to LLR for HCC of stage BCLC 0-A. RLRs and LLRs on patients with HCC of stage BCLC 0-A and preserved liver function (Child A or B if cirrhosis) were retrospectively reviewed. Propensity score matching (PSM) was used to mitigate selection bias. The primary endpoints were recurrence-free (RFS) and overall survival (OS); secondary endpoints were incidence, pattern, and treatment of recurrences. After 1:1 PSM, two groups (RLR = 68; LLR = 68) of patients with similar characteristics, liver function and HCC features were obtained: median age 71-years, males 73.5%, underlying cirrhosis 91.2% (Child A, 96.8%, MELD ≤ 9, 96.0%), portal hypertension 22.1%, single-HCC 90.4%. Two- and 5-year RFS were 78.0 vs 59.0% and 54.0 vs 53.0% (p = 0.107), while OS was 97.0 vs 90.0% and 87.0 vs 90.0% (p = 0.951) for RLR vs LLR, respectively. Incidence of HCC recurrence was similar (35.3 vs 39.7%; p = 0.723). Recurrences developed mostly within the liver (29.4 vs 30.9%; p = 1.000) and within 2 years after hepatectomy (19.1 vs 32.4%, p = 0.116) in RLR vs LLRs. Curative-intent treatment of recurrences did not differ (liver transplantation 19.6%, redo-resection 15.7%, locoregional treatments 52.9%) except for a tendency toward more redo-resections for recurrences after RLR. Oncologic outcomes of RLR were not inferior to those of LLR in selected HCC patients of stage BCLC 0-A with underlying cirrhosis. Both techniques guaranteed similar salvageability in case of HCC recurrence.

Long-Term Liver Morbidity and Mortality After Hepatitis C Virus Elimination by Direct-Acting Antivirals.

More accurate stratification of patients with chronic hepatitis C after permanent hepatitis C virus (HCV) clearance by direct-acting antivirals (DAAs) is important for improving long-term surveillance and treatment. The aim of this study was to stratify patients with chronic hepatitis C who are at risk of developing hepatocellular carcinoma (HCC) after HCV cure. This multicenter, retrospective cohort study included 3177 consecutive adult chronic hepatitis C patients without decompensated cirrhosis who were treated with all-oral DAAs. The primary study endpoints were long-term cumulative de novo HCC incidence, HCC recurrence rates, and survival. Additionally, we analyzed the development of HCC by patients without cirrhosis, stratified by age and fibrosis status according to the FIB-4 index. After exclusions, data from 3024 patients were available for analysis. The overall median follow-up period was 6.5 years. None of the patients with non-cirrhosis/FIB-4 < 1.45 (n = 475) developed HCC regardless of background factors. For patients with non-cirrhosis/FIB-4 ≥ 3.25, older age had a greater impact on HCC incidence (log-rank test: p = 0.038). In addition, metabolic factors, including body mass index and diabetes mellitus, were not related to HCC incidence. HCC recurrence commonly occurred within 5 years after HCV cure; nevertheless, HCV cure contributed to an improvement of survival rates. Age is a pivotal factor in predicting de novo HCC development following HCV cure in patients with moderate to advanced fibrosis. Conversely, patients with mild fibrosis (FIB-4 < 1.45) may be eligible for discharge from specialized care after achieving HCV elimination.

DAA-PASS: A Prospective Evaluation of HCC Recurrence After Direct Acting Antiviral Therapy.

Direct-acting antiviral (DAA) therapy is associated with a significant reduction in hepatocellular carcinoma (HCC) incidence among patients with cirrhosis, but data are conflicting about the risk of recurrence following DAA therapy. DAA-PASS was a prospective, pragmatic, observational study designed to estimate the risk of HCC recurrence associated with DAA therapy exposure during routine clinical care. Eligible patients were DAA treatment naive with Barcelona Clinic Liver Cancer (BCLC) stage A. Patients were followed at regular intervals for up to 24 months. To provide additional data, outcomes were compared to the Italian Liver Cancer Group (ITA.LI.CA) cohort. Of 42 patients enrolled, 24 were treated with DAA therapy. Ten HCC recurrence events were observed during the study, with 5 each in DAA-treated and DAA-untreated patients (cumulative incidences of 23 and 37 per 100 PY, respectively). The overall crude hazard ratio (HR) for HCC recurrence associated with DAA therapy was 0.6 (95% CI, 0.2-2.2). In the ITA.LI.CA cohort, HCC recurrence was observed in 193 patients during 24 months of follow-up, resulting in a cumulative incidence rate of 28 per 100 PY. Although limited by small sample size, this prospective study suggests DAA therapy is not associated with increased HCC recurrence risk among patients with a history of complete response to prior HCC therapy.

Evaluating the safety of immune checkpoint inhibitors prior to liver transplant.

614 Background: Liver transplantation (LT) offers a 5-year survival exceeding 70% for selected patients with hepatocellular carcinoma (HCC). Immune checkpoint inhibitors (ICIs) may be used to downstage or bridge to transplantation. This study aims to evaluate the safety of ICIs prior to LT. Methods: Multicenter retrospective study, involving 9 centers, included adults who received ICIs and, subsequent LT, between 2019 and 2023. The ICI cohort was matched by age, sex, liver diseases and transplant date (1:3) with a similar cohort of HCC transplanted patients that did not receive ICIs. Results: The ICI cohort included 45 patients (Table part 1). The most common underlying liver diseases were viral. 15.5% of patients had macrovascular invasion and, 62.2% multifocal disease. The most commonly used ICI was nivolumab (75.6%), followed by atezolizumab-bevacizumab (17.8%). The median follow up was 32.5 months (17.4 - 47.6). The median ICI duration was 147 days (129.5-276.5), with a median interval of 58 days (22–193) between the last ICI dose and LT. There were 8 (17.8%) cases of graft rejection, 2 steroid-resistant leading to 1 graft failure. There were 4 (8%) HCC recurrences. During follow-up there were 6 deaths, 2 related to HCC recurrence and 4 non liver related. When compared with 135 non-ICI cohort patients, there were no differences within the groups (Table part 2). Importantly, we found no significant differences in crude rejection rates (p=0.5). Conclusions: Our study suggest that ICI treatment prior to LT is safe. ICI rejection primarily occurs in the acute post-transplant period (within 3 months), with a low risk of death due to graft failure. Further clinical trials are needed. Part 1: ICI cohort descriptive analysis. N (%); Median (IQR); Part 2: Comparison between cohorts. N (%); Mean (SD). (part 1) ICI-cohort n=45 General data Male 38 (84.4) Age 61.2 (7.6) Etiology of liver diseases Hepatitis C 17 (37.8)Hepatitis B 6 (13.3)MASLD 6 (13.3)Viral +Alcohol 5 (11.1)Alcohol 3 (6.7)Autoimmune 3 (6.7)Other 3 (6.7)Combined viral 2 (4.4) Largest tumor (mm) 39 (22) Macrovascular invasion 7 (15.5) Multifocal 28 (62.2) Locoregional therapy 36 (80.0) Number of locoregional therapies 2 (2) Immunotherapy Nivolumab 34 (75.6) Atezolizumab/bevacizumab 8 (17.8) Pembrolizumab 1 (2.2) Nivolumab+pembrolizumab 1 (2.2) PD1 inhibitor clinical trial 1 (2.2) Days of ICI treatment 147 (203) Radiological tumor response ICI No 17 (37.8) Transplant Deceased donor 43 (95.6) Washout period (days) 58 (171) Induction therapy (anti-thymoglobulin) 8 (17.8) Outcomes Rejection Biopsy proven 8 (17.8) 8 (100) Time to rejection (days) 43 (102) Graft failure Rejection 2 (4.4)1 (2.2) HCC recurrence 4 (8) Deaths 6 (13.3) Follow up Since transplant (months) 32.5 (30.2) (part 2) ICI-cohort (n=45) Non-ICI cohort (n= 135) P Post transplant rejection rate 8 (17.8) 32 (23.7) 0.53 Time to rejection (days) 180.1 (SD 218) 62.2 (SD 62.8) 0.25 Overall deaths 6 (13.3) 10 (7.4) 0.36

Non-contrast MRI as a surveillance tool for recurrent hepatocellular carcinoma after curative treatment: A prospective multicenter intra-individual comparison trial.

530 Background: Hepatocellular carcinoma (HCC) often recurs following curative treatment, significantly impacting long-term survival. Contrast-enhanced multiphasic computed tomography (CECT) is widely utilized for HCC recurrence surveillance but carries risks such as radiation exposure and adverse reactions to contrast agents. This prospective multicenter trial aimed to compare the accuracy of non-contrast abbreviated magnetic resonance imaging (NC-MRI) with CECT in detecting late recurrent HCC. Methods: This prospective multicenter intra-individual head-to-head comparison trial (study identifier: NCT05690451, KCT0006395) enrolled participants who had undergone curative treatment for HCC and remained recurrence-free for over two years. Participants underwent three rounds of surveillance at 2–6-month intervals using both CECT and NC-MRI. The primary outcome was the detection accuracy of each modality, compared using the McNemar test. Secondary outcomes included detection sensitivity and specificity. Results: A total of 203 participants underwent 528 rounds of paired CECT and NC-MRI, detecting recurrent HCC in 22 participants (10.8%). Among these cases, 21 showed intrahepatic recurrent HCC with a median tumor size of 1.3 cm, and one exhibited aortocaval lymph node metastasis. NC-MRI demonstrated a detection accuracy of 96.6% (196/203), significantly higher than CECT's 91.6% (186/203) (P=0.006). NC-MRI also exhibited significantly higher sensitivity in detecting recurrent HCC compared to CECT (77.3% [17/22] vs. 36.4% [8/22]; P=0.012), while specificity did not differ significantly between NC-MRI and CECT (98.9% [179/181] vs. 98.3% [178/181]; P=0.999). Conclusions: NC-MRI showed significantly higher sensitivity and accuracy in detecting recurrent HCC among patients who had been disease-free for more than two years after curative treatment, establishing it as the preferred surveillance modality for late recurrence. Clinical trial information: NCT05690451 . Contrast enhanced CT Non-contrast MRI Difference, % (95% CI) P-value Estimates, % (n/N) 95% CI, % Estimates, % (n/N) 95% CI, % Accuracy 91.6% (186/203) 87.8-95.5 96.6% (196/203) 94.0-99.1 4.9 (1.7, 8.2) 0.006 Sensitivity 36.4% (8/22) 14.5-58.2 77.3% (17/22) 58.3-96.3 40.9 (16.8, 65.0) 0.012 Specificity 98.3% (178/181) 96.5-100 98.9% (179/181) 97.4-100 0.6 (-0.5, 1.6) 0.999

Sorafenib as Adjuvant Therapy Post-Liver Transplant: A Single-center Experience.

Hepatocellular carcinoma (HCC) has a rising incidence and mortality in North America. Liver transplantation (LT) with adjunctive therapies offers excellent outcomes. However, HCC recurrences are associated with high mortality. We investigate whether adjuvant systemic therapy can reduce recurrence, as shown with other malignancies. Medical records of patients undergoing LT for HCC at a single center between January 2016 and December 2022 were retrospectively reviewed. Patients were stratified into 3 groups: (1) recipients of adjuvant sorafenib, (2) nonrecipients at high recurrence risk, and (3) nonrecipients at low risk by explant pathology features. The outcomes were overall survival (OS) and recurrence-free survival (RFS). Adjuvant sorafenib recipients were also propensity score matched 1:2 to nonadjuvant recipients based on recurrence risk features. During the study period, 273 patients with HCC underwent LT and 16 (5.9%) received adjuvant sorafenib therapy. Adjuvant sorafenib recipients were demographically similar to nonrecipients and, on explant pathology, had greater tumor burden, lymphovascular invasion, and poorer differentiation (all P < 0.001). Adverse events were observed in 12 adjuvant sorafenib recipients (75%). OS was similar among the 3 groups (P = 0.2), and adjuvant sorafenib was not associated with OS in multivariable analysis (hazard ratio, 1.31; 95% confidence interval, 0.45-3.78; P = 0.62). RFS was significantly lower in sorafenib patients (hazard ratio, 6.99; 95% confidence interval, 2.12-23.05; P = 0.001). Following propensity matching, adjuvant sorafenib use was not associated with either OS (P = 0.24) or RFS rates (P = 0.65). In this single-center analysis, adjuvant sorafenib was not associated with OS. Recipients were observed to have shorter RFS, likely due to the increased prevalence of high-risk features, and sorafenib use was associated with high frequencies of adverse events.

P53 status combined with MRI findings for prognosis prediction of single hepatocellular carcinoma

ObjectTo develop and validate a nomogram for predicting recurrence in individuals suffering single hepatocellular carcinoma (HCC) after curative hepatectomy. Material and methodsA retrospective analysis was conducted on 189 patients with single HCC undergoing curative resection in our center were randomized into training and validation cohorts. P53 status was determined using immunohistochemistry. Clinical data, such as age, and gender were collected. MRI findings, such as tumor size, intratumoral arteries, the presence of peritumoral enhancement and intratumoral necrosis were also recorded. Nomograms were established based on the predictors selected in the training cohort, and receiver operating characteristic (ROC) curve analyses were used to compare the predictive ability among single predictors and nomogram model. The Kaplan-Meier method were used to assess the impact of each predictor and nomogram model on HCC recurrence. The results were validated in the validation cohort. ResultsMultivariate Cox regression analysis showed that P53 (P < 0.001), tumor size (P = 0.009), and intratumoral artery (P = 0.026) were the independent risk factors for HCC recurrence. The nomogram model demonstrated favorable C-index of 0.740 (95 %CI:0.653–0.826) and 0.767 (95 %CI: 0.633–0.900) in the training and validation cohorts, and the area under the curve was 0.740 and 0.752, which was better than the performance of P53 and MR factors alone. Calibration curves indicated a good agreement between observed actual outcomes and predicted values. Kaplan-Meier curves indicated that nomogram model was powerful in discrimination and clinical usefulness. ConclusionsThe integrated nomogram combining P53 status and MRI findings can be a valuable prognostic tool for predicting postoperative recurrence of single HCC.

Clinical outcome of radiofrequency ablation in elderly hepatocellular carcinoma patients over 80 years old.

603 Background: The SURF trial showed the efficacy and safety of radiofrequency ablation(RFA). However, patients over 80 years old were excluded from the study. Aims: To evaluate clinical outcomes of RFA for largest hepatocellular carcinoma (HCC) diameter ≤3 cm, and ≤3 HCC nodules in patients over 80 years. Methods: Patients who underwent RFA at our institution for initial treatment of largest HCC diameter ≤3 cm, and ≤3 HCC nodules from January 2011 to December 2023. Treatment outcome and prognosis were examined in the elderly group for cases 80 years or older and in the non-elderly group for cases under 80 years. The Cox proportional hazards model was used to analyze the factors associated with treatment outcome and prognosis. Results: Of the 518 eligible patients, 136 patients were 80 years or older. Median overall Survival (OS) was 80 (95%CI 60-96) vs. 123 (95%CI 101-NA) months (p=0.021) in the elderly vs. nonelderly group. The median recurrence-free survival was 16 (95%CI 14-22) vs. 26 (95%CI 19-30) months (p=0.023), better in the non-elderly group, Interestingly, for liver disease-related deaths, median OS was 97 (95% CI 80-NA) vs. NR (95% CI NA-NA) months (p=0.62) in the elderly vs. non-elderly group. In the multivariate analysis, factors associated with OS were ALBI grade 2 or 3 (HR 1.67, 95%CI 1.07-2.60), DCP ≥ 40mAU/ml (HR 2.08, 95%CI 1.42-3.05), persistent HCV infection (HCV non-SVR) (HR 5.45, 95%CI 3.07-9.67), nonviral liver disease (HR 4.18, 95%CI 2.31-7.55). HCC recurrence was significantly associated with male (HR 1.51, 95%CI 1.18-1.94), elderly group (HR 1.46,95%CI 1.10-1.95), PT ≥80% (HR 0.69, 95%CI 0.53-0.91), DCP ≥40mAU/ml (HR 1.37, 95%CI 1.07-1.76), and HCV non-SVR (HR 1.73, 95%CI 1.35-2.21). The factors associated with liver disease-related death were ALBI grade 2 or 3 (HR 2.16, 95% CI 1.25-3.73), DCP ≥ 40mAU/ml (HR 2.34, 95% CI 1.48-3.70) and HCV non-SVR (HR 2.22, 95% CI 1.39-3.56). Conclusions: In RFA for diameter ≤3 cm, and ≤3 HCC nodules, over 80 years was not a significant factor associated with OS or liver disease-related death. The results support that RFA would be a promising treatment option for HCC patients over 80 years.

Clinical outcome after complete response with immunotherapy in hepatocellular carcinoma.

573 Background: Immunotherapy has shown great efficacy in hepatocellular carcinoma (HCC). No clear consensus exists on when to stop the immune checkpoint inhibitor (ICI) after complete response (CR), and clinical course after stopping ICI remains unknown. Methods: We identified 138 HCC patients who received ICI at Cedars-Sinai Medical Center and Mayo Clinic Rochester from 2016-2023. Modified Response Evaluation Criteria In Solid Tumors (mRECIST) was used to assess treatment response. We further described the clinical course of patients who achieved CR after ICI discontinuation, including cancer recurrence, subsequent treatment, liver transplantation (LT) listing and outcomes. Results: The median age at ICI initiation was 68 years; 79% were male; 55.9% were white; 51.5% were BCLC stage C. 9.4% CRs, 25.4% partial responses, 39.9% stable diseases, and 25.4% progressive disease. Hepatitis C etiology was associated with higher likelihood of CR (P=0.005). Among 13 patients who achieved CR, 10 stopped ICI (60% for LT evaluation, 40% for toxicity). After stopping ICI, 40% had recurrence (Table). 3 patients underwent local therapy for recurrent HCC within Milan criteria and 1 patient restarted ICI for recurrence beyond Milan criteria. Among CR patients, 9 patients underwent LT evaluation after stopping ICI and 7 patients were waitlisted. After listing, 3 dropouts were observed, due to recurrent HCC beyond Milan criteria, sepsis leading to death, and personal preference. 4 patients underwent LT. 2 patients underwent local therapy before LT for recurrent HCC (Table). All transplanted patients had the last dose of ICI more than 1 year before LT (12, 21, 24, and 29 months). On explanted livers, 2 patients had no residual viable tumor and 2 patients had residual HCC within Milan criteria. 1 patient developed acute cellular rejection and was treated with immunosuppressants and maintained stable graft function. None had graft loss or evidence of HCC recurrence in the follow-up period at 8, 20, 28, and 51 months. Conclusions: Immunotherapy demonstrated excellent effects on a subset of HCC patients, including 9.4% who achieved CR. After stopping ICI, 40% had cancer recurrence but 3 out of 4 were within Milan criteria. 4 underwent successful LTs (2.9%) with excellent post LT outcome. Larger prospective data is needed to establish a protocol for ICI use, especially to determine the optimal timing for ICI discontinuation after CR. BCLC at ICI initiation ICI cycles before stopping, ICI Recurrence after last ICI (days) Within Milan at recurrence Treatment(s) received after recurrence and outcomes OS (days) Patient 1 B 7, Nivolumab 730 No Nivolumab. Died from GI bleeding 1065 Patient 2 B 64, Atezo/Bev 149 Yes TACE with CR, followed by LT without recurrence. 1203 Patient 3 A 8, Nivolumab 1393 Yes Y90 with CR. No recurrence. 1984 Patient 4 C NA, Pembrolizumab 407 Yes TACE and MWA with CR, followed by LT without recurrence. 1722

Impact of interferon-free regimens in patients with chronic HCV and successfully ablated HCC

BackgroundHepatocellular carcinoma (HCC) ranks sixth amongst all cancers and is the 2nd top cause of mortality attributable to cancer.Aim of the workThis study aimed to ascertain the sustained virological response (SVR) to interferon-free regimens in chronic people with HCV after the successful treatment of hepatocellular carcinoma, as well as the percentage of persons who would demonstrate any radiological or laboratory alterations indicating a local or de novo recurrence of HCC.Patients and methodsThis trial was carried out on 90 Egyptian persons with chronic HCV infection who were eligible for treatment with oral antiviral agents (DAAs) with hepatic focal lesion(s). Patients were referred to from both the outpatient clinic and hepatocellular carcinoma clinic at the National Hepatology and Tropical Medicine Research Institute (NHTMRI), and the trial was conducted in the period between October 2017 and May 2021.ResultsFour patients with distant metastasis, three dying from liver-related incidents, received surgical resection, TACE, and RFA treatment, while one patient survived with compensated chronic liver disease. By multivariate logistic regression, we found that AFP is an independent predictor of HCC recurrence, while baseline urea level and FIB4 before antiviral therapy protect against recurrence. PLT was the best predictor, with AFP having a sensitivity of 52% and specificity of 93.8% at a cutoff value of 135 and PCR having a sensitivity of 72%.ConclusionThe HCC recurrence rate was 27.8%, slightly higher than the estimated annual HCC recurrence rate following curative procedures (20%).

Economic burden of hepatocellular carcinoma recurrence after curative treatment in Spain.

640 Background: The literature on burden of disease studies of hepatocellular carcinoma is scarce. The aim of this analysis was to quantify the economic burden of disease recurrence in very early or early-stage HCC patients who underwent liver resection, ablation or transplantation in Spain. Methods: A decision-tree model was developed to estimate the cost of a recurrence after curative treatment with an initial complete response of very early or early-stage primary HCC tumor over a 5-year time horizon. Clinical parameters were collected by a multidisciplinary group of experts who also validated the assumptions and results of the analysis. According to the Barcelona Clinic Liver Cancer (BCLC) recommendations, patients with recurrent HCC were classified into five HCC stages (0, A, B, C, and D) and allocated to different treatment options. A payer perspective was adopted, so only direct costs (€2024) were considered (local/locoregional treatments costs, drug acquisition and administration costs, adverse events management costs, diagnostic and follow-up costs and end-of-life costs). Sensitivity analyses were performed to assess uncertainty. Results: A total of 1,250 HCC recurrences were estimated in Spain, resulting in a total cost of €32,817,142 in the first year of recurrence management. After 5-years follow-up, an additional €10,1M was estimated, mainly due to patient surveillance (€2,8M) and 228 new recurrences (€5,7M). The average cost of a relapse was €26,253 euros in the first year of recurrence management, rising to €34,342 euros for 5-years follow-up. A hypothetical patient experiencing a second relapse 5 years after their first relapse would incur costs of €58,758. Conclusions: This study is the first in Spain to explore the economic burden of hepatocellular carcinoma. Estimating the cost of recurrence after curative treatment and complete response of a primary HCC tumor is complex and depends on multiple factors, so further studies exploring both efficacy and costs in hepatocellular carcinoma are needed.

Rates and risk factors for recurrence of hepatocellular carcinoma after initial complete remission in response to transcatheter arterial chemoembolization: A systematic review and meta-analysis.

612 Background: Transcatheter arterial chemoembolization (TACE) is used for palliative treatment of patients with inoperable hepatocellular carcinoma (HCC). Despite remarkable initial remission rates, frequent recurrences of HCC after TACE have resulted in questionable survival benefit. Our investigation aimed to study the rates and risk factors for HCC recurrence following remission after TACE. Methods: Comprehensive search of 5 databases (EMBASE, Web of Science, PubMed, CINAHL, ClinicalTrials.gov) was conducted to yield 4263 studies, which were screened based on prespecified inclusion and exclusion criteria. Outcomes assessed were total recurrence rate; 6-month, 1, 2, and 3-year cumulative recurrence rates; and 1 and 3-year survival rates for patients with and without recurrence. Meta-analysis was conducted by the random-effects model and heterogeneity was assessed by the I 2 statistic and 95% prediction interval. Systematic review of risk factors for recurrence was performed. Results: Twelve studies and 1,152 patients who underwent complete remission in response to TACE were included. The pooled rate of total recurrence was 60% (95% CI 53-67%). The pooled 6-month, 1-year, 2-year, and 3-year cumulative recurrence rates were 26% (95% CI 18-33%), 33% (95% CI 22-43%), 49% (95% CI 34-64%), and 62% (95% CI 53-71%), respectively. The pooled 1-year survival rates for patients with and without recurrence were 94% (95% CI 89-99%) and 99% (95% CI 99-100%), respectively. The pooled 3-year survival rates for patients with and without recurrence were 61% (95% CI 31-90%) and 91% (95% CI 81-100%). Heterogeneity was considerable based on the 95% prediction interval. Predominant risk factors for recurrence were larger tumor size, multinodularity, portal vein thrombosis, and higher AFP levels. Conclusions: HCC frequently recurs after initial remission achieved through TACE, with differences in survival rates between patients with and without recurrence. Identifying high-risk patients based on tumor size, multinodularity, portal vein thrombosis, and AFP levels could improve long-term outcomes.

Efficacy evaluation of postoperative adjuvant TACE in preventing HCC recurrence within Milan criteria: A multi-center propensity score matching analysis based on pathological indicators.

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. 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. 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). 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.

Transarterial Chemoembolization with Radiofrequency Ablation versus Surgical Resection for Small Late-Recurrence Hepatocellular Carcinoma.

Background Radiofrequency ablation (RFA) has comparable clinical outcomes to surgical resection (SR) for treating small recurrent hepatocellular carcinoma (HCC). However, whether combined transarterial chemoembolization (TACE) with RFA (hereafter, TACE-RFA) outperforms SR for treating small late-recurrence HCCs remains unknown. Purpose To compare the clinical outcome of TACE-RFA with that of SR in patients with small late-recurrence HCCs. Materials and Methods This randomized clinical trial recruited patients between July 2013 and March 2019. Patients with small late-recurrence HCCs (a single recurrent HCC nodule [≤ 5 cm in diameter] or three or fewer nodules [each ≤ 3 cm in diameter] and recurrence at least 12 months after radical therapy of primary HCC) were randomly assigned to receive TACE-RFA or SR. The primary end point was overall survival (OS). The secondary end points included recurrence-free survival (RFS) and the incidence of complications. OS and RFS were assessed using the Kaplan-Meier method and log-rank test. Results In the intention-to-treat analysis, 210 patients (mean age, 52 years ± 12 [SD]; 194 male) were included, with 105 patients in each group. The 1-, 3-, and 5-year OS rates were 99%, 81%, and 69%, respectively, in the TACE-RFA group and 96%, 81%, and 76%, respectively, in the SR group (hazard ratio [HR], 1.34; 95% CI: 0.81, 2.23; P = .26). The 1-, 3-, and 5-year RFS rates were 71%, 38%, and 24%, respectively, in the TACE-RFA group and 73%, 43%, and 29%, respectively, in the SR group (HR, 1.05; 95% CI: 0.76, 1.45; P = .78). The incidence of complications was greater in the SR group than in the TACE-RFA group (41% [43 of 104] vs 24% [23 of 96]; P = .01). Conclusion For patients with small late-recurrence HCCs, TACE-RFA did not yield better survival outcomes than SR. However, the incidence of complications was lower in patients who received TACE-RFA therapy. ClinicalTrials.gov Identifier: NCT01833286 © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Ronot in this issue.

Standardized immunosuppressive protocol to prevent rejection under immunotherapy for post liver transplantation HCC recurrence: A French center's experience

Standardized immunosuppressive protocol to prevent rejection under immunotherapy for post liver transplantation HCC recurrence: A French center's experience

Hepatocellular carcinoma with multiple primary malignancy: ARetrospective Study of 106 Cases.

Multiple primary malignancies (MPM) are a rare scenario, particularly in patients with hepatocellular carcinoma (HCC). Research addressing MPM patients with HCC is limited. Therefore, we conducted a retrospective study to explore the clinical features and outcomes of MPM patients involving HCC. We retrospectively analyzed records of patients diagnosed with HCC from January 2013 to October 2023 in the First Affiliated Hospital of Xiamen University.HCC patients with extrahepatic tumors were identified. Their clinical characteristics and survival data were were further analyzed. Among the 1556patients with HCC,106 (6.8%) were identified with EHPM,of which29weresynchronous and 77weremetachronous. A total of 96 patientshad doubleprimary cancers,and10patientshad triple primary cancers. The most common EHPMs were lung cancer (15%), followed by colorectal tumors and stomach cancer. Compared with the synchronous group, the curative treatment rate of HCC and EHPMin the metachronous groupis higher. Duringfollow-up period,29 patients died,of which20 (69%)diedfrom HCC-related causes. The median overall survival (OS) time was 88 months, with 1-, 3-, 5-, and 10-year cumulative survival rates of 92.4%, 88%, 82.5%, and 69.6%, respectively. The 1-, 3-, and 5-year HCC-specific OS (HOS) rates were 81.8%, 75.8%, and 71.9%, respectively. Univariate analysis revealed that Child-Pugh class (B-C), HCC tumor size >5cm, non-radical treatment for HCC or EHPM, HCC recurrence, BCLC staging (C-D), and synchronous appearance were significantly associated with shorter OS and HOS. Factors such as Childs class, tumor size, treatment modality, and synchronous presentation were identified as independent predictors of OS through Cox analysis. Childs class, tumor size, non-radical treatment, BCLC staging, and HCC recurrence were found to be independent factors affecting HOS. The occurrence of extrahepatic primary tumors is not rare, underscoring the importance for oncologists being alerttothedevelopment of secondary tumor development in HCC patients. However, the co-occurrence of other primary tumors alongside HCC does not appear to worsen patient prognosis. Notably, curative resection, where feasible, emerges as a vital factor in extending patient survival.

TERT-TP53 mutations: a novel biomarker pair for hepatocellular carcinoma recurrence and prognosis

Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, and ranks among the most lethal malignancies globally, primarily due to its high rates of recurrence and metastasis. Despite the urgency, no reliable biomarkers currently exist for predicting tumor recurrence in HCC. Telomerase reverse transcriptase (TERT) promoter mutations (TERTpm) and cellular tumor antigen p53 mutations (TP53m) have been frequently documented in HCC, but their combined clinical significance remains undefined. In this study, we investigated the clinical implications of TERTpm, TP53m, and their co-occurrence in 50 HCC tissue samples using the next-generation sequencing (NGS) technology. We identified TERTpm (C228T) and TP53m in 16 (32%) and 24 (48%) samples, respectively. Our findings indicate that these mutations are more prevalent in male patients (100% for TERTpm, 83.33% for TP53m), in those with solitary tumors (87.5% for both), in individuals with G2-G3 hepatitis (100% / 83.3%), and in cases of moderately differentiated tumors (75.0% / 83.3%). Furthermore, patients with both TERTpm and TP53m exhibited a significantly higher risk of tumor relapse (P < 0.05) and shorter progression-free survival (P < 0.05). Collectively, our results suggest that presence of both TERTpm and TP53m may serve as a robust predictor of tumor recurrence and a marker of poor prognosis in HCC.

Immune infiltration landscape and potential drug-targeted implications for hepatocellular carcinoma with ‘progression/hyper-progression’ recurrence

Background and aims Hepatocellular carcinoma (HCC) recurrence was previously characterized into four types, and patients with progression/hyper-progression recurrence (type III–IV) have an extremely poor prognosis. However, the immune background of resectable HCC, particularly in patients who experience recurrence, remains underexplored. Therefore, this study aimed to describe the immune landscape of resectable HCC, especially postoperative type III–IV recurrent HCC, and explore potential immune-targeted anti-relapse strategies for treated populations. Methods The differences in gene expression in patients with recurrent HCC (type I–II (solitary or multi-intrahepatic oligo recurrence) vs. type III–IV) were investigated using bulk sequencing. Multiple immune infiltration methods (single-sample gene set enrichment analysis (GSEA), Microenvironment Cell Populations-counter and ESTIMATE) were used, and patients were divided into four groups to identify four distinct immune subtypes: immune-enrichment/matrix-poor (IE1), immune-enrichment/matrix-rich (IE2), immune intermediate/matrix-rich (ITM) and immune desert/matrix-poor (ID). Co-expression and protein interaction analyses were used to identify characteristic genes in ITM closely associated with type III–IV recurrence, which was matched with drug targets for Huaier granules (HG) and lenvatinib. Virtual docking was used to identify potential therapeutic targets, and the results were verified using single-nuclei RNA sequencing and histological analysis. Results ITM was closely related to type III–IV recurrence and exhibited immunotherapy potential. The potential efficacy of inhibiting CCNA2, VEGFA, CXCL8, PLK2, TIMP1, ITGB2, ALDOA, ANXA5 and CSK in ITM reversal was determined. Molecular docking demonstrated that the proteins of these genes could bind to HG or lenvatinib. The immunohistochemical findings demonstrated differential VEGFA (p < .01) and PLK2 (p < .001) expression in ITM type and ID in type III–IV recurrent HCC. Conclusions Three primary immunotypes of resectable HCC (IE2, ITM and ID) were identified, and HG and lenvatinib could potentially overcome immune checkpoint blockade (ICB) resistance in ITM patients with HCC, particularly those classified as type III–IV.

Association of LR treatment response category with outcome of patients with hepatocellular carcinoma on explant pathology.

Liver transplant (LT) is an effective treatment for hepatocellular carcinoma (HCC) in appropriately selected patients. Locoregional therapy (LRT) is often performed to extend a patient's eligibility for LT. Imaging has a modest sensitivity of approximately 40-77% for detecting pathologically viable HCC in post-LRT patients. The impact on overall survival (OS) and disease-free survival (DFS) is unclear. We hypothesize that Liver Imaging Reporting & Data Systems Treatment Response (LI-RADS TR) category is equivalently correlated with long-term survival and overall disease-free progression when compared to explant pathology findings. We additionally hypothesize that neoadjuvant LRT can improve OS and DFS in LT patients initially within MC. Patients found to have HCC on explant between January 2005 and December 2021 were included. A total of 167 patients were divided into treatment (any pre-LT LRT except for Y-90 therapy) and control (no pre-LT LRT) groups. Of the patients who received pre-LT LRT, imaging studies were reviewed by two abdominal radiologists using 2018 LI-RADS criteria. Statistical analysis was performed using Kaplan-Meier survival curves and Cox proportional hazard models to assess OS and DFS. No statistically significant difference in OS or DFS (p = 0.23 and p = 0.22 respectively) was initially found. Given significant difference in age between the groups (p < 0.0001), Cox proportional hazard models were used to adjust for age with statistical significance reached for better OS and DFS in the treatment group (p = 0.05 and p = 0.05 respectively). Contrary to our hypothesis, there was no difference between treatment response groups regarding overall survival or disease-free survival, presumably because of low number of HCC recurrences in our patient population (4%). Despite not reaching statistical significance, LI-RADS TR categorization demonstrates a good interreader agreement (Kappa 0.6), helping radiologists feel comfortable that modest sensitivity of the LI-RADS TR treatment response category for detecting pathologically active malignancy does not confer a negative clinical outcome.