Etiology Of Hepatocellular Carcinoma Research Articles

Immunotherapy and the Combination with Targeted Therapies for Advanced Hepatocellular Carcinoma.

One of the most important abilities of a tumor is to establish a state of immunosuppression inside the tumor microenvironment. This is made possible through numerous mechanisms of tumor immune escape that have been identified in experimental studies during the last decades. In addition, the hepatic microenvironment is commonly oriented towards a state of immune tolerance because the liver receives blood from the hepatic arteries and portal veins containing a variety of endogenous antigens. Therefore, the hepatic microenvironment establishes an autoimmune tolerance, preventing an autoimmune reaction in the liver. On this basis, hepatic tumor cells may escape the immune system, avoiding being recognized and destroyed by immune cells. Moreover, since the etiology of Hepatocellular Carcinoma (HCC) is often related to cirrhosis, and hepatitis B or C, this tumor develops in the context of chronic inflammation. Thus, the HCC microenvironment is characterized by important immune cell infiltration. Given these data and the poor prognosis of advanced HCC, different immunotherapeutic strategies have been developed and evaluated for these patients. In this review, we describe all the clinical applications of immunotherapy for advanced HCC, from the drugs that have already been approved to the ongoing clinical trials.

Role of Etiology in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Counterfactual Event-Based Mediation Analysis.

Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival (OS). Data derived from a multicenter series of 313 HCC patients treated with lenvatinib between 2019 and 2022 were analyzed. Actuarial survival estimates were computed using the Kaplan-Meier method and compared with the log-rank test. We performed an event-based counterfactual mediation analysis to estimate direct (chronic inflammation and immunosuppression), indirect (tobacco smoking, alcohol use, illicit drug abuse with injections), and the total effect of viral etiology on OS. Results were expressed as hazard ratio (HR) and 95% CI. Median OS was 21 months (95% CI: 20-23) in the group with other etiologies and 15 months (14-16) in the group with viral etiology (p < 0.0001). The total effect of viral etiology was associated with OS (HR 2.76, 1.32-5.21), and it was mainly explained by the pure direct effect of viral etiology (HR 2.74, 1.15-4.45). By contrast, its total indirect effect was not associated with poorer survival (HR 1.05, 0.82-2.13). These results were confirmed when considering tobacco, alcohol consumption, or injection drug abuse as potential mediators. Median progression-free survival was 9 months (8-10) in patients with other etiologies and 6 months (5-7) in patients with viral etiology (p < 0.0001). No difference in terms of adverse event rate was observed between the two groups. Patients affected by HCC with nonviral etiology treated with lenvatinib exhibit longer survival than those with viral etiology. This finding may have relevance in the treatment decision-making process.

Immunotherapy in hepatocellular carcinoma: How does underlying liver disease influence therapeutic strategy and outcomes?

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, with up to 90% of HCC cases occurring in the setting of underlying cirrhosis. Therapeutic landscape for advanced HCC has dramatically changed in recent years with the advent of immunotherapy, including several combinations. Data suggest that the surrounding liver milieu may influence tumour response. In addition, different aetiologies of HCC and their effects on the host liver may impact response to immunotherapy. However, to date, guidelines do not take into account this parameter to guide therapeutic selection, and phase III trials are likewise performed in patients irrespective of HCC aetiology. Moreover, most clinical trial data are collected in highly selected patients with preserved liver function (defined as Child-Pugh class A) and controlled portal hypertension, which does not accurately reflect routine clinical practice. In this review, we discuss the influence of liver disease aetiology on the response to immunotherapy in patients with advanced HCC. We also discuss the safety and efficacy of various immunotherapeutic agents in Child-Pugh B patients to determine if these treatments are beneficial in this vulnerable patient population.

Clinical practice guidelines and real-life practice on hepatocellular carcinoma: the Hong Kong perspective.

Hepatocellular carcinoma (HCC) is a major public health burden in Hong Kong, and chronic hepatitis B is the most common HCC etiology in our region. With the high case load, extensive local expertise on HCC has been accumulated. This article summarized local guidelines and real-life practice on HCC management in Hong Kong. For HCC surveillance, liver ultrasound and serum alpha-fetoprotein for periodic screening is recommended in viral hepatitis or cirrhotic patients, and this is adhered to in clinical practice. HCC diagnosis is not covered in local guidelines, yet our practice is in-line with regional guidelines, where diagnosis is usually achieved by cross-sectional imaging and without the need for histology. Our guidelines recommend using the Hong Kong Liver Cancer Staging for pre-treatment staging, yet we routinely use other widely-adopted systems such as the Barcelona Clinic Liver Cancer Staging and the Tumor-Node-Metastasis Staging as well. Our local guidelines have provided clear treatment algorithms for the whole range of HCC therapies, including resection, ablation, transplant, transarterial chemoembolization, transarterial radioembolization, stereotactic body radiation therapy, targeted therapy, and immunotherapy. Real-life treatment choices are largely in line with the guidelines, although treatment protocols are individualized, and availability of specific therapies can vary between centers. Overall, HCC guidelines in Hong Kong are tailored based on local expertise and our unique patient population. The guidelines are up-to-date and provide practical pathways to assist our routine practice. Regular updates of local guidelines are warranted to account for the rapidly evolving paradigm of HCC management.

Hypersensitivity Reactions to Transarterial Chemoembolization with Cisplatin and Ethiodized Oil: A Retrospective Cohort Study

PurposeTo assess the incidence of hypersensitivity reactions (HSRs) and risk factors in patients with unresectable hepatocellular carcinoma (HCC) who have undergone transarterial chemoemblization (TACE) with cisplatin–ethiodized oil emulsion. Materials and MethodsBetween September 2014 and December 2019, patients with HCC in the authors’ institution undergoing TACE with cisplatin–ethiodized oil emulsion were retrospectively reviewed. Clinical, laboratory, and imaging data (including age, sex, etiology of HCC, serum bilirubin, albumin, alpha-fetoprotein, prothrombin time, dose of cisplatin, and details of TACE procedure) and data on procedural complications were retrieved from the registry of TACE. The incidence of HSRs was calculated, and variables were compared between the patient groups with and without HSRs. Predictive factors were analyzed using binary logistic regression. ResultsA total of 882 TACE procedures were involved in 257 patients with HCC. The median number of TACE procedures performed per patient was 3 (range, 1–23). The median dose of cisplatin per TACE session was 4.58 mg (range, 0.42–21 mg), and the median accumulated dose of cisplatin per patient was 15.42 mg (range, 0.52–125 mg). HSRs were identified in 22 (2.49%) of 882 procedures (17 [6.61%] of 257 patients). The median number of TACE procedures performed in these patients was 2.5 (range, 1–17). The median dose of cisplatin per TACE session was 5.42 mg (range, 0.63–20 mg), and the median accumulated dose of cisplatin per patient was 18.44 mg (range, 3.33–47.99 mg). Upon binary logistic regression analysis, parameters that showed statistically significant and independent association with HSRs included performance of ≥6 TACE procedures (odds ratio, 3.773; P = .012). ConclusionsPerformance of ≥6 TACE procedures was found to be independently associated with the incidence of HSRs. Patients undergoing multiple TACE procedures should be monitored closely for HSRs.

Hsa_circ_0006988 Promotes Sorafenib Resistance of Hepatocellular Carcinoma by Modulating IGF1 Using miR-15a-5p.

Hepatocellular carcinoma (HCC) is the most frequently occurring cancer and contributes to the largest number of cancer-associated deaths worldwide. Recent evidence suggests that circular RNAs (circRNAs), which are critical for HCC etiology and metastasis, are distinctly modulated in HCC. Nevertheless, the underlying mechanism of circRNA-mediated sorafenib resistance (SOR) in HCC is yet to be determined. The hsa_circ_0006988, IGF1, and miR-15a-5p contents were quantified via ELISA and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Cell Counting Kit-8 (CCK-8) was used for the IC50 evaluation. Lastly, associations among hsa_circ_0006988, IGF1, and miR-15a-5p were validated through dual-luciferase reporter (DLR) and RNA immunoprecipitation (RIP) assays. Herein, a new circRNA, hsa_circ_0006988, was identified, and its levels were markedly enhanced in SOR-resistant (SOR-R) HCC tissues. Functionally, hsa_circ_0006988 strongly suppressed SOR toxicity in vitro. Our examination of the signaling pathway revealed that hsa_circ_0006988 sequestered miR-15a-5p, a negative modulator of IGF1, thus suggesting that hsa_circ_0006988 deficiency diminished SOR resistance of HCC, and this action utilized the release of excess miR-15a-5p, which suppressed IGF1 levels. Moreover, miR-15a-5p overexpression reversed the hsa_circ_0006988-mediated SOR-R and enhanced IGF1 levels in HCC cells. Hsa_circ_0006988 partly promoted the SOR-R of HCC cells through miR-15a-5p sequestering and upregulation of IGF1 levels.

Adverse events as potential predictive factors of therapeutic activity in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

To investigate the possible correlation between the development of adverse events (AEs) and prognosis in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). A total of 286 patients with unresectable HCC treated with Atez/Bev as first-line systematic therapy were included. Regarding treatment-related AEs, decreased appetite of any grade, proteinuria of any grade, and fatigue of any grade were found with a frequency of ≥20%. Multivariate analysis adjusted for immune-related liver injury, immune-related endocrine dysfunction, proteinuria, fatigue, decreased appetite, hypertension, sex, age, Eastern Cooperative Oncology Group performance status, HCC etiology, HCC stage, Child-Pugh score, and α-fetoprotein showed that hypertension of any grade (hazard ratio [HR], 0.527; 95% confidence interval [CI], 0.326-0.854; p= 0.009) and α-fetoprotein ≥100 ng/ml (HR, 1.642; 95% CI, 1.111-2.427; p= 0.013) were independently associated with progression-free survival. Multivariate analysis adjusted for the same AEs showed that fatigue (HR, 2.354; 95% CI, 1.299-4.510; p= 0.010) was independently associated with overall survival. Median progression-free survival was 6.5months (95% CI, 5.2-8.1) in patients without hypertension of any grade and 12.6months (95% CI, 6.7-not available) in patients with hypertension of any grade (p= 0.035). The overall survival was significantly shorter in patients in whom treatment-related fatigue of any grade was observed (p< 0.001). Regarding response rates, the disease control rate of patients who developed treatment-related hypertension (94.2%) was significantly higher than those who did not (79.1%) (p= 0.009). Treatment-related hypertension is associated with good outcomes in patients with HCC treated with Atez/Bev.

Hepatocellular cancer of non-viral etiology: more questions than answers?

Hepatocellular carcinoma (HCC) is a public health problem worldwide and is one of the most common and lethal cancers worldwide, the sixth among the most common cancers and the second mortal cancer worldwide. Viral hepatitis is the main risk factor. Growing evidence suggests that the metabolic syndrome, which includes hyperlipidemia, dyslipidemia, and hypertension, increases the risk of developing HCC. Epidemic of obesity, the proportion of HCC with non-alcoholic fatty liver disease (NAFLD) in the Russian population is 17.4 %. In clinical practice, it is often difficult to identify the leading etiological factor. In a patient with concomitant viral hepatitis, HCC may be associated with alcohol abuse or metabolic disorders. In clinical trials, investigators evaluate the most likely etiology of HCC, and studies analyze subgroup: HBV, HCV, and non-viral etiologies, which include a variety of liver diseases: alcoholic liver disease, NAFLD, autoimmune hepatitis, and others. Differences in the effectiveness of systemic therapy depend on the main etiological factor has been published recently. Pivotal studies of combinations of immuno-oncological drugs have shown mixed results in efficacy. For the combination of atezolizumab with bevacizumab and pembrolizumab with lenvatinib, there was no difference in OS in non-viral subgroups, although the difference was significant for the combination of durvalumab with tremelimumab compared with TKIs from the control group. A multivariate analysis of patient characteristics showed that lenvatinib is an independent prognostic factor for OS, reducing the risk of death by 35 % compared with atezolizumab in combination with bevacizumab in patients with non-viral HCC etiology in the A. Casadei-Gardini study. The same has been proven for the NASH/NAFLD subgroup. Currently, it is difficult to conduct prospective clinical trials to assess the efficacy and safety of treatment depending on the etiology, it is important to focus on data from real-world evidence in order to have guidelines for making decisions regarding the treatment of non-viral HCC.

Comparisons of Viral Etiology and Outcomes of Hepatocellular Carcinoma Undergoing Liver Resection between Taiwan and Vietnam.

Epidemiologic data have suggested that etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas, and might be associated with different outcomes. We compared the viral etiology, clinicopathological characteristics and surgical outcomes between 706 Taiwanese and 1704 Vietnamese patients with HCC undergoing liver resection. Vietnamese patients had a significantly higher ratio of hepatitis B virus (HBV) (p &lt; 0.001) and a lower ratio of hepatitis C virus (HCV) (p &lt; 0.001) and non-B non-C than Taiwanese patients. Among patients with HBV or non-B non-C, the mean age was younger in Vietnam than in Taiwan (p &lt; 0.001, p = 0.001, respectively). The HCC patients in Vietnam had significantly higher serum alpha-fetoprotein (AFP) levels (p &lt; 0.001), larger tumors (p &lt; 0.001), and a higher ratio of macrovascular invasion (p &lt; 0.001) and extrahepatic metastasis (p &lt; 0.001), compared to those in Taiwan. Patients treated in Vietnam had a higher tumor recurrent rate (p &lt; 0.001), but no difference in overall survival was found between both groups. In subgroup analysis, the recurrent rate of HCC was the highest in patients with dual HBV/HCV, followed by HCV or HBV, and non-B non-C (p &lt; 0.001). In conclusion, although the viral etiology and clinicopathological characteristics of HCC differed, postoperative overall survival was comparable between patients in Taiwan and Vietnam.

IL-32 and IL-34 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a major challenge to clinicians due to its unacceptably high mortality and morbidity. The etiology of HCC is multi-faceted, including viral infection, alcoholism and non-alcoholic fatty liver disease. Dysregulated host immunity contributes to tumorigenesis among these susceptible individuals with pre-existing condition(s). IL-32 and IL-34 are key cytokines driving the development of chronic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, as well as chronic liver diseases. IL-32 and IL-34 play an important role augmenting the development of HCC, due to their direct influence over host inflammation, however, new roles for these cytokines in HCC are emerging. Here we comprehensively review the latest research for IL-32 and IL-34 in HCC, identifying a subset of potential therapeutic targets for use in precision medicine.

The beneficial impact of metabolic dysfunction-associated fatty liver disease on lenvatinib treatment in patients with non-viral hepatocellular carcinoma.

Lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Metabolic dysfunction-associated fatty liver disease (MAFLD) is becoming a major etiology of HCC. We aimed to evaluate the impact of MAFLD on the efficacy of lenvatinib. We enrolled 320 patients with HCC who were treated with lenvatinib. All patients were classified into the MAFLD (n=155) and non-MAFLD (n=165) groups. Independent factors for overall survival (OS) were analyzed. In the stratification analysis, HCC was categorized as non-viral (n=115) or viral HCC (n=205). The OS rate was significantly higher in the MAFLD group than in the non-MAFLD group (median 21.1 vs. 15.1months, p=0.002). Multivariate analysis demonstrated that, in addition to albumin-bilirubin grade and Barcelona Clinic Liver Cancer stage, MAFLD was identified as an independent factor for OS (HR 0.722, 95% CI 0.539-0.966, p=0.028). In the stratification analysis, the OS rate was significantly higher in the MAFLD group than in the non-MAFLD group among patients with non-viral HCC (median 21.1 vs. 15.1months, p=0.002), but not in patients with viral HCC. Furthermore, MAFLD was an independent negative risk factor for OS in patients with non-viral HCC (HR 0.506, 95% CI 0.297-0.864, P<0.01). However, MAFLD was not an independent factor for OS in patients with viral HCC. MAFLD was a beneficial factor for survival in patients with HCC treated with lenvatinib. Moreover, the better OS of the MAFLD group was more pronounced in patients with non-viral HCC. Lenvatinib may be a suitable agent for patients with non-viral HCC and MAFLD.

Efficacy of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma by Underlying Liver Disease Etiology

<h3>Purpose/Objective(s)</h3> The use of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been steadily increasing. Recently, it was reported that patients with HCC have a differential response to immune-checkpoint inhibitor based on the background liver disease etiology. Whether outcomes of SBRT are affected by underlying liver disease etiology is currently unknown. We therefore reviewed outcomes of SBRT with special focus on tumor size, BED, and underlying liver disease etiology. <h3>Materials/Methods</h3> This study is a retrospective review of HCC patients treated with SBRT at one institution between 2009 and 2021. Patients with tumor thrombus or extrahepatic disease were excluded. Kaplan-Meier curves and Cox regression models were used to describe freedom from local progression (FFLP) and overall survival (OS) rates and examine potential prognostic factors. <h3>Results</h3> One-hundred and sixty-four patients met study entry criteria. Median gross tumor volume (GTV) size was 9.3 cc (range 0.3 to 762.4 cc). 67% of patients had a history of hepatitis C, and 9% had a history of hepatitis B. 71% of patients received our institutional standard SBRT dose of 50 Gy in 5 fractions (biological effective dose [BED] 100 Gy). Other patients received lower doses ranging from 30 to 47.5 Gy in three to five fractions (BED range 48 to 93 Gy) if necessary to preserve normal liver tissue. Median follow-up time was 43 months (interquartile range [IQR] 36 to 52 months). Seventeen in-field failures and 67 deaths have occurred. 3- and 5-year FFLP rates were 84% and 75%, and 3- and 5-year OS rates were 65% and 48%, respectively. History of hepatitis C was associated with better FFLP (HR=0.36 (95% CI:0.14, 0.94), p=0.038). Treatment with 50 Gy was associated with better FFLP compared to treatment with lower doses for patients with hepatitis C (HR=0.15 (95%CI: 0.04, 0.63), p=0.01) but not for other patients (HR=3.1 (95%CI: 0.38, 24.7), p=0.29). <h3>Conclusion</h3> SBRT for HCC yields excellent local control, particularly for patients with hepatitis C. In hepatitis C patients, dose escalation beyond a BED of 100Gy may be more important for local control than in non-hepatitis C patients. More studies are necessary to better understand if HCC etiology should be considered when planning SBRT.

Clinical characteristics and prognosis of Korean patients with hepatocellular carcinoma with respect to etiology.

The profile of patients with hepatocellular carcinoma (HCC) has changed globally; the role of etiology in predicting prognosis of HCC patients remains unclear. We aimed to analyze the characteristics and prognosis of Korean patients with HCC according to disease etiology. This retrospective observational study included patients diagnosed with HCC between 2010 and 2014 in a single center in Korea. Patients with HCC aged <19 years old, had coinfection with other viral hepatitis, had missing follow-up data, were Barcelona Clinic Liver Cancer stage D, or died before 1 month were excluded. A total of 1,595 patients with HCC were analyzed; they were classified into the hepatitis B virus (HBV) group (1,183 [74.2%]), hepatitis C virus (HCV) group (146 [9.2%]), and non-B non-C (NBNC) group (266 [16.7%]). The median overall survival of all patients was 74 months. The survival rates at 1, 3, and 5 years were 78.8%, 62.0% and 54.9% in the HBV group; 86.0%, 64.0%, and 48.6% in the HCV group; and 78.4%, 56.5%, and 45.9% in the NBNC group, respectively. NBNC-HCC has a poorer prognosis than other causes of HCC. Survival was significantly longer in the HBV group with early-stage HCC than in the NBNC group. Furthermore, survival was shorter in patients with early-stage HCC and diabetes mellitus (DM) than in those without DM. The etiology of HCC affected clinical characteristics and prognosis to some extent. NBNC-HCC patients showed shorter overall survival than viral-related HCC patients. Additionally, the presence of DM is an additional important prognostic factor in patients with early-stage HCC.

Hepatocellular carcinoma (HCC) is changing its face: analysis of the temporal trends in aetiology and clinical patterns of HCC in South Australia.

The epidemiology of chronic liver disease is changing with the introduction of potent antiviral therapies for chronic hepatitis C virus (HCV) and the increasing prevalence of non-alcoholic steatohepatitis (NASH). To establish the impact of this change on the rates and clinical patterns of hepatocellular carcinoma (HCC) in South Australia (SA). Newly diagnosed HCC patients from January 2014 until December 2019 from four tertiary centres in SA were included. The overall age-standardised incidence rates (ASIR) of HCC were calculated using 2016 SA population as the standard. To assess the trends, Join-Point regression models were used to calculate the average annual percentage change (AAPC). Forecasting of overall and aetiology-specific HCC from 2020 to 2024 was performed using linear regression. There were 626 new cases of HCC in SA (males 80%; median age 64 years) during the study period. There was a significant increase in NASH-related HCC (AAPC: +7.0%; P < 0.05) from 2014 to 2019. However, there were no significant differences in the ASIR for overall HCC (AAPC: -4.1%), HCV-related HCC (AAPC: -8.0%) and stage of HCC diagnosis (AAPC: +3.0%; P > 0.05). Forecasting analysis projected the decline and increase in the incidence of HCV and NASH-related HCC, respectively, over the next few years. Overall ASIR of HCC has plateaued in SA. However, NASH-related HCC has increased significantly and is expected to continue to increase in the near future. Further research and intervention is required to reduce NASH-related HCC, a major contributor to the current and future burden of HCC.

Function of the Long Noncoding RNAs in Hepatocellular Carcinoma: Classification, Molecular Mechanisms, and Significant Therapeutic Potentials.

Hepatocellular carcinoma (HCC) is the most common and serious type of primary liver cancer. HCC patients have a high death rate and poor prognosis due to the lack of clear signs and inadequate treatment interventions. However, the molecular pathways that underpin HCC pathogenesis remain unclear. Long non-coding RNAs (lncRNAs), a new type of RNAs, have been found to play important roles in HCC. LncRNAs have the ability to influence gene expression and protein activity. Dysregulation of lncRNAs has been linked to a growing number of liver disorders, including HCC. As a result, improved understanding of lncRNAs could lead to new insights into HCC etiology, as well as new approaches for the early detection and treatment of HCC. The latest results with respect to the role of lncRNAs in controlling multiple pathways of HCC were summarized in this study. The processes by which lncRNAs influence HCC advancement by interacting with chromatin, RNAs, and proteins at the epigenetic, transcriptional, and post-transcriptional levels were examined. This critical review also highlights recent breakthroughs in lncRNA signaling pathways in HCC progression, shedding light on the potential applications of lncRNAs for HCC diagnosis and therapy.

Lysine demethylase KDM1A promotes cell growth via FKBP8–BCL2 axis in hepatocellular carcinoma

Advanced hepatocellular carcinoma (HCC) has a dismal prognosis. KDM1A (lysine demethylase 1A), overexpressed in multiple cancer types, is a lysine demethylase that targets both histone and nonhistone proteins. However, it is unclear how KDM1A expression affects HCC etiology. Here, we show that KDM1A can interact with and demethylate FKBP8 (FKBP prolyl isomerase 8), a cytoplasmic protein that regulates cell survival through the antiapoptotic protein BCL2 (B-cell lymphoma-2). We show that demethylation of FKBP8 enhances its ability to stabilize BCL2. Consistently, we observed positive correlation between KDM1A and BCL2 protein levels in liver cancer patients. Functionally, we reveal that FKBP8 demethylation by KDM1A is critical for liver cancer cell growth in vitro and in vivo. We went on to explore the mechanisms that might regulate KDM1A cytoplasmic localization. We found that the cytoplasmic localization and protein stability of KDM1A were promoted by acetylation at lysine-117 by the acetyl transferase KAT8 (lysine acetyltransferase 8). In agreement with this, we show that KDM1A–K117 (lysine 117) acetylation promotes demethylation of FKBP8 and level of BCL2. Finally, it has been shown that the efficacy of sorafenib, a first-line treatment for advanced HCC, is limited by clinical resistance. We show that KDM1A and BCL2 protein levels are increased during acquired sorafenib resistance, whereas inhibiting KDM1A can antagonize sorafenib resistance. Collectively, these results define a functional KDM1A–FKBP8–BCL2 axis in HCC.

Does HCC Etiology Impact the Efficacy of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma? An Asian Liver Radiation Therapy Group Study.

Background/PurposeThe Asian Liver Radiation Therapy Study Group has formed a large and detailed multinational database of outcomes following stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). Here, we explored the potential impact of HCC etiology on SBRT efficacy. Tumor control probability (TCP) models were established to estimate the likelihood of local control (LC).MethodsData from 415 patients who were treated with SBRT for HCC were reviewed. Cox proportional hazards models were used to identify key predictors of LC. TCP models accounting for biologic effective dose (BED) and tumor diameter were generated to quantify associations between etiology and LC.ResultsCox models demonstrated that hepatitis C virus (HCV) infection was associated with favorable LC following SBRT (HR=0.52, 95% CI 0.04–0.96, p=0.036). The 2-year LC rate for patients with HCV etiology was 88%, compared to 78% for other patients. Small tumor and high BED were also associated with favorable LC. TCP models demonstrated a 10–20% absolute increase in predicted LC across the range of SBRT doses and tumor sizes.ConclusionWe found a novel association between HCV status and LC after SBRT for HCC that warrants further exploration. If validated in other datasets, our findings could help clinicians tailor SBRT schedules.

Contemporary Changes in Etiology for Hepatocellular Carcinoma in Liver Transplantation

The major risk factor for developing hepatocellular carcinoma (HCC) is chronic liver disease, with hepatitis C virus (HCV) and alcohol-related liver disease (ARLD) predominating historically in the United States.1 However, with the recent availability of safe and effective direct-acting antiviral (DAA) therapy for HCV, and the continuing rise in nonalcoholic steatohepatitis (NASH), the relative etiology of HCC could further evolve.1–4 In 2016, ARLD and NASH surpassed HCV as the leading indication for liver transplant (LT) in patients without HCC; similar trends may be expected for HCC LT downstream.

Hepadnavirus DNA Is Detected in Canine Blood Samples in Hong Kong but Not in Liver Biopsies of Chronic Hepatitis or Hepatocellular Carcinoma.

Chronic hepatitis and hepatocellular carcinoma (HCC) caused by the hepadnavirus hepatitis B virus (HBV) are significant causes of human mortality. A hepatitis-B-like virus infecting cats, domestic cat hepadnavirus (DCH), was reported in 2018. DCH DNA is hepatotropic and detectable in feline blood or serum (3.2 to 12.3%). Detection of HBV DNA has been reported in sera from 10% of free-roaming dogs in Brazil, whereas 6.3% of sera from dogs in Italy tested positive for DCH DNA by real-time quantitative PCR (qPCR). If DCH, HBV, or another hepadnavirus is hepatotropic in dogs, a role for such a virus in the etiology of canine idiopathic chronic hepatitis (CH) or HCC warrants investigation. This study investigated whether DCH DNA could be detected via qPCR in blood from dogs in Hong Kong and also whether liver biopsies from dogs with confirmed idiopathic CH or HCC contained hepadnaviral DNA using two panhepadnavirus conventional PCRs (cPCR) and a DCH-specific cPCR. DCH DNA was amplified from 2 of 501 (0.4%) canine whole-blood DNA samples. A second sample taken 6 or 7 months later from each dog tested negative in DCH qPCR. DNA extracted from 101 liver biopsies from dogs in Hong Kong or the USA, diagnosed by board-certified pathologists as idiopathic CH (n = 47) or HCC (n = 54), tested negative for DCH DNA and also tested negative using panhepadnavirus cPCRs. This study confirms that DCH DNA can be detected in canine blood by qPCR, although at a much lower prevalence than that reported previously. We identified no evidence to support a pathogenic role for a hepadnavirus in canine idiopathic CH or HCC.

Implementation of a Hepatocellular Carcinoma Screening Program for At-risk Patients Safety-Net Hospital: A Model for National Dissemination.

This study aimed to enhance hepatocellular carcinoma (HCC) screening to achieve earlier diagnosis of patients with hepatitis C (HCV) cirrhosis in our Safety-Net population. Adherence to HCC screening guidelines at Safety-Net hospitals is poor. Only 23% of patients with HCC at our health system had a screening exam within 1-year of diagnosis and 46% presented with stage IV disease. HCV-induced cirrhosis remains the most common etiology of HCC (75%) in our patients. In the setting of an established HCV treatment clinic, an HCC screening quality improvement initiative was initiated for patients with stage 3 fibrosis or cirrhosis by transient elastography. The program consisted of semiannual imaging. Navigators scheduled imaging appointments and tracked compliance. From April 2018 to April 2021, 318 patients were enrolled (mean age 61 years, 81% Black race, 38% uninsured). Adherence to screening was higher than previously reported: 94%, 75%, and 74% of patients completed their first, second, and third imaging tests. Twenty-two patients (7%) were diagnosed with HCC; 55% stage I and 14% stage IV. All patients were referred and 13 (59%) received treatment. Median time to receipt of treatment was 77 days (range, 32-282). Median overall survival for treated patients was 32 months. Implementation of an HCC screening program at a safety-net hospital is feasible and facilitated earlier diagnosis in this study. Patient navigation and tracking completion of imaging tests were key components of the program's success. Next steps include expanding the program to additional at-risk populations.