DEB-TACE versus cTACE for unresectable HCC with B1-type bile duct invasion after successful biliary drainage: A propensity score matching analysis.

BACKGROUND: Transarterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Given the lack of specific recommendations for conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE) in patients having unresectable HCC with tumor infiltrating the common hepatic duct or the first-order branch of the bile ducts (B1-type bile duct invasion; B1-BDI) after biliary drainage, we retrospectively compared the safety and efficacy of DEB-TACE with cTACE in this patient population. MATERIALS AND METHODS: Using data from five tertiary medical centers (January 2017-December 2021), we compared complications, overall survival (OS), time to progression (TTP), and tumor response rate between patients having unresectable HCC with B1-BDI who underwent DEB-TACE or cTACE after successful biliary drainage. X-tile software calculated the pre-TACE total bilirubin (TBil) cutoff value, indicating optimal timing for sequential TACE after drainage. Propensity score matching (PSM) was performed. RESULTS: The study included 108 patients with unresectable HCC (B1-BDI) who underwent DEB-TACE and 114 who received cTACE as initial treatment. After PSM (n = 53 for each group), the DEB-TACE group had a longer TTP (8.9 vs. 6.7 months, p = 0.038) and higher objective response rate (64.2% vs. 39.6%, p = 0.011) than did the cTACE group, although OS was comparable (16.7 vs. 15.3 months, p = 0.115). The DEB-TACE group exhibited fewer post-procedural increments in the mean albumin-bilirubin score, TBil, and alanine aminotransferase (ALT), along with a significantly lower incidence of serious adverse events within 30 days (hepatic failure, ALT increase, and TBil increase) than the cTACE group (all p < 0.05). The pre-TACE TBil cutoff value was 99 µmol/L; patients with higher values (>99 µmol/L) had poorer OS in both groups (p < 0.05). CONCLUSION: DEB-TACE is safe and effective after successful biliary drainage in unresectable HCC with B1-BDI, potentially better than cTACE in terms of liver toxicity, TTP, and ORR. Lowering TBil below 99 µmol/L through successful drainage may create ideal conditions for sequential TACE.

Association of modifiable metabolic risk factors and lifestyle with all-cause mortality in patients with hepatocellular carcinoma.

We aimed to investigate the potential impact of metabolic risk factors and lifestyles on mortality in hepatocellular carcinoma (HCC) patients. From the Korean Central Cancer Registry database (2008-2016), 8,505 HCC patients were included in the analysis. Patients with 2 or more metabolic risk factors (n = 2384, 28.0%) showed significantly worse overall survival (OS, 29 months, 95% confidence interval [CI] 27-33) than patients with 0 (n = 2269 [26.7%]; 41 months, 95% CI 37-47), or 1 (n = 3852 [45.3%]; 42 months; 95% CI 38-46) metabolic risk factor. (P < 0.001) In the multivariable Cox analysis, patients with ≥ 2 metabolic risk factors had significantly elevated risk of overall mortality (adjusted hazards ratio (HR) = 1.14 [95% CI 1.06-1.23], P < 0.001) and HCC-specific mortality (sub-distribution HR = 1.09 [95% CI 1.00-1.09], P = 0.046), compared to those without. Alcohol and smoking were also independent risk factors for worse overall and HCC-specific mortality (all P < 0.05). Metabolic comorbidities were associated with greater risk of mortality in a dose-dependent manner in HCC patients, regardless of tumor stage and liver function. Alcohol intake and smoking significantly increased mortality by themselves and even further with the presence of metabolic risk.

Hepatocellular carcinoma outcomes and potential implications for surveillance in elderly patients.

International liver societies recommend hepatocellular carcinoma (HCC) surveillance for those at high-risk of developing HCC. While previous studies have shown the benefits of surveillance for middle-aged patients, but its necessity for elderly patients is unclear. This study aimed to assess the benefits of HCC surveillance in the elderly by comparing diagnosis mode of HCC. Consecutive, elderly patients aged 75 years or older who were newly diagnosed with HCC were screened at our institution between January 2009 and December 2021. Patients were grouped into those who were diagnosed with HCC during surveillance (n = 235, surveillance group) and those who were diagnosed with HCC due to symptoms (n = 184, symptomatic group). The study outcome was overall survival. It was compared in the overall cohort and a propensity score (PS)-matched cohort. Early-stage diagnosis was more frequent in the surveillance group than in the symptomatic group (mUICC stage I/II: 72.3% vs. 39.1%, p < 0.001). The overall survival rate was better in the surveillance group than in the symptomatic group (median 4.4 vs. 2.1 years, log-rank p < 0.001). In multivariable-adjusted models, the hazard ratio (HR) of mortality of the surveillance group compared to the symptomatic group was 0.64 (95% confidence interval (CI): 0.47-0.87). However, further adjustment for the tumor stage markedly attenuated this association, which was no longer statistically significant (adjusted HR = 0.75; 95% CI: 0.54-1.02). In the PS-matched cohort analysis, outcomes were similar when the PS matching variables included the tumor stage. In contrast, when PS matching variables did not include the tumor stage, outcomes were better for the surveillance group. The surveillance group of elderly patients showed better survival than the symptomatic group, which was largely explained by earlier tumor stage at diagnosis. This suggests that the overall outcome of elderly HCC patients could be improved by increasing surveillance-detected cases compared to symptom-driven cases.

Construction and validation of prognostic signature for transcription factors regulating T cell exhaustion in hepatocellular carcinoma.

In the tumor microenvironment (TME), CD8+ T cells showed stage exhaustion due to the continuous stimulation of tumor antigens. To evaluate the status of CD8+ T cells and reverse the exhaustion is the key to evaluate the prognosis and therapeutic effect of tumor patients. The aim of this study was to establish a prognostic signature that could effectively predict prognosis and response to immunotherapy in patients with hepatocellular carcinoma (HCC). We used univariate Cox analysis to obtain transcription factors associated with CD8+ T cell exhaustion from The Cancer Genome Atlas dataset. Then, the prognostic signature for transcription factors basic leucine zipper ATF-like transcription factor, Eomesodermin, and T-box protein 21 regulating T cell exhaustion was constructed using LASSO Cox regression. The relative expression levels of the mRNA of the 3 transcription factors were detected by reverse transcription-quantitative polymerase chain reaction in 23 pairs of HCC and paracancer tissues, and verified internally in The Cancer Genome Atlas dataset and externally in the International Cancer Genome Consortium dataset. Cox regression analysis showed that risk score was an independent prognostic variable. The overall survival of the high-risk group was significantly lower than that of the low-risk group. The low-risk group had higher immune scores, matrix scores, and ESTIMATE scores, and significantly increased expression levels of most immune checkpoint genes in the low-risk group. Therefore, patients with lower risk scores benefit more from immunotherapy. The combination of the 3 transcription factors can evaluate the exhaustion state of CD8+ T cells in the TME, laying a foundation for evaluating the TME and immunotherapy efficacy in patients with HCC.

The impact of surging transplantation of alcohol-associated liver disease on transplantation for HCC and other indications.

BACKGROUND: Liver transplantation (LT) for alcohol-associated liver disease (ALD) is increasing and may impact LT outcomes for patients listed for HCC and other indications. METHODS: Using US adults listed for primary LT (grouped as ALD, HCC, and other) from October 8, 2015, to December 31, 2021, we examined the impact of center-level ALD LT volume (ATxV) on waitlist outcomes in 2 eras: Era 1 (6-month wait for HCC) and Era 2 (MMaT-3). The tertile distribution of ATxV (low to high) was derived from the listed candidates as Tertile 1 (T1): <28.4%, Tertile 2 (T2): 28.4%-37.6%, and Tertile 3 (T3): >37.6% ALD LTs per year. Cumulative incidence of waitlist death and LT within 18 months from listing by LT indication were compared using the Gray test, stratified on eras and ATxV tertiles. Multivariable competing risk regression estimated the adjusted subhazard ratios (sHRs) for the risk of waitlist mortality and LT with interaction effects of ATxV by LT indication (interaction p). RESULTS: Of 56,596 candidates listed, the cumulative waitlist mortality for those with HCC and other was higher and their LT probability was lower in high (T3) ATxV centers, compared to low (T1) ATxV centers in Era 2. However, compared to ALD (sHR: 0.92 [0.66-1.26]), the adjusted waitlist mortality for HCC (sHR: 1.15 [0.96-1.38], interaction p = 0.22) and other (sHR: 1.13 [0.87-1.46], interaction p = 0.16) were no different suggesting no differential impact of ATxV on the waitlist mortality. The adjusted LT probability for HCC (sHR: 0.89 [0.72-1.11], interaction p = 0.08) did not differ by AtxV while it was lower for other (sHR: 0.82 [0.67-1.01], interaction p = 0.02) compared to ALD (sHR: 1.04 [0.80-1.34]) suggesting a differential impact of ATxV on LT probability. CONCLUSIONS: The high volume of LT for ALD does not impact waitlist mortality for HCC and others but affects LT probability for other in the MMAT-3 era warranting continued monitoring.

Outcomes of hepatocellular carcinoma patients treated in the lenvatinib and immunotherapy era (2018-2021) compared to the sorafenib era (2008-2018).

BACKGROUND: Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these landmark trials, sorafenib (SOR) served as the standard first-line treatment for a decade. Our study aimed to assess the outcomes of HCC patients treated during the SOR era (2008-2018) in contrast to those in the post-SOR era (2018-2021), of which the predominant first-line treatments were LEN or A + B. METHODS: Inclusion criteria of the study were all HCC patients in the Canadian province of Alberta who started first-line systemic therapy at cancer centers between 1 January 2008 and 31 December 2021. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), along with clinician-assessed response rate (RR), were subject to retrospective analysis. RESULTS: Of 372 total patients, 230 received treatment in the SOR era and 142 in the post-SOR era. The demographic and clinical characteristics for the SOR era and post-SOR era groups are as follows, respectively: the median age was 63 and 64 years, 80% and 81% were male, and 24% and 11% were of East Asian ethnicity. Before receiving systemic treatment, 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT in the two eras, respectively. In the post-SOR era, patients received A + B (23%), LEN (51%), and SOR (23%) as first-line treatment. There was a statistically significant improvement in RR (15% vs. 26%; p = 0.02), median PFS (3.8 months vs. 7.9 months; p < 0.0001), and median OS (9.8 months vs. 17.0 months; p < 0.0001). CONCLUSIONS: In this retrospective multicenter real-world study, HCC patients treated in the post-SOR era, where LEN and A + B were commonly used first-line treatments, exhibited superior OS, PFS, and RR compared to patients treated in the SOR era. The findings of this study affirm the tangible progress achieved in the real world in enhancing outcomes for HCC patients through advancements in treatments over the past 15 years.

Impact of multiple primary cancers on overall survival of patients with hepatocellular carcinoma.

The increasing occurrence of multiple primary cancers (MPC) is a long-term trend, but the prevalence of MPC in patients with hepatocellular carcinoma (HCC) and its impact on overall survival (OS) remains unknown. We retrospectively analyzed 497 patients with HCC treated at two tertiary centers. The cohort was divided into two subgroups - liver transplant (LT, 324 patients) and non-liver transplant (non-LT, 173 patients). We analyzed MPC occurrence, its impact on survival, and identified variables predicting unfavorable outcomes. The MPC were detected in 88 patients (18%). The most common MPC were prostate (17%), skin (15.9%), kidney (12.5%), and lung (10.2%). The median OS of the whole cohort and the LT and non-LT subgroups were 70, 116, and 17 months, respectively (p<0.0001). The median OS in patients with HCC only and HCC with another cancer was 77 (95% CI, 67-96) and 50 months (95% CI, 37-62), respectively (p=0.25). The OS of LT patients was significantly better than that of those in whom LT had been contraindicated owing to concomitant MPC (116 vs. 35 months, p<0.0009). Autoimmune etiology, non-alcoholic steatohepatitis (NASH), HCC as the first diagnosed malignancy, and male sex were identified as factors significantly influencing the patients' outcomes (HR 0.43, 3.2326, 0.70, and 1.43, respectively). The MPC frequency was 18%. The impact of MPC on OS was not significant, except for individuals contraindicated for LT because of MPC. A better prognosis is associated with the autoimmune etiology of cirrhosis, and when HCC is diagnosed as the first malignancy. Male sex and NASH worsened the outcomes.

Impact of bile leak on the prognosis of patients with hepatocellular carcinoma who have undergone liver resection.

PURPOSE: The impact of postoperative bile leak on the prognosis of patients with hepatocellular carcinoma who underwent liver resection is controversial. This study aimed to investigate the prognostic impact of bile leak for patients with hepatocellular carcinoma who underwent liver resection. METHODS: Patients with hepatocellular carcinoma who underwent liver resection between 2009 and 2019 at Kobe University Hospital and Hyogo Cancer Center were included. After propensity score matching between the bile leak and no bile leak groups, differences in 5-year recurrence-free and overall survival rates were evaluated using the Kaplan-Meier method. RESULTS: A total of 781 patients, including 43 with postoperative bile leak, were analyzed. In the matched cohort, 40 patients were included in each group. The 5-year recurrence-free survival rates after liver resection were 35% and 32% for the bile leak and no bile leak groups, respectively (P = 0.857). The 5-year overall survival rates were 44% and 54% for the bile leak and no bile leak groups, respectively (P = 0.216). CONCLUSION: Overall, bile leak may not have a profound negative impact on the prognosis of patients with hepatocellular carcinoma who have undergone liver resection.

High expression of YEATS2 as a predictive factor of poor prognosis in patients with hepatocellular carcinoma.

YEATS domain containing 2 (YEATS2), it may function as a proto-oncogene. This study aims to investigate if YEATS2 correlates with prognosis in hepatocellular carcinoma. The prognostic landscape of YEATS2 and its relationship with expression in hepatocellular carcinoma were deciphered with public databases, RT-qPCR and western-blot in tissue samples. The expression profiling and prognostic value of YEATS2 were explored using UALCAN, TIMER, OncoLnc database. Transcription and survival analyses of YEATS2 in hepatocellular carcinoma were investigated with cBioPortal database. The STRING database was explored to identify molecular functions and signaling pathways downstream of YEATS2. YEATS2 expression was significantly higher in hepatocellular carcinoma compared with adjacent non-malignant tissues. Promoter methylation of YEATS2 exhibited different patterns in hepatocellular carcinoma. High expression of YEATS2 was associated with poorer survival. Mechanistically, YEATS2 was involved in mediating multiple biological processes including morphogenesis and migration.

Transcription factor 7 like 2 promotes metastasis in hepatocellular carcinoma via NEDD9-mediated activation of AKT/mTOR signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system, and the exact mechanism of HCC is still unclear. Transcription factor 7 like 2 (TCF7L2) plays a pivotal role in cell proliferation and stemness maintenance. However, the exact mechanism of TCF7L2 in HCC remains unclear. METHODS: Clinical samples and public databases were used to analyze the expression and prognosis of TCF7L2 in HCC. The function of TCF7L2 in HCC was studied in vitro and in vivo. ChIP and luciferase assays were used to explore the molecular mechanism of TCF7L2. The relationship between TCF7L2 and NEDD9 was verified in HCC clinical samples by tissue microarrays. RESULTS: The expression of TCF7L2 was upregulated in HCC, and high expression of TCF7L2 was associated with poor prognosis of HCC patients. Overexpression of TCF7L2 promoted the metastasis of HCC in vitro and in vivo, while Knockdown of TCF7L2 showed the opposite effect. Mechanically, TCF7L2 activated neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) transcription by binding to the -1522/-1509 site of the NEDD9 promoter region, thereby increasing the phosphorylation levels of AKT and mTOR. The combination of TCF7L2 and NEDD9 could distinguish the survival of HCC patients. CONCLUSIONS: This study demonstrated that TCF7L2 promotes HCC metastasis by activating AKT/mTOR pathway in a NEDD9-dependent manner, suggesting that potential of TCF7L2 and NEDD9 as prognostic markers and therapeutic targets for HCC.

Identification and characterization of RAC1-related immune and prognostic subtypes of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor with significant variability in prognosis among patients. Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key focus in the area of cancer research. However, the molecular mechanisms of RAC1 in HCC remain incompletely elucidated. MATERIALS AND METHODS: In this study, bioinformatics analysis was used, and public databases were used to obtain information about HCC cases. The samples were categorized into two groups of high and low expression based on the expression level of RAC1 gene. The limma package was used to calculate the differentially expressed genes between the two groups, and univariate Cox regression analysis was used to screen the prognostic related factors. Consensus clustering analysis was performed using the ConsensusClusterPlus package to identify molecular subtypes of HCC patients. Immune cell infiltration and ESTIMATE scores were assessed using the single sample gene set enrichment analysis and ESTIMATE algorithms. The sensitivity of different isoforms to chemotherapeutic agents was predicted by the oncoPredict package. Finally, we also performed cell function experiments to validate the biological role of RAC1 in vitro. Initially, we classified patients into high and low expression groups based on RAC1 gene expression levels and identified 195 up-regulated genes and 107 down-regulated genes. Through univariate Cox regression analysis, we screened out 169 prognosis-related factors. Furthermore, HCC patients were categorized into two subtypes. Subsequently, Kaplan-Meier survival curves showed that there was a significant difference in prognosis between the two molecular subtypes. Further analysis indicated substantial differences in gene expression levels and TIDE scores between two molecular subtypes. Moreover, these two subtypes exhibited varying sensitivity to chemotherapy drugs, as evidenced by differences in IC50 values. In addition, we found that the silence of RAC1 could effectively inhibit the migration and invasion of HCC cells in vitro. CONCLUSION: This study sheds light on the molecular intricacies of RAC1 in HCC and identifies patient populations that may benefit from immunotherapeutic interventions, with potential implications for tailored treatment strategies.

Screening for Hepatocellular Carcinoma and Survival in Patients With Cirrhosis After Hepatitis C Virus Cure.

Importance: The risk of hepatocellular carcinoma (HCC) declines over time after hepatitis C virus (HCV) cure by direct-acting antiviral (DAA) therapies. Liver society guidelines recommend continuing HCC screening for these patients, but data on screening outcomes are lacking. Objective: To evaluate the association of HCC screening after HCV cure with overall survival. Design, Setting, and Participants: This cohort study evaluated patients with HCV cirrhosis who achieved DAA-induced HCV cure in the Veterans Affairs health care system between January 2014 and December 2022. Data analysis occurred from October 2023 to January 2024. Exposures: The percentage of time spent up to date with recommended HCC screening was calculated by year of follow-up and during the 4 years preceding HCC diagnosis (the detectable asymptomatic phase). Main Outcomes and Measures: The primary outcome was overall survival after HCC diagnosis and was compared by percentage of time spent up to date with screening using Kaplan-Meier analyses and Cox proportional hazards regression. Early-stage HCC at diagnosis and curative treatment were secondary outcomes assessed using logistic regression. Results: A total of 16 902 individuals were included (median [IQR] age, 64.0 [60.5-67.4] years; 16 426 male [97.2%]), of whom 1622 developed HCC. The cumulative incidence of HCC declined from 2.4% (409 of 16 902 individuals) to 1.0% (27 of 2833 individuals) from year 1 to year 7 of follow-up. Being up to date with screening for at least 50% of time during the 4 years preceding HCC diagnosis was associated with improved overall survival (log-rank test of equality over strata P = .002). In multivariate analysis, each 10% increase in follow-up spent up to date with screening was associated with a 3.2% decrease in the hazard of death (hazard ratio, 0.97; 95% CI, 0.95-0.99). There was a statistically significant interaction between time since HCV cure and screening, with no association observed among those who received a diagnosis of HCC more than 5 years after HCV cure. Each 10% of time spent up to date with screening was associated with a 10.1% increased likelihood of diagnosis with early-stage HCC (95% CI, 6.3%-14.0%) and a 6.8% increased likelihood of curative treatment (95% CI, 2.8%-11.0%). Conclusions and Relevance: In this cohort study of persons with HCV-related cirrhosis who achieved HCV cure and subsequently developed HCC, remaining up to date with screening was associated with improved overall survival, supporting the screening of eligible individuals.

Prognostic impact of the high-sensitivity modified glasgow prognostic score on patients undergoing radical surgery for hepatocellular carcinoma : Authorship.

OBJECTIVE: Our study aimed to assess the ability of high-sensitivity modified Glasgow prognostic Score (HS-mGPS) predicting survival in patients undergoing radical surgery for hepatocellular carcinoma (HCC) and to compare the impact with other Inflammation-Based prognostic scoring systems including Glasgow prognostic Score (GPS) and modified GPS (mGPS). METHODS: Our study evaluated 293 patients with HCC who had undergone hepatectomy at the Third Affiliated Hospital of Soochow University between 2010 and 2018. The HS-mGPS, mGPS, and GPS were calculated based on particular cut-off values of preoperative C-reactive protein and albumin, and the correlations between HS-mGPS and clinicopathological parameters were evaluated. Univariate and multivariate survival analyses were conducted by Kaplan-Meier method and Cox proportional hazards model. To evaluate the discrimination ability of each prognostic score, the receiver operating characteristic (ROC) curve were generated and the areas under the curve (AUC) were measured and compared. RESULT: The study results indicated a correlation between elevated HS-mGPS scores and adverse clinical factors, including higher BCLC stage, C-P grade, multiple tumors, and larger tumor diameter. Kaplan-Meier and univariate survival analyses revealed that higher scores of HS-mGPS, GPS, and mGPS were all associated with significantly reduced overall survival (OS) (all p < 0.001). In multivariate survival analysis, HS-mGPS emerged as an independent risk factor for poor OS in patients undergoing hepatectomy for HCC (p = 0.010), along with factors including maximal tumor diameter (p < 0.001), microvascular invasion (MVI) (p = 0.008), and BCLC stage (p = 0.001). The analysis of ROC curves and the AUC values indicated that HS-mGPS outperforms GPS and mGPS in predicting the long-term prognosis of patients with resectable HCC. CONCLUSION: Preoperative HS-mGPS proves superior in predicting adverse long-term outcomes in HCC patients undergoing radical surgery.

Mitotic catastrophe heterogeneity: implications for prognosis and immunotherapy in hepatocellular carcinoma.

Background and aims: The mitotic catastrophe (MC) pathway plays an important role in hepatocellular carcinoma (HCC) progression and tumor microenvironment (TME) regulation. However, the mechanisms linking MC heterogeneity to immune evasion and treatment response remain unclear. Methods: Based on 94 previously published highly correlated genes for MC, HCC patients' data from the Cancer Genome Atlas (TCGA) and changes in immune signatures and prognostic stratification were studied. Time and spatial-specific differences for MCGs were assessed by single-cell RNA sequencing and spatial transcriptome (ST) analysis. Multiple external databases (GEO, ICGC) were employed to construct an MC-related riskscore model. Results: Identification of two MC-related subtypes in HCC patients from TCGA, with clear differences in immune signatures and prognostic risk stratification. Spatial mapping further associates low MC tumor regions with significant immune escape-related signaling. Nomogram combining MC riskscore and traditional indicators was validated great effect for early prediction of HCC patient outcomes. Conclusion: MC heterogeneity enables immune escape and therapy resistance in HCC. The MC gene signature serves as a reliable prognostic indicator for liver cancer. By revealing clear immune and spatial heterogeneity of HCC, our integrated approach provides contextual therapeutic strategies for optimal clinical decision-making.

No lipiodol, no beads-another transcatheter arterial chemoembolization (TACE) with fine cisplatin powder and porous gelatin particles for TACE-naïve, multifocal, up-to-seven out hepatocellular carcinoma.

AIM: The Japanese Interventional oncology group (JIVROSG) showed the efficacy and safety of nonselective transarterial chemoembolization (TACE) with fine cisplatin powder (diamminedichloroplatinum; DDP-H) (65 mg/m2) and porous gelatin particles (DDP-H TACE) without lipiodol for extensive multifocal hepatocellular carcinoma (HCC). However, there are no studies on this method following the JIVROSG study. Therefore, we aimed to evaluate the efficacy of this new DDP-H TACE and its effect on liver function. METHODS: We retrospectively reviewed the medical records of TACE-naïve patients with multifocal HCC (Child-Pugh class A, up-to-seven out, no prior history of systemic therapy) who underwent whole-liver DDP-H TACE between January 2006 and December 2019. RESULTS: Sixty patients were included in this study. The median age of the patients was 71 (range, 35-88) years. The median maximum size of tumors was 26 (range, 8-184) mm; 86.7% of patients met the up-to-11 criteria out. The overall survival duration was 30.3 months. At the time of initial evaluation (median, 45 days), the overall response rate was 65.0%; the disease control rate was 86.7% based on the modified response evaluation criteria in solid tumors guideline. Although nine patients' liver function had deteriorated to Child-Pugh class B at initial evaluation, six of them recovered to Child-Pugh class A. Only three patients (5%) showed permanently impaired liver function. CONCLUSIONS: Whole-liver DDP-H TACE without lipiodol or beads effectively reduced tumors and preserved liver function.

A-to-I RNA co-editing predicts clinical outcomes and is associated with immune cells infiltration in hepatocellular carcinoma.

Aberrant RNA editing has emerged as a pivotal factor in the pathogenesis of hepatocellular carcinoma (HCC), but the impact of RNA co-editing within HCC remains underexplored. We used a multi-step algorithm to construct an RNA co-editing network in HCC, and found that HCC-related RNA editings are predominantly centralized within the network. Furthermore, five pairs of risk RNA co-editing events were significantly correlated with the overall survival in HCC. Based on presence of risk RNA co-editings resulted in the categorization of HCC patients into high-risk and low-risk groups. Disparities in immune cell infiltrations were observed between the two groups, with the high-risk group exhibiting a greater abundance of exhausted T cells. Additionally, seven genes associated with risk RNA co-editing pairs were identified, whose expression effectively differentiates HCC tumor samples from normal ones. Our research offers an innovative perspective on the etiology and potential therapeutics for HCC.

Effects of the subtypes of apolipoprotein E on immune inhibition and prognosis in patients with Hepatocellular Carcinoma.

PURPOSE: To investigate whether prognosis of patients with hepatocellular carcinoma (HCC) is affected by the abundance and subgroups of myeloid-derived suppressor cells (MDSCs) as well as subtypes and expression of apolipoprotein E (apoE). METHODS: 31 HCC patients were divided into three groups according to blood total apoE level for detecting the abundance of immunoregulatory cells by flow cytometry. Tumour tissue microarrays from 360 HCC patients were evaluated about the abundance and subgroups of MDSCs and the expression of apoE2, apoE3, apoE4 by immunofluorescence staining and immunohistochemistry staining. Survival analysis by means of univariate, multivariate COX regression and Kaplan-Meier methods of the 360 patients was performed based on clinical and pathological examinations along with 10 years' follow-up data. RESULTS: The lower apoE group presented higher abundance of MDSCs in the peripheral blood of HCC patients than higher apoE group. The abundance of monocyte-like MDSCs (M-MDSCs) was higher in the apoE low level group than high level group (p = 0.0399). Lower H-score of apoE2 (HR = 6.140, p = 0.00005) and higher H-score of apoE4 (HR = 7.001, p = 0.009) in tumour tissue were significantly associated with shorter overall survival (OS). The higher infiltration of polymorphonuclear granulocyte-like MDSCs (PMN-MDSCs, HR = 3.762, p = 0.000009) and smaller proportion of M-MDSCs of total cells (HR = 0.454, p = 0.006) in tumour tissue were independent risk factors for shorter recurrence-free survival (RFS). CONCLUSION: The abundance of MDSCs in HCC patients' plasma negatively correlates with the level of apoE. The expression of apoE4 in HCC tissue indicated a poor prognosis while apoE2 might be a potential protective factor.

Transjugular Intrahepatic Portosystemic Shunt Is Associated With Better Waitlist Management of Liver Transplant Candidates With Hepatocellular Carcinoma.

Transjugular intrahepatic portosystemic shunt (TIPS) reduces portal hypertension complications. Its impact on hepatocellular carcinoma (HCC) remains unclear. We evaluated 42,843 liver transplant candidates with HCC from the Scientific Registry of Transplant Recipients (2002-2022). 4,484 patients with and without TIPS were propensity score-matched 1:3. Analysing wait-list changes in total tumor volume, HCC count, and alpha-fetoprotein levels, and assessing survival from listing and transplantation; TIPS correlated with a decreased nodule count (-0.24 vs. 0.04, p = 0.028) over a median wait period of 284 days (IQR 195-493) and better overall survival from listing (95.6% vs. 91.5% at 1 year, p < 0.0001). It was not associated with changes in tumor volume (0.28 vs. 0.11 cm³/month, p = 0.58) and AFP (14.37 vs. 20.67 ng/mL, p = 0.42). Post-transplant survival rates (91.8% vs. 91.7% at 1 year, p = 0.25) and HCC recurrence (5.1% vs. 5.9% at 5 years, p = 0.14) were similar, with a median follow-up of 4.98 years (IQR 2.5-8.08). While TIPS was associated with a reduced nodule count and improved waitlist survival, it did not significantly impact HCC growth or aggressiveness. These findings suggest potential benefits of TIPS in HCC management, but further studies need to confirm TIPS safety.

Etiology and Outcomes of Patients with Extreme Hyperbilirubinemia in Korea: A Retrospective Cohort Study.

Background/Aim: Extreme hyperbilirubinemia is occasionally observed in intensive care unit (ICU) and non-ICU settings. This study examined the etiologies of extreme hyperbilirubinemia (bilirubin level ≥12 mg/dL) and the factors associated with the 30-day mortality. Methods: This retrospective observational cohort study identified 439 patients with extreme hyperbilirubinemia at the Gyeongsang National University Changwon Hospital between 2016 and 2020. The patients were classified into three groups and 11 diseases according to their etiology. The risk factors associated with 30-day mortality at the baseline were investigated using the Cox proportional hazards model. Results: Of 439 patients with extreme hyperbilirubinemia, 287, 78, and 74 were in the liver cirrhosis/malignancy group, the ischemic injury group, and the benign hepatobiliary-pancreatic etiological group, respectively, with corresponding 30-day mortality rates of 42.9%, 76.9%, and 17.6%. The most common disease leading to hyperbilirubinemia was a pancreatobiliary malignancy (28.7%), followed by liver cirrhosis (17.3%), hepatocellular carcinoma (10.9%), and liver metastases (8.4%). The etiologies of hyperbilirubinemia, obstructive jaundice, infection, albumin level, creatinine level, and prothrombin time-international normalized ratio were independently associated with the 30-day mortality. Conclusions: This study suggests three etiologies of extreme hyperbilirubinemia in the ICU and non-ICU settings. The prognosis of patients with extreme hyperbilirubinemia depends largely on the etiology and the presence of obstructive jaundice.

Developing an advanced diagnostic model for hepatocellular carcinoma through multi-omics integration leveraging diverse cell-death patterns.

Introduction: Hepatocellular carcinoma (HCC), representing more than 80% of primary liver cancer cases, lacks satisfactory etiology and diagnostic methods. This study aimed to elucidate the role of programmed cell death-associated genes (CDRGs) in HCC by constructing a diagnostic model using single-cell RNA sequencing (scRNA-seq) and RNA sequencing (RNA-seq) data. Methods: Six categories of CDRGs, including apoptosis, necroptosis, autophagy, pyroptosis, ferroptosis, and cuproptosis, were collected. RNA-seq data from blood-derived exosomes were sourced from the exoRBase database, RNA-seq data from cancer tissues from the TCGA database, and scRNA-seq data from the GEO database. Subsequently, we intersected the differentially expressed genes (DEGs) of the HCC cohort from exoRBase and TCGA databases with CDRGs, as well as DEGs obtained from single-cell datasets. Candidate biomarker genes were then screened using clinical indicators and a machine learning approach, resulting in the construction of a seven-gene diagnostic model for HCC. Additionally, scRNA-seq and spatial transcriptome sequencing (stRNA-seq) data of HCC from the Mendeley data portal were used to investigate the underlying mechanisms of these seven key genes and their association with immune checkpoint blockade (ICB) therapy. Finally, we validated the expression of key molecules in tissues and blood-derived exosomes through quantitative Polymerase Chain Reaction (qPCR) and immunohistochemistry experiments. Results: Collectively, we obtained a total of 50 samples and 104,288 single cells. Following the meticulous screening, we established a seven-gene diagnostic model for HCC, demonstrating high diagnostic efficacy in both the exoRBase HCC cohort (training set: AUC = 1; testing set: AUC = 0.847) and TCGA HCC cohort (training set: AUC = 1; testing set: AUC = 0.976). Subsequent analysis revealed that HCC cluster 3 exhibited a higher stemness index and could serve as the starting point for the differentiation trajectory of HCC cells, also displaying more abundant interactions with other cell types in the microenvironment. Notably, key genes TRIB3 and NQO1 displayed elevated expression levels in HCC cells. Experimental validation further confirmed their elevated expression in both tumor tissues and blood-derived exosomes of cancer patients. Additionally, stRNA analysis not only substantiated these findings but also suggested that patients with high TRIB3 and NQO1 expression might respond more favorably to ICB therapy. Conclusions: The seven-gene diagnostic model demonstrated remarkable accuracy in HCC screening, with TRIB3 emerging as a promising diagnostic tool and therapeutic target for HCC.