HCC-related Death Research Articles

Hierarchically Positioning Laparoscopic Microwave Ablation in the Therapeutic Span of Early Hepatocellular Carcinoma: A Real-Life Comparative Analysis.

Laparoscopic microwave ablation (LMWA) has yet to gain a specific place in treatment guidelines for early hepatocellular carcinoma (HCC). This study compared the outcomes of LMWA and trans-arterial chemoembolization (TACE) for early non-resectable patients with HCC, taking percutaneous radiofrequency ablation (PRFA) as the reference treatment. A retrospective multicenter observational study was conducted, enrolling non-transplantable, non-resectable patients who had early HCC treated with LMWA (n = 658) from Padua and Milan centers, and with PRFA (n = 844), and TACE (n = 425) from the ITA.LI.CA multicenter database. The matching-adjusted indirect comparison (MAIC) method was used to obtain weighted LMWA and TACE populations similar to the reference PRFA population. Laparoscopic ablation showed an excellent safety profile, and MAIC-weighted early postoperative deaths were comparable among the groups. The MAIC-weighted overall survival was similar between the LMWA (1-, 3-, and 5year survival of 91.0 %, 67.9 %, 47.0 %, respectively) and PRFA (1-, 3- and 5year survivals of 90.0 %, 64.7 %, 46.6 %, respectively) groups (p = 0.678) and significantly better for the LMWA group than for the TACE group (1-, 3- and 5year survivals of 84.7 %, 48.8 %, 33.6 %, respectively) (p < 0.001). Weighted multivariate overall survival analysis and competing risk/subgroup analyses confirmed the non-inferiority of LMWA to PRFA and its superiority to TACE. The LMWA- and PRFA-treated patients had a significantly lower risk of HCC-related death (p = 0.004) than the TACE-treated patients (p = 0.001). Conversely, the groups did not differ significantly in terms of non-HCC-related deaths. The non-inferiority of LMWA to PRFA, its superiority to TACE, and its applicability to a wide range of presentations with few contraindications support its inclusion among radical therapies for treating early-HCC patients.

Trends in Hepatocellular Carcinoma Mortality Rates in the US and Projections Through 2040

ImportanceThe burden of liver cancer varies worldwide. An upward trend in both hepatocellular carcinoma (HCC) incidence and mortality in the past 2 decades has been observed.ObjectiveTo assess observed HCC-related age-standardized mortality rates (ASMRs) in the US for 2006 to 2022 and provide ASMR projections through 2040.Design, Setting, and ParticipantsThis cross-sectional study used data from the National Vital Statistics System, which is accessible through the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research website. Data on deaths attributed to HCC (from January 1, 2006, to December 31, 2022) were obtained for adults 25 years or older and were stratified by liver disease etiology, age, sex, and race and ethnicity. Etiologies included alcohol-associated liver disease (ALD), hepatitis B virus (HBV), hepatitis C virus (HCV), and metabolic dysfunction–associated steatotic liver disease (MASLD).Main Outcomes and MeasuresThe main outcomes were (1) observed ASMRs of HCC per 100 000 persons using Joinpoint regression (National Cancer Institute) to assess trends during 2006 to 2022 and (2) ASMRs projected for 2023 to 2040 using Prophet and AutoARIMA modeling.ResultsThis study included 188 280 HCC-related deaths from 2006 to 2022. Most deaths occurred among males (77.4%). The annual percentage change was 4.1% (95% CI, 2.2% to 7.7%) for 2006 to 2009 and decreased to 1.8% (95% CI, 0.7% to 2.0%) for 2009 to 2022, with an overall observed ASMR of 5.03 per 100 000 persons in 2022 and a projected ASMR of 6.39 per 100 000 persons by 2040, with consistent trends for both sexes. By etiology, ASMRs decreased for HCV- and HBV-related mortality but increased for ALD- and MASLD-related mortality. In 2022, MASLD surpassed HBV as the third-leading cause of HCC-related death and was projected to overtake HCV in 2032 as the second-leading cause; ALD was projected to be the leading cause of HCC-related death in 2026. In 2022, the ASMR was higher among individuals aged 65 years or older compared with those aged 25 to 64 years (18.37 vs 1.79 per 100 000 persons). The American Indian or Alaska Native population had the largest increase in projected ASMR by 2040 (14.71 per 100 000 persons) compared with the Asian population (3.03 per 100 000 persons).Conclusions and RelevanceIn this cross-sectional study, ASMRs for ALD- and MASLD-related HCC death increased rapidly from 2006 to 2022; ALD-related HCC was projected to be the leading cause by 2026, with MASLD as the second-leading cause by 2032. These findings may serve as a reference for public health decision-making and timely identification of groups at high risk of HCC death.

Changing spectrum and mortality disparities of etiology of liver cirrhosis in Beijing, China.

Liver cirrhosis remains a major health concern globally, but its epidemiology and etiology evolve with time. However, the changing pattern in etiology and cause of liver-related mortality for patients with cirrhosis are not fully elucidated. Herein, our aim was to characterize the temporal trend of the etiological spectrum and evaluate the impact of etiology on liver-related death among patients with compensated cirrhosis (CC) in Beijing, China. Clinical profiles of patients with CC discharged between January 2008 and December 2015 were retrieved from the Beijing hospital discharge database. The mortalities of different etiologies of cirrhosis were calculated. The risks of readmission and liver-related death associated with etiologies were evaluated by the Cox regression model. A total of 23 978 cirrhotic patients were included. The predominant cause was hepatitis B virus (HBV) (58.93%), followed by alcohol (21.35%), autoimmune (14.85%), miscellaneous etiologies (3.55%), and hepatitis C virus (HCV) (1.32%). From 2008 to 2015, the proportion of HBV-related cirrhosis decreased to 28.11%. Meanwhile, the proportions of autoimmune- and miscellaneous-related cirrhosis increased to 28.54% and 13.11%. The risk of liver-related death ranked the highest in patients with miscellaneous cirrhosis, followed by HBV-related cirrhosis, alcohol-related cirrhosis, autoimmune-related cirrhosis, and HCV-related cirrhosis. The 5-year rates of liver-related death were 22.56%, 18.99%, 18.77%, 16.01%, and 10.76%, respectively. HBV-related cirrhosis caused the highest risk of hepatocellular carcinoma (HCC)-related death, whereas alcohol- and miscellaneous-related cirrhosis caused higher risks of decompensation (DC)-related death than HBV-related cirrhosis, with hazard ratios of 1.35 (95% confidence interval [CI]: 1.24-1.48) and 1.20 (95% CI: 1.03-1.40), respectively. HBV remained a common cause of liver cirrhosis but gradually decreased. Mortality disparities existed in etiologies, with higher risks of HCC-related death in HBV-related cirrhosis, and DC-related death in alcohol- and miscellaneous-related cirrhosis.

Hepatocellular carcinoma surveillance - utilization, barriers and the impact of changing aetiology.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Surveillance for HCC is critical for early detection and treatment, but fewer than one-quarter of individuals at risk of HCC undergo surveillance. Multiple failures across the screening process contribute to the underutilization of surveillance, including limited disease awareness among patients and health-care providers, knowledge gaps, and difficulty recognizing patients who are at risk. Non-alcoholic fatty liver disease and alcohol-associated liver disease are the fastest-rising causes of HCC-related death worldwide and are associated with unique barriers to surveillance. In particular, more than one-third of patients with HCC related to non-alcoholic fatty liver disease do not have cirrhosis and therefore lack a routine indication for HCC surveillance on the basis of current practice guidelines. Semi-annual abdominal ultrasound with measurement of α-fetoprotein levels is recommended for HCC surveillance, but the sensitivity of this approach for early HCC is limited, especially for patients with cirrhosis or obesity. In this Review, we discuss the current status of HCC surveillance and the remaining challenges, including the changing aetiology of liver disease. We also discuss strategies to improve the utilization and quality of surveillance for HCC.

Plasma Antithrombin III Levels Can Be a Prognostic Factor in Liver Cirrhosis Patients with Portal Vein Thrombosis.

Liver function influences the plasma antithrombin (AT)-III levels. AT-III is beneficial for patients with portal vein thrombosis (PVT) and low plasma AT-III levels. However, whether these levels affect prognosis in patients with cirrhosis-associated PVT remains unknown. This retrospective study involved 75 patients with cirrhosis and PVT treated with danaparoid sodium with or without AT-III. The plasma AT-III level was significantly lower in patients with liver failure-related death than in those with hepatocellular carcinoma (HCC)-related death (p = 0.005), although the Child-Pugh and albumin-bilirubin (ALBI) scores were not significantly different between these two groups. Receiver operating characteristic curve analysis of the plasma AT-III levels showed cutoff values of 54.0% at 5-year survival. Low plasma AT-III levels (<54.0%) were associated with significantly worse prognosis than high levels in both overall survival (p = 0.0013) and survival excluding HCC-related death (p < 0.0001). Low plasma AT-III (<54.0%) was also associated with a significantly worse prognosis among patients with Child-Pugh A/B or ALBI grade 1/2 (p < 0.0001). Multivariate analyses indicated that low plasma AT-III levels (<54.0%) were an independent prognostic factor for poor survival outcome. Low plasma AT-III levels may be associated with mortality, particularly liver failure-related death, independent of liver function.

Overall Survival Rates Become Similar Between Percutaneous Ablation and Hepatic Resection With Increasing Age Among Elderly Patients With Early Hepatocellular Carcinoma

This study aimed to investigate the efficacy and safety of percutaneous ablation versus hepatectomy in an elderly population with hepatocellular carcinoma (HCC).Retrospective data on patients aged ≥ 65 years with very-early/early stages of HCC (≤ 50 mm) were obtained from three centers in China. Inverse probability of treatment weighting analysis was performed after stratifying the patients by age (65 - 69, 70 - 74 and ≥ 75 years).Of the 1,145 patients, 561 and 584 underwent resection and ablation, respectively. For patients aged 65 - 69 and 70 - 74 years, resection resulted in significantly better overall survival (OS) than ablation (age 65 - 69, P < 0.001, hazard ratio (HR) = 0.27; age 70 - 74, P = 0.012, HR = 0.64). However, in patients aged ≥ 75 years, resection and ablation resulted in a similar OS (P = 0.44, HR = 0.84). An interactive effect existed between treatment and age (effect of treatment on OS, age 65 - 69 as the reference, for age 70 - 74, P = 0.039; for age ≥ 75, P = 0.002). The HCC-related death rate was higher in patients aged 65 - 69, and the liver/other cause-related death rate was higher in patients aged > 69. Multivariate analyses showed that the type of treatment, number of tumors, α-fetoprotein level, serum albumin level and associated diabetes mellitus were independent factors associated with OS, but not hypertension or heart diseases.With increasing patient age, the treatment outcomes of ablation become similar to those of resection. A higher liver/other cause-related death rate in very elderly patients may shorten the life expectancy, which may lead to the same OS regardless of whether resection or ablation is chosen.

The Combination of AFP and "Up-To-Seven" Criteria May Be a Better Strategy for Liver Transplantation in Chinese Cirrhotic HCC Patients.

BackgroundOrthotopic liver transplantation (OLT) is a life-saving option for patients with hepatocellular carcinoma (HCC), but the expanded OLT criteria remain controversial.ObjectiveThe study aimed to explore whether expanded OLT criteria can be applied to Chinese cirrhotic patients with HCC.MethodsThis retrospective study analyzed risk factors for HCC recurrence and death and compared patients’ tumor characteristics and outcomes in groups of Milan, “Up-to-seven,” and Hangzhou criteria, and groups between met and unmet the combinative criteria of “Up-to-seven” and AFP of < 1000 ng/mL.ResultsAmong 153 patients who underwent OLT for HCC from January 2015 to February 2019 in 4 years of follow-up, 20 (13.1%) patients had HCC recurrence, and 11 (7.2%) had HCC-related death. Multivariate Cox regression analysis showed that preoperative alpha-fetoprotein (AFP) of > 1000 ng/mL (hazard ratio [HR]: 10.05, 95% confidence interval [CI]: 2.45–41.13, P = 0.001) was an independent risk factor for HCC recurrence and HCC-related death (HR: 6.63, 95%CI: 1.31–33.52, P = 0.022). Patients who did not meet Milan criteria but satisfied the “Up-to-seven” criteria had no differences in overall survival (OS) (P = 0.69) and disease-free survival (DFS) (P = 0.35) than patients who met the Milan criteria. The combination of “Up-to-seven” criteria and AFP of < 1000 ng/mL differed significantly (HR: 18.9; 95% CI: 4.0–89.2; P < 0.001). Patients with HCC who met the “Up-to-seven” criteria and AFP of < 1000 ng/mL (n = 121) had excellent survival with 4-year OS of 91.6% (P < 0.001) and DFS of 90.8% (P < 0.001), which is significantly better compared to the other group (n = 32) (OS of 67.5% and DFS of 46.5%) and patients who met the Milan criteria (n = 108, OS of 89.8%, DFS of 89.6%), allowing 28.9% (13/45) of patients who did not meet the Milan criteria to benefit from OLT.ConclusionChinese cirrhotic patients with HCC who met the combinative criteria of “Up-to-seven” and AFP of < 1000 ng/mL had better survival than those who met the Milan criteria, and these combinative criteria benefited more patients and may become a better option for OLT.

DYRK1A reinforces epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma via cooperatively activating STAT3 and SMAD

BackgroundHepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases, while metastasis is considered the leading cause of HCC-related death. However, the currently available treatment strategies for efficient suppression of metastasis are limited. Therefore, novel therapeutic targets to inhibit metastasis and effectively treat HCC are urgently required.MethodsWound healing and Transwell assays were used to determine the migration and invasion abilities of HCC cells in vitro. Quantitative real-time PCR (qRT-PCR), protein array, immunofluorescence, and immunoprecipitation experiments were used to study the mechanism of DYRK1A-mediated metastasis. A tail vein metastasis model and H&E staining were utilized to assess metastatic potential in vivo.ResultsThe results of the current study demonstrated that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) was upregulated in HCC tissues compared with normal liver tissues. Additionally, the level of DYRK1A was increased in primary HCC tissues of patients with metastasis compared with those of patients without metastasis, and DYRK1A overexpression correlated with worse outcomes in liver cancer patients. Gain- and loss-of-function studies suggested that DYRK1A enhanced the invasion and migration abilities of HCC cells by promoting epithelial-mesenchymal transition (EMT). Regarding the promoting effect of DYRK1A on cell invasion, the results showed that DYRK1A was coexpressed with TGF-β/SMAD and STAT3 signalling components in clinical tumour samples obtained from patients with HCC. DYRK1A also activated TGF-β/SMAD signalling by interacting with tuberous sclerosis 1 (TSC1) and enhanced metastasis of HCC cells by activating STAT3. Furthermore, DYRK1A promoted EMT by cooperatively activating STAT3/SMAD signalling.ConclusionOverall, the present study not only uncovered the promoting effect of DYRK1A on HCC metastasis and revealed the mechanism but also provided a new approach to predict and treat metastatic HCC.

Prognostic Factors for 10-Year Survival in Patients With Hepatocellular Cancer Receiving Liver Transplantation.

BackgroundLong-term survival after liver transplantation (LT) for hepatocellular cancer (HCC) continues to increase along with the modification of inclusion criteria. This study aimed at identifying risk factors for 5- and 10-year overall and HCC-specific death after LT.MethodsA total of 1,854 HCC transplant recipients from 10 European centers during the period 1987–2015 were analyzed. The population was divided in three eras, defined by landmark changes in HCC transplantability indications. Multivariable logistic regression analyses were used to evaluate the significance of independent risk factors for survival.ResultsFive- and 10-year overall survival (OS) rates were 68.1% and 54.4%, respectively. Two-hundred forty-two patients (13.1%) had HCC recurrence. Five- and 10-year recurrence rates were 16.2% and 20.3%. HCC-related deaths peaked at 2 years after LT (51.1% of all HCC-related deaths) and decreased to a high 30.8% in the interval of 6 to 10 years after LT. The risk factors for 10-year OS were macrovascular invasion (OR = 2.71; P = 0.001), poor grading (OR = 1.56; P = 0.001), HCV status (OR = 1.39; P = 0.001), diameter of the target lesion (OR = 1.09; P = 0.001), AFP slope (OR = 1.63; P = 0.006), and patient age (OR = 0.99; P = 0.01). The risk factor for 10-year HCC-related death were AFP slope (OR = 4.95; P < 0.0001), microvascular (OR = 2.13; P < 0.0001) and macrovascular invasion (OR = 2.32; P = 0.01), poor tumor grading (OR = 1.95; P = 0.001), total number of neo-adjuvant therapies (OR = 1.11; P = 0.001), diameter of the target lesion (OR = 1.11; P = 0.002), and patient age (OR = 0.97; P = 0.001). When analyzing survival rates in function of LT era, a progressive improvement of the results was observed, with patients transplanted during the period 2007–2015 showing 5- and 10-year death rates of 26.8% and 38.9% (vs. 1987–1996, P < 0.0001; vs. 1997–2006, P = 0.005).ConclusionsLT generates long-term overall and disease-free survival rates superior to all other oncologic treatments of HCC. The role of LT in the modern treatment of HCC becomes even more valued when the follow-up period reaches at least 10 years. The results of LT continue to improve even when prudently widening the inclusion criteria for transplantation. Despite the incidence of HCC recurrence is highest during the first 5 years post-transplant, one-third of them occur later, indicating the importance of a life-long follow-up of these patients.

Hepatocellular Carcinoma-Related Mortality in the USA, 1999-2018.

The burden of hepatocellular carcinoma (HCC) is increasing, and certain groups may be at higher risk. We analyzed trends in HCC-related mortality in the USA (1999-2018) using national death data. Age-adjusted trends in death rates (annual percentage change, APC) were calculated using joinpoint regression analysis. HCC-related death rates increased by 2.1% (95% CI 1.9 to 2.3) annually. Hepatitis C (HCV)-related HCC death rates increased from 1999 to 2012 (8.9%, 95% CI 7.6 to 10.2) followed by a -1.3% (95% CI -3.5 to 0.9) decrease annually. For adults > 65years, HCV-related HCC death rates increased (7.3% annually, 95% CI 6.5 to 8.1), especially for rural areas (11.1% annually, 95% CI 6.9 to 15.5) with high rates among African-Americans and Hispanics. Increases in non-HCV-related HCC death rates were larger: 13.5% annually (95% CI 3.6 to 24.3, 2005-2010) followed by 4.2% annually (95% CI 2.3 to 6.2, 2010-2018). Annual rates of increase were similar for men (6.8%, 95% CI 5.9 to 7.8) and women (7.0%, 95% CI 5.5 to 8.4) from 1999 to 2018. Rate of increase across races was Whites 8.3% (95% CI 7.2 to 9.4, 1999-2018), African-Americans 11.2% (95% CI -6.6 to 32.3, 2015-2018), and Hispanics 3.7% (95% CI 1.0 to 6.5, 2012-2018). HCC-related mortality has increased, driven by increases in non-HCV-related mortality with important demographic and regional trends. In addition, HCV-HCC mortality remains high particularly in older persons and those in rural areas despite advances in HCV therapy. These data underscore the need for targeted approaches to mitigate the burden of HCC-related mortality similar to efforts for other cancers.

Effect of age on the short- and long-term outcomes of patients undergoing curative liver resection for HCC

BackgroundFew studies have evaluated the outcomes of curative liver resection (LR) in octogenarian patients, analysed cancer-specific survival (CSS) with HCC-related death or explored the age-varying effect of HCC-related death in elderly patients undergoing LR. We aim to determine the effect of age on the short and long-term outcomes of LR for HCC. MethodologyBetween 2000 and 2018, 1,092 patients with primary HCC who underwent LR with curative intent were retrospectively reviewed. The log-rank test and Gray's test were used to assess the equality of survivor functions and competing risk-adjusted cumulative incidence functions between patients in the three age categories respectively. Regression adjustment was used to control for confounding bias via a Principal Component Analysis. Quantile, Firth logistic, Cox, and Fine-Gray competing risk regression were used to analyse continuous, binary, time-to-event, and cause-specific survival respectively. Restricted cubic splines were used to illustrate the dose-effect relationship between age and patient outcomes. ResultsThe study comprised of 764 young patients (<70 years), 278 septuagenarians (70–79 years old) and 50 octogenarians (≥80 years). Compared to young patients, octogenarians had significantly lower 5-year OS(62.1% vs 37.7%, p < 0.001). However, there was no significant difference in 1-year RFS(73.1% vs 67.0%, p = 0.774) or 5-year CSS (5.4% vs 15.2%, p = 0.674). Every 10-year increase in age was significantly associated with an increase length of stay (p < 0.001), postoperative complications (p = 0.004) and poorer OS(p = 0.018) but not significantly associated with major complications (p = 0.279), CSS(p = 0.338) or RFS(p = 0.941). ConclusionAge by itself was associated with OS after LR for HCC but was not a significant risk factor for HCC-related death.

Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002–2033: the ITA.LI.CA database

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to...

HCC in the Era of Direct-Acting Antiviral Agents (DAAs): Surgical and Other Curative or Palliative Strategies in the Elderly.

Simple SummaryThis study investigated HCC onset in a cohort of patients receiving DAA therapy for HCV infection. It highlights that HCC onset after HCV-clearance might show more aggressive behavior and might exclude the patient from curative treatments, such as surgery or radiofrequency ablation. Moreover, HCC may develop in livers with mild to moderate fibrosis, indicating that multiple factors (host immune response, host metabolism, etc.) may play an important role in determining the cancer onset or its recurrence after HCV eradication. It is crucial to classify long-term chronically infected patients as at high risk for HCC development and to implement strict follow-up for them after eradication.Hepatocellular carcinoma (HCC) accounts for 75–85% of primary liver malignancies, and elderlies have the highest incidence rates. Direct-acting antiviral agents (DAAs) have shown satisfying results in terms of HCV sustained viral response (SVR). However, data regarding HCC risk post-DAA-SVR is still conflicting. This study aims to consider HCC onset in moderate underlying liver disease. We conducted a retrospective study on 227 chronically infected patients (cHCV), treated with DAAs. Patients were divided into three groups: “de novo occurrent HCC”, “recurrent HCC”, and “without HCC”. Fifty-six patients aged <65 years (yDAA) were studied separately. HCC patients aged ≥65 years (DAA-HCC) were compared to a historical group of 100 elderly HCC patients, treated with peginterferon (Peg-IFN) ± ribavirin antiviral agents, non-SVR (hHCC). The HCC prevalence in DAA patients was 32.75%: “de novo occurrent’’ 18.13% and “recurrent’’ 14.62%, despite 42.85% of them having no fibrosis to mild or moderate fibrosis (F0-F1-F2). yDAA showed 5.36% “de novo occurrent” HCC. Curative procedure rates were compared between DAA-HCC and hHCC at the first and at recurrent presentation (22 (39.29%) vs. 72 (72%); 17 (30.36%) vs. 70 (70%), respectively (p < 0.001)). No significant difference was found in 3-year OS (p = 0.6). However, in cause-specific mortality analysis, HCC-related death was higher in the DAA-treated group, whereas cirrhosis-related death was more common in the historical group (p = 0.0288), considering together the two causes of death. A more accurate patient stratification according to multifactorial and new diagnostic investigations identifying HCC risk might allow an improvement in management and access to curative therapies.

The Impact of Time Interval between Hepatic Resection and Liver Transplantation on Clinical Outcome in Patients with Hepatocellular Carcinoma.

Simple SummaryRecurrence of disease or worsening of liver function after hepatic resection (HR) for hepatocellular carcinoma (HCC) may require secondary liver transplantation (SLT). However, a history of HR is supposed to increase the surgical complexity of LT. This is one of the largest series of SLT and it demonstrates that among all the features analyzed regarding the prior HR, only time interval between HR and SLT was an independent predictor of severe complications after SLT. In particular, an increasing probability of severe complications was observed in those patients who were transplanted close (<15 months) to the HR. There was no significant association between HCC-related death and the time between HR and SLT at the multivariable competing risks regression model. Furthermore, these results remained inside the benchmark values recently reported for LT, confirming that tertiary referral centers with consistent experience in HPB surgery and LT may have benefits in both fields.Hepatic resection (HR) for hepatocellular carcinoma (HCC) may require secondary liver transplantation (SLT). However, a previous HR is supposed to worsen post-SLT outcomes. Data of patients treated by SLT between 2000 and 2018 at two tertiary referral centers were analyzed. The primary outcome of the study was to analyze the impact of HR on post-LT complications. A Comprehensive Complication Index ≥ 29.6 was chosen as cutoff. The secondary outcome was HCC-related death by means of competing-risk regression analysis. In the study period, 140 patients were included. Patients were transplanted in a median of 23 months after HR (IQR 14–41). Among all the features analyzed regarding the prior HR, only time interval between HR and SLT (time HR-SLT) was an independent predictor of severe complications after LT (OR = 0.98, p < 0.001). According to fractional polynomial regression, the probability of severe complications increased up to 15 months after HR (43%), then slowly decreased over time (OR = 0.88, p < 0.001). There was no significant association between HCC-related death and time HR-SLT at the multivariable competing risks regression model (SHR, 1.06; 95% CI: 0.69–1.62, p = 0.796). This study showed that time HR-SLT was key in predicting complications after LT, without affecting HCC-related death.

Blood Salvage and Autotransfusion With Single Leukoreduction Does Not Increase the Risk of Tumor Recurrence After Liver Transplantation for Advanced Hepatocellular Carcinoma.

The aim of this study was to determine whether autotransfusion of salvaged blood with single leukoreduction is associated with post-transplant tumor recurrence in patients with advanced hepatocellular carcinoma (HCC). Previous studies have consistently demonstrated the safety of autotransfusion of salvaged and leukoreduced blood during liver transplantation for HCC. However, the effects of this technique remained unknown for advanced HCC. Of 349 patients who underwent living donor liver transplantation for advanced HCC: 74 of 129 without autotransfusion were matched with 74 of 220 with autotransfusion using propensity score based on tumor biology, allogeneic transfusion, and others. Survival analysis was performed with death as a competing risk event. The primary outcome was HCC recurrence. Recipients in autotransfusion group received 811 (497-1247) mL of salvaged blood with single leukoreduction. In the matched cohort, cumulative overall recurrence probability at 1/2/5 years after transplantation was 24.6%/ 38.3%/39.7% for nonautotransfusion group and 16.2%/23.1%/32.5% for autotransfusion group. There were no significant differences between the 2 groups in overall recurrence [hazard ratio (HR) = 0.72 (0.43-1.21)], intrahepatic recurrence [HR = 0.70 (0.35-1.40)], and extrahepatic recurrence [HR = 0.82 (0.46-1.47)]. Also, there were no significant differences in overall death [HR = 0.57 (0.29-1.12)], HCC-related death [HR = 0.59 (0.29-1.20)], and HCC-unrelated death [HR = 0.48 (0.09-2.65)]. When allogeneic transfusion was matched, autotransfusion was not significantly related to HCC recurrence, with more favorable probabilities for autotransfusion, in patients with advanced HCC. Thus, blood salvage and autotransfusion could be safely used with single leukoreduction, without double-filtered leukoreduction, during liver transplantation for HCC with potential benefits from avoiding allogeneic red blood cell transfusion.

Liver resection in elderly patients with hepatocellular carcinoma: age does matter.

Increasing proportions of elderly patients with hepatocellular carcinoma (HCC) requiring oncological treatment have been noted. We aim to evaluate the impact of elderly age on outcomes of liver resection (LR) for HCC. This retrospective study enrolled 1004 patients with HCC who underwent curative LR in our institution from 2007 to 2017, dividing them into three groups according to age (18-59years, n = 461; 60-74years, n = 447; ≥ 75years, n = 96). Elderly patients were defined as those ≥ 75years old. Outcomes were then compared among the three groups, with a multivariate competing risk model used to estimate cause-specific subdistribution hazard ratios (SHRs) for HCC- and non-HCC-related deaths. The OS was significantly lower in the elderly than younger patients. However, recurrence-free survival was similar among the three groups. The cumulative incidence of HCC-related death was similar among the three groups; however, the cumulative incidence of non-HCC-related death was significantly higher in the elderly than younger patients. Moreover, the multivariate analysis showed that elderly age was not an independent variable associated with HCC-related death. However, elderly age was an independent variable associated with non-HCC-related death. The 60-year SHR for non-HCC-related death increased with increasing age. The elderly patients had significantly worse OS after LR than the younger patients, possibly due to the cumulative incidence of non-HCC-related death being significantly higher among the elderly than among the younger patients. Elderly patients should be more stringently selected for LR.

Posttransplant Outcomes in Older Patients With Hepatocellular Carcinoma Are Driven by Non-Hepatocellular Carcinoma Factors.

The incidence of hepatocellular carcinoma (HCC) is growing in the United States, especially among the elderly. Older patients are increasingly receiving transplants as a result of HCC, but the impact of advancing age on long-term posttransplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium of 4980 patients. We divided the patients into 4 groups by age at transplantation: 18 to 64 years (n=4001), 65 to 69 years (n=683), 70 to 74 years (n=252), and ≥75years (n=44). There were no differences in HCC tumor stage, type of bridging locoregional therapy, or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic, and cancer-related factors on multivariable analysis. A dose-response effect of age on survival was observed, with every 5-year increase in age older than 50years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non-HCC-related mortality (P=0.004), and not HCC-related death (P=0.24). To delineate the precise cause of death, we further analyzed a single-center cohort of patients who received a transplant as a result of HCC (n=302). Patients older than 65years had a higher incidence of de novo cancer (18.1% versus 7.6%; P=0.006) after transplantation and higher overall cancer-related mortality (14.3% versus 6.6%; P=0.03). Even carefully selected elderly patients with HCC have significantly worse posttransplant survival rates, which are mostly driven by non-HCC-related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve the outcomes in elderly patients who received a transplant as a result of HCC.

A Machine Learning Approach Yields a Multiparameter Prognostic Marker in Liver Cancer.

A number of staging systems have been developed to predict clinical outcomes in hepatocellular carcinoma (HCC). However, no general consensus has been reached regarding the optimal model. New approaches such as machine learning (ML) strategies are powerful tools for incorporating risk factors from multiple platforms. We retrospectively reviewed the baseline information, including clinicopathologic characteristics, laboratory parameters, and peripheral immune features reflecting T-cell function, from three HCC cohorts. A gradient-boosting survival (GBS) classifier was trained with prognosis-related variables in the training dataset and validated in two independent cohorts. We constructed a 20-feature GBS model classifier incorporating one clinical feature, 14 laboratory parameters, and five T-cell function parameters obtained from peripheral blood mononuclear cells. The GBS model-derived risk scores demonstrated high concordance indexes (C-indexes): 0.844, 0.827, and 0.806 in the training set and validation sets 1 and 2, respectively. The GBS classifier could separate patients into high-, medium- and low-risk subgroups with respect to death in all datasets (P < 0.05 for all comparisons). A higher risk score was positively correlated with a higher clinical stage and the presence of portal vein tumor thrombus (PVTT). Subgroup analyses with respect to Child-Pugh class, Barcelona Clinic Liver Cancer stage, and PVTT status supported the prognostic relevance of the GBS-derived risk algorithm independent of the conventional tumor staging system. In summary, a multiparameter ML algorithm incorporating clinical characteristics, laboratory parameters, and peripheral immune signatures offers a different approach to identify patients with the greatest risk of HCC-related death.

A comparison of factors associated with the temporal improvement in the overall survival of BCLC stage 0 hepatocellular carcinoma patients

BackgroundIt is uncertain whether the prognosis of Barcelona Clinical Liver Cancer (BCLC) stage 0 hepatocellular carcinoma (HCC) has improved. AimsTo evaluate whether the outcomes of BCLC stage 0 patients has improved, and if so, what are the reasons behind the noted improved outcome. MethodsA total of 591 patients with BCLC stage 0 HCC diagnosed at Samsung Medical Center, Seoul, Korea were grouped based on year of diagnosis (earlier cohort; 2007–2009 and later cohort; 2013–2015) and compared. ResultsThe overall survival (OS) was improved for BCLC stage 0 patients at later cohort (5-year survival rate: 82.1% vs. 92.0% for earlier cohort and later cohort, p = 0.015). However, after adjustment, the treatment period was not an independent factor for OS, especially when the albumin-bilirubin (ALBI) grade was adjusted. The incidence of liver cirrhosis (LC)-related death was increased from 10.4% to 33.3%, while the incidence of HCC-related death decreased from 57.5% to 28.6% in the latter cohort. ConclusionsThe survival improvement of BCLC stage 0 patients was largely explained by better liver function at diagnosis. Mortality from LC-related death was increasing, which calls for careful attention for finding strategies for preserving the liver function for BCLC stage 0 patients.

From the Editor's Desk…

From the Editor's Desk…