Conventional Hepatocellular Carcinoma Research Articles

Clinical significance of upregulated Rho GTPase activating protein 12 causing resistance to tyrosine kinase inhibitors in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major health challenge with high incidence and poor survival rates in China. Systemic therapies, particularly tyrosine kinase inhibitors (TKIs), are the first-line treatment for advanced HCC, but resistance is common. The Rho GTPase family member Rho GTPase activating protein 12 (ARHGAP12), which regulates cell adhesion and invasion, is a potential therapeutic target for overcoming TKI resistance in HCC. However, no studies on the expression of ARHGAP12 in HCC and its role in resistance to TKIs have been reported. To unveil the expression of ARHGAP12 in HCC, its role in TKI resistance and its potential associated pathways. This study used single-cell RNA sequencing (scRNA-seq) to evaluate ARHGAP12 mRNA levels and explored its mechanisms through enrichment analysis. CellChat was used to investigate focal adhesion (FA) pathway regulation. We integrated bulk RNA data (RNA-seq and microarray), immunohistochemistry and proteomics to analyze ARHGAP12 mRNA and protein levels, correlating with clinical outcomes. We assessed ARHGAP12 expression in TKI-resistant HCC, integrated conventional HCC to explore its mechanism, identified intersecting FA pathway genes with scRNA-seq data and evaluated its response to TKI and immunotherapy. ARHGAP12 mRNA was found to be highly expressed in malignant hepatocytes and to regulate FA. In malignant hepatocytes in high-score FA groups, MDK-[integrin alpha 6 (ITGA6) + integrin β-1 (ITGB1)] showed specificity in ligand-receptor interactions. ARHGAP12 mRNA and protein were upregulated in bulk RNA, immunohistochemistry and proteomics, and higher expression was associated with a worse prognosis. ARHGAP12 was also found to be a TKI resistance gene that regulated the FA pathway. ITGB1 was identified as a crossover gene in the FA pathway in both scRNA-seq and bulk RNA. High expression of ARHGAP12 was associated with adverse reactions to sorafenib, cabozantinib and regorafenib, but not to immunotherapy. ARHGAP12 expression is elevated in HCC and TKI-resistant HCC, and its regulatory role in FA may underlie the TKI-resistant phenotype.

Clinicopathologic features and prognosis of steatohepatitic hepatocellular carcinoma based on varying cutoffs of tumoral steatohepatitic changes.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is currently recognized as a distinct histologic subtype of HCC. The prognosis and specific criteria for determining the amount of steatohepatitis required to define SH-HCC are still unclear. After excluding all recognized HCC subtypes from 505 HCC cases (2010-2019), the remaining cases were categorized as conventional HCC (CV-HCC) (n = 223). The cases classified as SH-HCC (n = 171) were further divided into groups based on the percentage of steatohepatitis: 5% or more, 30% or more, and 50% or more. Hepatitis C virus infection was the predominant underlying liver disease in both the CV-HCC and SH-HCC groups. Metabolic dysfunction-associated steatotic liver disease (formerly nonalcoholic fatty liver disease) was more prevalent in all cases of SH-HCC with different steatohepatitic cutoffs than in cases of CV-HCC. There were no differences in the stage of fibrosis of the background liver between the CV-HCC and SH-HCC groups. SH-HCC with different cutoffs exhibited a notable increase in the presence of glycogenated nuclei, Mallory-Denk bodies, and hyaline globules in tumor cells. Survival analysis did not reveal substantial differences in overall survival between the CV-HCC and SH-HCC groups and among patients with SH-HCC with different steatohepatitis cutoffs. The degree of intratumoral steatohepatitis in patients with SH-HCC does not appear to be a notable prognostic factor. The presence of steatohepatitis in the tumor is better recognized as 1 of the histopathologic patterns of HCC.

Mixed hepatocellular carcinoma and high-grade neuroendocrine neoplasm with ambiguous histopathological features: a case report.

Well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC) are distinct entities with different biological behavior. However, difficult cases showing equivocal morphology have been reported in some organs. Herein, we report a case of primary hepatic neuroendocrine neoplasm (NEN) with ambiguous histopathological features admixed with conventional hepatocellular carcinoma (HCC). A 70-year-old man with untreated chronic hepatitis B underwent left medial sectionectomy because of two incidental liver masses. On pathological examination, one of the resected tumors had intermingling NEN and HCC components. The NEN component consisted of relatively uniform tumor cells proliferating in trabecular, cord-like, or solid patterns with peripheral nuclear palisading. The tumor cells were immunopositive for synaptophysin, chromogranin A, cluster of differentiation 56 (CD56), and focally hepatocyte paraffin 1. p53 showed wild-type expression. The Ki-67 labeling index was 27% at the hot spot. Eleven months after the surgery, he died of a cerebral hemorrhage without evidence of recurrent liver cancer. The intermediate degree of differentiation and the modest proliferative activity can challenge the distinction between NEC and NET G3. While the coexisting HCC indicates NEC rather than NET in a pathogenetic viewpoint, such ambiguous tumor may not be as aggressive as typical NECs.

Combination Therapy of Lenvatinib and Hepatic Arterial Infusion Chemotherapy Using Cisplatin With Lipiodol and 5-Fluorouracil: A Potential Breakthrough Therapy for Unresectable Advanced Hepatocellular Carcinoma.

In 2021, the LEOPARD trial reported that the combination of lenvatinib+one-shot cisplatin infusion might contribute to improving the results of conventional advanced hepatocellular carcinoma (HCC) treatment. Thus, combination therapy with lenvatinib and catheterization has emerged as a focal point in treating advanced HCC. Conversely, the New FP regimen consists of low-dose cisplatin (CDDP) combined with 5-fluorouracil (5-FU) and lipiodol via hepatic arterial infusion chemotherapy (HAIC), with a high response rate of approximately 70%. Therefore, lenvatinib+New FP (LEN-New FP) may be a more promising treatment for HCC. Here, we report six patients who were administered LEN+New FP and achieved high therapeutic efficacy. Among them, one case had an interesting clinical course, which has been described in detail. This study included six patients who were administered 12 mg or 8 mg of lenvatinib once daily based on a body weight of ≥60 kg or <60 kg, respectively, along with 50 mg of cisplatin in 5-10 mL lipiodol, and a continuous infusion of 5-FU (1500 mg/5 days) infused every 2-4 weeks. Tumor evaluations were performed 4-8 weeks after the initiation of New FP administration and every 8-12 weeks thereafter. The median patient age was 65 years. All patients had a history of prior treatment with atezolizumab and bevacizumab and one of the factors associated with poor overall survival for New FP monotherapy, such as a maximum tumor diameter ≥7 cm and bilobular multifocal distribution. Four (67%) patients had severe vascular invasion. The best objective response and disease control rates were 83% and 100%, respectively. The best response of the target lesion was complete remission in four out of six patients. The LEN-New FP combination for advanced HCC showed a high response rate and was more effective in high-risk patients with factors associated with poor overall survival than that reported with conventional New FP monotherapy. Additionally, LEN-New FP exhibited extremely high objective response and disease control rates and was well tolerated, including in cases where it was considered second- or third-line systemic chemotherapy for advanced HCC. Thus, LEN-New FP can serve as a breakthrough therapy for advanced HCC based on appropriate case selection.

Sonic hedgehog expression in steatohepatitic hepatocellular carcinoma and its clinicopathological significance.

Hedgehog (Hh) signaling pathway dysregulation is involved in the pathogenesis of metabolic dysfunction-associated steatohepatitis, and the sonic Hh (SHh) protein, a pivotal molecule in the Hh pathway, is expressed in ballooned hepatocytes. The present study aimed to investigate the clinicopathological significance of SHh expression in steatohepatitic hepatocellular carcinoma (SH-HCC). Reverse transcription-quantitative polymerase chain reaction and immunohistochemistry were performed to examine SHh gene and SHh protein expression in SH-HCC. Additionally, patients with conventional HCC (C-HCC) were included in the control group. Comparisons of patient and tumor characteristics were also performed. The prevalence of SH-HCC was 3% in the whole cohort, and it was significantly associated with a high prevalence of diabetes mellitus. SHh mRNA was detected in all patients with SH-HCC, but not in 23% of patients with C-HCC. Notably, SHh mRNA expression was not significantly different between patients with SH-HCC and those with C-HCC; however, high SHh protein expression was significantly more frequent in SH-HCC patients than in those with C-HCC. Although the prognosis was not significantly different between the SH-HCC and C-HCC groups, high SHh protein expression was an independent poor prognostic factor for HCC. In conclusion, SHh could potentially serve as a therapeutic target for patients with HCC.

Fibrolamellar hepatocellular carcinoma (FL-HCC) epidemiology, survival characteristics, and outcomes: Surveillance, epidemiology, and end results database (SEER) study.

e16213 Background: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinctive form of liver cancer that primarily affects adolescents and young adults without underlying liver disease. Unlike conventional HCC, it exhibits unique clinical and histological features and poses a diagnostic and therapeutic challenge. Using a national registry, we sought to evaluate the incidence, demographics, survival, and treatment characteristics of FL-HCC. Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with microscopically confirmed FL-HCC between 2000-2020 using ICD-O-3 site code C22.0 and an 8171/3 histology code. The epidemiological characteristics included were age, gender, ethnicity, American Joint Committee on Cancer [AJCC] staging, annual income, and treatment modalities. The Kaplan-Meier survival curve was used to compare survival. Survival was stratified according to age, gender, race, stage, income, and treatment modalities. Multivariate analysis was done with Cox regression analysis on R programming language version 3.6.3. Results: We identified a total of 362 patients with fibrolamellar hepatocellular carcinoma with median age at diagnosis 27(8-84) years. It was found to be more common in males (62.2%) and among whites (78.2%). There was a striking increment in incidence with 1.9% in 2005 compared to 5.8% in 2020. The majority of the patients had stage IV disease (26.4%). Alpha-fetoprotein was noted to be positive only in 15.8% of patients. The majority of the patients received surgery (50.3%) and chemotherapy (48.1%) with a median time from diagnosis to treatment of 1.00 month (IQR: 0.00–1.00). A total of 11% of patients received radiation, and 25% received multiple treatments. Survival analysis revealed a median overall survival of 24.50 months (IQR: 7.00, 63.00), with a majority experiencing death attributable to the cancer diagnosis (60.2%). Median overall and cause-specific survival for stage I disease was 92 months, and stage IV disease was 21 months (p &lt; 0.05). Patients below the age of 20 had a median survival of 85 months (95% CI: 41 to NA) compared to those aged between 20 and 59, i.e., 30 months (95% CI: 22 to 41 months). The higher-income categories, $55,000−59,999 (HR = 0.29, p = 0.05) and $60,000−64,999 (HR = 0.24, p = 0.03), demonstrated significantly lower hazards compared to &lt; $35,000. We concluded that sex, location, and race did not influence the survival of FL-HCC. Conclusions: Our comprehensive analysis of FL-HCC revealed that diagnosis at a younger age, stage I disease, and higher annual income improved survival, whereas gender and race did not affect outcomes. Further collaborative efforts are warranted to advance our understanding of FL-HCC pathogenesis, optimize treatment strategies, and improve outcomes for affected individuals.

Clinical and immunophenotype correlating with response to immunotherapy in paediatric patients with primary liver carcinoma. A case series

Paediatric hepatocellular carcinomas (HCC) traditionally arise in the context of a normal structural and functional liver and carry a dismal prognosis. While chemotherapy is the frontline standard, there is emerging interest in the study of immunotherapies for paediatric patients with relapsed/refractory disease. There is limited data to support whether immunotherapies will be of utility in this patient population. Six paediatric patients (median age:16 years, range: 12-17at the time of treatment) with advanced hepatocellular neosplams, either conventional hepatocellular or fibrolamellar carcinoma, were treated with immunotherapy. Patients were consented to institutional genomic profiling and biobanking protocols. Baseline samples and serial tissue samples, when available, were evaluated for somatic mutation rate, actionable gene mutations, and pan-immune bulk RNA expression profiling. Results were correlated with clinical course. Three patients responded to checkpoint inhibition: one achieved a complete, durable response and the other two, prolonged stable disease. Three additional patients progressed. Diagnostic tissue from the complete responder demonstrated a higher relative mutational burden and robust immune infiltrate. Pre-treatment samples from the three responders demonstrated decreased expression of genes associated with T-cell dysfunction. A subset of patients with primary paediatric hepatocellular tumours will respond to immunotherapy. Immunotherapies are currently under prospective study for relapsed/refractory liver tumours in paediatric patients. Results from this report support the prospective collection of serial serum and tissue samples which may further identify genomic and immunophenotypic patterns predictive of response. This work was supported by Philanthropic funds (Pan Mass Challenge, Team Angus and Team Perspective).

Development and validation of nomograms to predict survival and recurrence after hepatectomy for intermediate/advanced (BCLC stage B/C) hepatocellular carcinoma

BackgroundDespite the Barcelona Clinic Liver Cancer system discouraging hepatectomy for intermediate/advanced hepatocellular carcinoma, the procedure is still performed worldwide, particularly in Asia. This study aimed to develop and validate nomograms for predicting survival and recurrence for these patients. MethodsWe analyzed patients who underwent curative-intent hepatectomy for intermediate/advanced hepatocellular carcinoma between 2010 and 2020 across 3 Chinese hospitals. The Eastern Hepatobiliary Surgery Hospital cohort was used as the training cohort for the nomogram construction, and the Jilin First Hospital and Fujian Mengchao Hepatobiliary Hospital cohorts served as the external validation cohorts. Independent preoperative predictors for survival and recurrence were identified through univariable and multivariable Cox regression analyses. Predictive accuracy was measured using the concordance index and calibration curves. The predictive performance between nomograms and conventional hepatocellular carcinoma staging systems was compared. ResultsA total of 1,328 patients met the inclusion criteria. The nomograms for predicting survival and recurrence were developed using 10 and 6 independent variables, respectively. Nomograms’ concordance indices in the training cohort were 0.777 (95% confidence interval 0.759–0.800) and 0.719 (95% confidence interval 0.697–0.742) for survival and recurrence, outperforming 4 conventional staging systems (P < .001). Nomograms accurately stratified risk into low, intermediate, and high subgroups. These results were validated well by 2 external validation cohorts. ConclusionWe developed and validated nomograms predicting survival and recurrence for patients with intermediate/advanced hepatocellular carcinoma, contradicting Barcelona Clinic Liver Cancer surgical guidelines. These nomograms may facilitate clinicians to formulate personalized surgical decisions, estimate long-term prognosis, and strategize neoadjuvant/adjuvant anti-recurrence therapy.

Comprehensive molecular classification predicted microenvironment profiles and therapy response for HCC.

Tumor microenvironment (TME) heterogeneity leads to a discrepancy in survival prognosis and clinical treatment response for patients with HCC. The clinical applications of documented molecular subtypes are constrained by several issues. We integrated 3 single-cell data sets to describe the TME landscape and identified 6 prognosis-related cell subclusters. Unsupervised clustering of subcluster-specific markers was performed to generate transcriptomic subtypes. The predictive value of these molecular subtypes for prognosis and treatment response was explored in multiple external HCC cohorts and the Xiangya HCC cohort. TME features were estimated using single-cell immune repertoire sequencing, mass cytometry, and multiplex immunofluorescence. The prognosis-related score was constructed based on a machine-learning algorithm. Comprehensive single-cell analysis described TME heterogeneity in HCC. The 5 transcriptomic subtypes possessed different clinical prognoses, stemness characteristics, immune landscapes, and therapeutic responses. Class 1 exhibited an inflamed phenotype with better clinical outcomes, while classes 2 and 4 were characterized by a lack of T-cell infiltration. Classes 5 and 3 indicated an inhibitory tumor immune microenvironment. Analysis of multiple therapeutic cohorts suggested that classes 5 and 3 were sensitive to immune checkpoint blockade and targeted therapy, whereas classes 1 and 2 were more responsive to transcatheter arterial chemoembolization treatment. Class 4 displayed resistance to all conventional HCC therapies. Four potential therapeutic agents and 4 targets were further identified for high prognosis-related score patients with HCC. Our study generated a clinically valid molecular classification to guide precision medicine in patients with HCC.

Characterization of lymphocyte-rich hepatocellular carcinoma and the prognostic role of tertiary lymphoid structures.

Lymphocyte-rich hepatocellular carcinoma (LR-HCC) is largely unknown and a rare subtype of HCC with immune-rich stroma. Tertiary lymphoid structures (TLS), frequently observed in LR-HCC, are known to be prognostically significant in various malignancies; however, their significance in HCC remains unevaluated. Clinicopathologic data of 191 cases of surgically resected conventional HCC (C-HCC, n = 160) and LR-HCC (n = 31) were retrieved. Immunohistochemistry, multiplex immunofluorescence staining, RNA sequencing and proteomic analysis were conducted. Differences between the subtypes were statistically evaluated. LR-HCC was significantly correlated to larger tumour size, higher Edmondson-Steiner grade, presence of TLS and higher CD3-, CD8- and FOXP3-positive T cell, high PD-1 and PD-L1 expression (p < .001 for all) compared to C-HCC. Patients with LR-HCC exhibited significantly better overall survival (OS) (p = .044) and recurrence-free survival (RFS) (p = .025) than C-HCC. LR-HCC demonstrated TLS signatures with significantly higher proteomic-based immune scores in 14 of 17 types of tumour-infiltrating immune cells. Furthermore, C-HCC with secondary follicles, the most mature form of TLS, exhibited significantly better OS (p = .031) and RFS (p = .033) than those without. Across the global proteome, LR-HCC was well-differentiated from C-HCC and a map of protein-protein interactions between tumour-infiltrating lymphocytes and HCC in tumour microenvironment was completed. LR-HCC is clinicopathologically and molecularly distinct and shows better prognosis compared to C-HCC. Also, the presence of secondary follicle can be an important prognostic marker for better prognosis in both LR-HCC and C-HCC.

Immunophenotypes and Tumor Immune Microenvironment in Hepatocellular Carcinoma With Macrotrabecular Massive and Vessels Encapsulating Tumor Clusters.

Recently, vessels encapsulating tumor clusters (VETC) pattern and macrotrabecular massive (MTM) pattern of hepatocellular carcinoma (HCC) have been reported as aggressive histological types. These histological patterns showed an immunosuppressive tumor immune microenvironment (TIME). Since there have been no reports on the differences of these two subtypes simultaneously, this study examined the immunophenotypes and TIME of MTM-HCC and VETC-HCC immunohistochemically. Seventy-four cases of previously diagnosed HCC, including 32 MTM-HCCs, 21 VETC-HCCs, and 21 conventional HCCs, were enrolled in immunohistochemical analysis. We conducted immunohistochemical analysis. We found that MTM-HCC showed less frequent expression of HepPar-1, which is one of the most common hepatocytic markers. In MTM-HCC, the frequency of high expression levels of Keratin19, carbonic anhydrase (CA) IX, and PD-L1 was higher compared to VETC-HCC and conventional HCC. PD-L1 expression was found in 34.4% of MTM-HCC, 0% of VETC-HCC, and 19.0% of conventional HCC. The rate of PD-L1 expression in MTM-HCC was significantly higher than the others (p=0.0015). PD-L1 expression was significantly associated with epithelial cell adhesion molecules and CA IX expression, which are representative markers of tumor stemness and hypoxic conditions, respectively. The CD8 infiltration in VETC-HCC was significantly lower than that in conventional HCC. MTM-HCC had different immunophenotypes and TIMEs compared to HCC with the VETC pattern. Although both had immunosuppressive TIME, the elements forming TIME were quite different. To enhance the immune checkpoint inhibitor efficacy, changing TIME from a suppressive to an active form is essential.

Genomic Variations Between Fibrolamellar and Conventional Hepatocellular Carcinomas.

Aim The aim of this study isto define genomic variations between fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) Methods This study used the American Association for Cancer Research (AACR) Project GENIE data as a foundational element. Specifically, information about both fibrolamellar and conventional hepatocellular carcinoma was retrieved from this database. Results A total of 719 patients diagnosed with HCC and 52 individuals presenting with FL-HCC underwent thorough analysis. Notably, distinct variances in gene alterations were observed between the two cohorts. Predominantly, the HCC group exhibited frequent occurrences of mutations within the TP53 and CTNNB1 genes. Conversely, DNAJB1 fusion was uniquely identified in FL-HCC cases. Conclusion This study significantly broadens our understanding of the genetic makeup associated with FL-HCC and HCC. It is particularly notable because it reveals clear disparities in gene modifications between FL-HCC and HCC. Further investigation is essential to unravel the functional consequences of these genetic variances. This exploration will aid in the development of targeted therapeutic approaches to enhance the prognosis of patients diagnosed with diverse subtypes of HCC.

Fibrolamellar Hepatocellular Carcinoma in Young Adult: A Case Report and Literature Review

Fibrolamellar carcinoma (FLC), a truly unique and uncommon variation of hepatocellular carcinoma (HCC), accounting for barely 1%–9% of all HCC cases. Fibrolamellar carcinoma, an unclear malignancy, appears to be more commonly observed in youthful individuals without any preexisting liver conditions. The nomenclature "fibrolamellar" originates from the presence of dense fibrous collagen bands enveloping the neoplastic cells. Contrary to hepatocellular carcinoma (HCC), cirrhosis and viral hepatitis infection do not serve as predisposing factors for fibrolamellar carcinoma (FLC). Additionally, FLC is not typically associated with increased levels of serum alpha-fetoprotein. Patients with FLC frequently manifest with nonspecific abdominal discomfort, queasiness, general discomfort, and decreased in body mass. Surgical intervention, specifically resection or liver transplantation, serves as the cornerstone of treatment and represents the sole potentially curative avenue. FLCs, or fibrolamellar carcinomas, have historically exhibited lower responsiveness to chemotherapy compared to conventional hepatocellular carcinomas (HCC). Nevertheless, it is important to note that in cases of advanced FLCs, the utilization of multi-modality treatments has shown promising effectiveness. The purpose of this review is to explain the clinical characteristics, diagnostic techniques, and therapeutic approaches for this uncommon tumor in order to enhance the knowledge of healthcare professionals.

Novel online calculator to predict reduced risk of early recurrence from adjuvant transarterial chemoembolisation for patients with hepatocellular carcinoma

BackgroundThe role of adjuvant transarterial chemoembolisation (TACE) to reduce postoperative recurrence varies widely among patients undergoing hepatectomy with curative intent for hepatocellular carcinoma (HCC). Personalised predictive tool to select which...

Fusion imaging versus ultrasound-guided percutaneous thermal ablation of liver cancer: a meta-analysis.

Ultrasound-guided percutaneous thermal ablation has become an alternative treatment for small hepatocellular carcinoma (HCC). Recent evidence suggests that fusion imaging (FI) may improve the feasibility and efficacy of thermal ablation for HCC, while the clinical evidence remains limited. To compare FI versus ultrasound-guided thermal ablation for HCC. Relevant cohort or randomized controlled trials were found by searching Medline, Web of Science, Cochrane Library, and Embase. The pooling of results was performed using a random-effects model incorporating heterogeneity. In this meta-analysis, 15 studies involving 1472 patients (1831 tumors) for FI-guided ablation and 1380 patients (1864 tumors) for ultrasound-guided ablation were included. Pooled results showed that compared to conventional HCC ablation guided by ultrasound, the FI-guided procedure showed a similar technique efficacy rate (risk ratio [RR] = 1.01, 95% confidence interval [CI] = 1.00-1.02, P = 0.25; I2 = 30%). However, FI-guided tumor ablation was associated with a lower incidence of overall complications (RR = 0.70, 95% CI = 0.50-0.97, P = 0.03; I2 = 0%). Moreover, patients receiving FI-guided tumor ablation had a lower risk of local tumor progression during follow-up than those with ultrasound-guided ablation (RR = 0.61, 95% CI = 0.47-0.78, P < 0.001; I2 = 13%). Subgroup analysis according to FI strategy, imaging techniques in controls, and tumor diameter showed consistent results (p for subgroup difference all >0.05). FI-guided thermal ablation may be more effective and safer than ultrasound-guided ablation for patients with HCC.

A machine learning model for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B.

Machine learning (ML) algorithms can be used to overcome the prognostic performance limitations of conventional hepatocellular carcinoma (HCC) risk models. We established and validated an ML-based HCC predictive model optimized for patients with chronic hepatitis B (CHB) infections receiving antiviral therapy (AVT). Treatment-naïve CHB patients who were started entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were enrolled. We used a training cohort (n = 960) to develop a novel ML model that predicted HCC development within 5 years and validated the model using an independent external cohort (n = 1937). ML algorithms consider all potential interactions and do not use predefined hypotheses. The mean age of the patients in the training cohort was 48 years, and most patients (68.9%) were men. During the median 59.3 (interquartile range 45.8-72.3) months of follow-up, 69 (7.2%) patients developed HCC. Our ML-based HCC risk prediction model had an area under the receiver-operating characteristic curve (AUC) of 0.900, which was better than the AUCs of CAMD (0.778) and REAL B (0.772) (both p < .05). The better performance of our model was maintained (AUC = 0.872 vs. 0.788 for CAMD and 0.801 for REAL B) in the validation cohort. Using cut-off probabilities of 0.3 and 0.5, the cumulative incidence of HCC development differed significantly among the three risk groups (p < .001). Our new ML model performed better than models in terms of predicting the risk of HCC development in CHB patients receiving AVT.

Kinetics of serum O-glycosylated M-hepatitis B surface antigen with hepatocellular carcinoma history and nucleos(t)ide analogue therapy in hepatitis B patients.

A newly developed O-glycosylated M-hepatitis B surface antigen (HBsAgGi) measurement system can detect hepatitis B surface antigen (HBsAg) associated with infectious particles. We investigated the association of HBsAgGi levels with clinical parameters and a history of hepatocellular carcinoma (HCC) development in a cross-sectional cohort analysis (Study 1) as well as the quantitative changes in HBsAgGi during nucleos(t)ide analogue (NA) therapy in a longitudinal cohort analysis (Study 2). A total of 124 patients with genotype C chronic HBV infection were analysed in Study 1 to evaluate correlations of HBsAgGi with conventional HBV markers and HCC history. Among those, 36 patients receiving NA therapy were enrolled in Study 2 for quantitative comparisons between pre-treatment baseline and 48 weeks of NA therapy. In Study 1, serum HBsAgGi was significantly associated with HBsAg (r = .5857, p < .00001) and weakly but significantly correlated with HBV DNA (r = .2936, p = .001). Although HBsAgGi (p = .111) was comparable between HCC history (+) group and HCC history (-) group, the HBsAgGi/HBsAg ratio (p = .011) was significantly higher in HCC history (+) patients. In Study 2, HBsAgGi was significantly decreased after 48 weeks of NA therapy (p < .001). HBsAg findings were similar (p = .005) along with an HBV DNA reduction (p < .001). In the baseline hepatitis B e antigen (HBeAg) (+) subgroup, HBsAgGi decreased significantly between baseline and 48 weeks of NA (p = .005), while HBsAg was comparable (p = .051). Low HBsAg and high HBsAgGi were associated with a history of HCC development. HBsAgGi decreased significantly by 48-week NA therapy.

The prognosis of fibrolamellar carcinoma versus conventional hepatocellular carcinoma: a study based on propensity score matching

Background The prognosis of fibrolamellar carcinoma (FLC) versus conventional hepatocellular carcinoma (HCC) remains controversial. Thus, this study aimed to compare the prognosis of FLC and HCC. Methods Patients with FLC and HCC in the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2015 were included. Propensity score matching (PSM) was performed to balance the clinical characteristics between FLC and HCC. Cox regression and Kaplan-Meier analysis were applied to identify the effect of pathology in prognosis before and after match in the whole cohort, as well as in subgroups of fibrosis score, AJCC stage and therapy. Results A total of 213 patients with FLC and 33365 patients with HCC between 2000 and 2015 were identified. Before matching, the overall survival (OS) and cancer-specific survival (CSS) were significantly better in FLC than HCC. After matching, FLC patients had better OS than HCC patients, but the CSS was similar between groups. Further analyses found that in patients at early stage (AJCC I-III) and/or accepted curative therapy, the prognosis was comparable between HCC and FLC. In patients without cirrhosis (F0), the HCC patients had similar prognosis with FLC patients. Prognosis benefit of FLC was observed in subgroups of AJCC stage IV and non-curative therapy, however, the concomitant diseases may affect the results. Conclusions The prognosis of FLC was significantly better than HCC before matching. However, after matching for clinical characteristics, the CSS was comparable between FLC and HCC.

Inflammation-related nomogram for predicting survival of patients with unresectable hepatocellular carcinoma received conversion therapy

The efficacy of conversion therapy for patients with unresectable hepatocellular carcinoma (HCC) is a common clinical concern.To analyse the prognostic factors of overall survival (OS) in patients with unresectable HCC who received conversion therapy.One hundred and fifty patients who met the inclusion criteria were enrolled and divided into a training cohort (n = 120) and a validation cohort (n = 30). Using the independent risk factors in the training cohort, a nomogram model was constructed to predict OS for patients treated with transarterial chemoembolization following hepatic resection. The nomogram was internally validated with the bootstrapping method. The predictive performance of nomogram was assessed by Harrell's concordance index (C-index), calibration plot and time-dependent receiver operating characteristic curves and compared with six other conventional HCC staging systems.Multivariate Cox analysis identified that albumin, blood urea nitrogen, gamma-glutamyl transpeptidase to platelet ratio, platelet to lymphocyte ratio, macrovascular invasion and tumour number were the six independent prognostic factors correlated with OS in nomogram model. The C-index in the training cohort and validation cohort were 0.752 and 0.807 for predicting OS, which were higher than those of the six conventional HCC staging systems (0.563 to 0.715 for the training cohort and 0.458 to 0.571 for the validation cohort). The calibration plots showed good consistency between the nomogram prediction of OS and the actual observations of OS. Decision curve analyses indicated satisfactory clinical utility. With a total nomogram score of 196, patients were accurately classified into low-risk and high-risk groups. Furthermore, we have deployed the model into online calculators that can be accessed for free at https://ctmodelforunresectablehcc.shinyapps.io/DynNomapp/.The nomogram achieved optimal individualized prognostication of OS in HCC patients who received conversion therapy, which could be a useful clinical tool to help guide postoperative personalized interventions and prognosis judgement.

Development and validation of prognostic dynamic nomograms for hepatitis B Virus-related hepatocellular carcinoma with microvascular invasion after curative resection.

The prediction models of postoperative survival for hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) with microvascular invasion (MVI) have not been well established. The study objective was the development of nomograms to predict disease recurrence and overall survival (OS) in these patients. Data were obtained from 1046 HBV-related MVI-positive HCC patients who had undergone curative resection from January 2014 to December 2017. The study was approved by the Eastern Hepatobiliary Surgery Hospital and Jinling Hospital ethics committee, and patients provided informed consent for the use of their data. Nomograms for recurrence and OS were created by Cox regression model in the training cohort (n=530). The modes were verified in an internal validation cohort (n= 265) and an external validation cohort (n= 251). The nomograms of recurrence and OS based on preoperative serological indicators (HBV-DNA, neutrophil-lymphocyte ratio, a-fetoprotein), tumor clinicopathologic features (diameter, number), surgical margin and postoperative adjuvant TACE achieved high C-indexes of 0.722 (95% confidence interval [CI], 0.711-0.732) and 0.759 (95% CI, 0.747-0.771) in the training cohort, respectively, which were significantly higher than conventional HCC staging systems (BCLC, CNLC, HKLC).The nomograms were validated in the internal validation cohort (0.747 for recurrence, 0.758 for OS) and external validation cohort(0.719 for recurrence, 0.714 for OS) had well-fitted calibration curves. Our nomograms accurately stratified patients with HBV-HCC with MVI into low-, intermediate- and high-risk groups of postsurgical recurrence and mortality. Prediction models for recurrence-free survival (https://baishileiehbh.shinyapps.io/HBV-MVI-HCC-RFS/) and OS (https://baishileiehbh.shinyapps.io/HBV-MVI-HCC-OS/) were constructed. The two nomograms showed good predictive performance and accurately distinguished different recurrence and OS by the nomograms scores for HBV-HCC patients with MVI after resection.