Cases Of Primary Liver Cancer Research Articles

The switch triggering the invasion process: Lipid metabolism in the metastasis of hepatocellular carcinoma.

In humans, the liver is a central metabolic organ with a complex and unique histological microenvironment. Hepatocellular carcinoma (HCC), which is a highly aggressive disease with a poor prognosis, accounts for most cases of primary liver cancer. As an emerging hallmark of cancers, metabolic reprogramming acts as a runaway mechanism that disrupts homeostasis of the affected organs, including the liver. Specifically, rewiring of the liver metabolic microenvironment, including lipid metabolism, is driven by HCC cells, propelling the phenotypes of HCC cells, including dissemination, invasion, and even metastasis in return. The resulting formation of this vicious loop facilitates various malignant behaviors of HCC further. However, few articles have comprehensively summarized lipid reprogramming in HCC metastasis. Here, we have reviewed the general situation of the liver microenvironment and the physiological lipid metabolism in the liver, and highlighted the effects of different aspects of lipid metabolism on HCC metastasis to explore the underlying mechanisms. In addition, we have recapitulated promising therapeutic strategies targeting lipid metabolism and the effects of lipid metabolic reprogramming on the efficacy of HCC systematical therapy, aiming to offer new perspectives for targeted therapy.

Incidence of liver cancer in young adults according to the global burden of disease database 2019.

The worldwide burden of cancer is increasing in younger populations. However, the epidemiology of primary liver cancer remains understudied in young adults compared to other cancer forms. This study analyzed data from the Global Burden of Disease (GBD) study between 2010 and 2019 to assess the age-standardized incidence, mortality, and disability-adjusted life years (DALYs) associated with primary liver cancer in the young (15-49y), stratified by region, nation, sociodemographic index, and sex. The study found a global estimate of 78,299 primary liver cancer cases, 60,602 deaths, and 2.90 million DALYs in the young population. The Western Pacific region exhibited the highest burden in 2019, showing the most significant increase compared to other regions between 2010-2019. More than half of countries worldwide have undergone an increase in primary liver cancer incidence rates in young adults. Around 12.51% of deaths due to primary liver cancer occur in young individuals. Throughout the study period, there was a significant decline in primary liver cancer mortality due to most etiologies, except for metabolic dysfunction-associated steatotic liver disease (MASLD)-attributable primary liver cancer (annual percentage change [APC] +0.87%, 95% confidence interval 0.70-1.05%) and alcohol-attributable primary liver cancer (APC +0.21%, 95% confidence interval 0.01-0.42%). Limitations of the GBD database include reliance on the quality of primary data and possible underestimation of alcohol consumption. Over the past decade, there has been a marked increase in the burden of primary liver cancer, especially that originating from steatotic liver disease. This trend calls for the development of urgent and comprehensive strategies to mitigate this rising burden globally.

Application of Laennec extrathecal blockade combined with indocyanine green fluorescence imaging in laparoscopic anatomic hepatectomy.

To investigate the safety and application value of combining Laennec extracapsular occlusion with ICG fluorescence imaging in laparoscopic anatomic hepatectomy. Complete laparoscopic dissection was performed outside the Laennec sheath, blocking Glisson's pedicle of the corresponding liver segment or lobe. An appropriate amount of indocyanine green (ICG) dye was intravenously injected, and the boundary line between the pre-cut liver segment and liver lobe was identified using fluorescence laparoscopy. Complete resection of the liver segment or lobe was performed based on anatomical markers. Clinical data, including operation time, intraoperative blood loss, postoperative hospital stay, and postoperative complications, were collected. A total of 14 cases were included in the study, including seven cases of primary liver cancer, three cases of metastatic liver cancer, three cases of intrahepatic bile duct calculi, and one case of hepatic hemangioma. All 14 patients underwent anatomic hepatectomy under fluorescent laparoscopy, with four cases involving the right liver, seven cases involving the left liver, two cases involving the right anterior lobe, and one case involving the right posterior lobe. Combining laparoscopic follow-up of the Laennec membrane with Glisson outer sheath block and intraoperative ICG fluorescence imaging provides real-time guidance for locating the resection boundaries during anatomic hepatectomy. This approach helps in controlling intraoperative bleeding, reducing operation time, and ensuring high safety. It holds significant value in clinical application.

Sex-specific impact of dietary patterns on liver cancer incidence: updated results from two population-based cohort studies in China.

The associations between dietary patterns and liver cancer risk have received much attention, but evidence among the Chinese population is scarce. This study aims to update the results of two cohort studies and provide the sex-specific associations in the Chinese population. This study was based on two cohorts from the Shanghai Men's Health Study (SMHS) and the Shanghai Women's Health Study (SWHS). Diet information was collected by validated food frequency questionnaires. Dietary patterns were derived by factor analysis. Cox regression model was utilized to estimate the hazard ratio (HR) and 95% confidence interval (CI) for associations between dietary patterns and liver cancer risk. During median follow-up years of 11.2 (male) and 17.1 (female) years, 427 males and 252 females were identified as incident primary liver cancer cases. In males, vegetable-based dietary pattern was inversely associated with liver cancer (HRQ4-Q1: 0.67, 95%CI 0.51-0.88, Ptrend < 0.001). Interaction analysis indicated that in males lower vegetable-based dietary pattern score and older age/medical history of chronic hepatitis combined increase the hazard of liver cancer more than the sum of them, with a 114% and 1061% higher risk, respectively. In females, the fruit-based dietary pattern was associated with a reduced risk of liver cancer (HRQ4-Q1: 0.63, 95%CI 0.42-0.95, Ptrend = 0.03). In both males and females, null associations were observed between the meat-based dietary pattern and the risk of liver cancer. A vegetable-based dietary pattern in males and a fruit-based dietary pattern in females tended to have a protective role on liver cancer risk. This study provided updated information that might be applied to guide public health action for the primary prevention of liver cancer.

Effect of CT-Guided Microwave Ablation Combined with TACE on Liver Function and Survival of Patients with Primary Liver Cancer

Objective: To explore the effect of transarterial chemoembolization (TACE) + CT-guided microwave ablation (MWA) on treating patients with primary liver cancer. Methods: 78 primary liver cancer cases were enrolled and divided into groups according to their assigned surgical plans. The control group was treated with TACE alone, and the observation group was treated with TACE + CT-guided MWA. The efficacy of the treatment and the liver function indicators and follow-up results of the patients of the two groups were compared. Results: The efficacy of the treatment received by the observation group was higher than that of the control group. Besides, the patients in the observation group exhibited better improvement in liver function indicators after 3 months of treatment. Furthermore, the survival rates of 1 and 2 years after surgery of the observation group were all higher than those of the control group (P &lt; 0.05). Conclusion: TACE combined with CT-guided MWA is more effective in treating primary liver cancer compared to TACE alone. Besides, it resulted in better improvement of liver function and long-term survival rate. Therefore, this treatment regime should be popularized.

Dual-phenotype hepatocellular carcinoma: correlation of MRI features with other primary hepatocellular carcinoma and differential diagnosis.

Dual-phenotype hepatocellular carcinoma (DPHCC) is a rare subtype of hepatocellular carcinoma characterized by high invasiveness and a poor prognosis. The study aimed to compare clinical and magnetic resonance imaging (MRI) features of DPHCC with that of non-DPHCC and intrahepatic cholangiocarcinoma (ICC), exploring the most valuable features for diagnosing DPHCC. A total of 208 cases of primary liver cancer, comprising 27 DPHCC, 113 non-DPHCC, and 68 ICC, who undergone gadoxetic acid-enhanced MRI, were enrolled in this study. The clinicopathologic and MRI features of all cases were summarized and analyzed. Univariate and multivariate logistic regression analyses were conducted to identify the predictors. Kaplan-Meier survival analysis was used to evaluate the 1-year and 2-year disease-free survival (DFS) and overall survival (OS) rates in the cohorts. In the multivariate analysis, the absence of tumor capsule (P = 0.046; OR = 9.777), persistent enhancement (P = 0.006; OR = 46.941), arterial rim enhancement (P = 0.011; OR = 38.211), and target sign on DWI image (P = 0.021; OR = 30.566) were identified as independently significant factors for distinguishing DPHCC from non-DPHCC. Serum alpha-fetoprotein (AFP) >20 μg/L (P = 0.036; OR = 67.097) and hepatitis B virus (HBV) positive (P = 0.020; OR = 153.633) were independent significant factors for predicting DPHCC compared to ICC. The 1-year and 2-year DFS rates for patients in the DPHCC group were 65% and 50%, respectively, whereas those for the non-DPHCC group were 80% and 60% and for the ICC group were 50% and 29%, respectively. The 1-year and 2-year OS rates for patients in the DPHCC group were 74% and 60%, respectively, whereas those for the non-DPHCC group were 87% and 70% and for the ICC group were 55% and 37%, respectively. Kaplan-Meier survival analysis revealed significant differences in the 1-year and 2-year OS rates between the DPHCC and non-DPHCC groups (P = 0.030 and 0.027) as well as between the DPHCC and ICC groups (P = 0.029 and 0.016). In multi-parameter MRI, combining the assessment of the absence of tumor capsule, persistent enhancement, arterial rim enhancement, and target sign on DWI image with clinical data such as AFP >20 μg/L and HBV status may support in the diagnosis of DPHCC and differentiation from non-DPHCC and ICC. Accurate preoperative diagnosis facilitates the selection of personalized treatment options.

Efficacy of Yttrium-90 Transarterial Radioembolisation in Advanced Hepatocellular Carcinoma: An Experience With Hybrid Angio-Computed Tomography and Glass Microspheres

BackgroundHepatocellular carcinoma is one of the most common malignancies worldwide. Transarterial radioembolization (TARE) involves selective intra-arterial administration of microspheres loaded with a radioactive compound like Yttrium90. Conventionally, C-arm based cone-beam computed tomography has been used extensively during TARE. However, Angio-CT is a relatively new modality which combines the advantages of both fluoroscopy and Computed Tomography (CT). There is scarce literature detailing the use of Angio-CT in Y90 TARE. MethodsThis was a retrospective study of primary liver cancer cases in which TARE procedure was done from November 2017 to December 2021. Glass-based Y-90 microspheres were used in all these cases. All the cases were performed in the hybrid Angio-CT suite. A Single Photon Emission Computed Tomography – Computed Tomography (SPECT-CT) done post planning session determined the lung shunt fraction and confirmed the accurate targeting of the lesion. Post drug delivery, PET-CT was obtained to confirm the distribution of the Y-90 particles. The technical success, median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were recorded. ResultsA total of 56 hepatocellular carcinoma patients underwent TARE during this period out of which 36 patients (30 males and 6 females) underwent Y90 TARE. The etiology of cirrhosis included non-alcoholic steatohepatitis (NASH) (11), hepatitis C (HCV) (11), hepatitis B (HBV) (9), metabolic dysfunction and alcohol associated liver disease (MetALD) (2), alcoholic liver disease (ALD) (1), cryptogenic (1) and autoimmune hepatitis (AIH) (1). The technical success was 100% and median follow-up was 7 months (range: 1 - 32 months). The median OS was 15 months (range 10.73 – 19.27 months; 95% CI) and the median local PFS was 4 months (range 3.03 – 4.97 months; 95% CI). The ORR (best response, CR + PR) was 58%. No major complications were seen in this study. ConclusionTARE is a viable option for liver cancers in all stages but more so in the advanced stages. The use of Angio-CT in TARE aids in the precise delivery of the particles to the tumour and avoids non-target embolization.

From Conversion to Resection for Unresectable Hepatocellular Carcinoma: A Review of the Latest Strategies.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China, accounting for the majority of primary liver cancer cases. Liver resection is the preferred curative method for early-stage HCC. However, up to 80-85% of patients have already missed the opportunity of radical surgery due to tumor advances at the time of consultation. Conversion therapies are a series of medications and treatments for initially inoperable patients. For early-stage unresectable HCC (uHCC) patients, conversion therapies are designed to meet surgical requirements by increasing the volume of the residual liver. Meanwhile, for advanced cases, conversion therapies strive for tumor shrinkage and down-staging, creating the opportunity for liver resection or liver transplantation. This review summarizes the latest advances in conversion therapies and highlights their potential for improving the survival benefit of patients with uHCC.

A clinical study of targeted immunotherapy combined with hepatic arterial chemoembolization in the treatment of liver injury associated with primary liver cancer

Objective: To investigate the conditions of occurrence and factors influencing liver injury caused by molecular targeted drugs and immune checkpoint inhibitors combined with hepatic arterial chemoembolization (TACE) in the treatment of primary liver cancer. Methods: 105 cases of primary liver cancer admitted to the Third Hospital of Hebei Medical University from January 2020 to June 2023 were selected. Patients liver biochemical indicators conditional changes before and after treatment with targeted drugs+TACE and targeted drugs+immune checkpoint inhibitors (ICIs)+TACE were analyzed. Liver injuries above grade 2 and its independent risk factors to predict and evaluate model accuracy were established. Independent samples t-test, analysis of variance, and rank sum test were used for comparison of measurement data between groups. Count data were compared with a χ(2) test between groups. Results: A total of 50 (47.62%) of the 105 cases developed liver injury during the treatment course, with 26 (52%) cases of first-grade liver injury, 16 (32%) cases of second-grade liver injury, 8 (16%) cases of third-grade liver injury, and none of fourth-grade liver injury. There was no statistically significant difference in the incidence of liver injury between the two groups of patients (χ(2)=1.299, P = 0.637). Multivariate logistic regression analysis showed that total bilirubin, prealbumin, and prothrombin activity were independent risk factors for the occurrence of liver injury. The total bilirubin-prealbumin-prothrombin activity (TAP) model was established. TAP diagnosis of grade 2 or higher liver injury had an area under the receiver characteristic curve of 0.935, sensitivity of 84.35%, and specificity of 92.31% at a cut-off value of 1.24, and significantly better diagnostic performance than albumin-bilirubin (ALBI) grade. Conclusion: The occurrence of severe liver injury is minimal and well tolerated in the targeted drug + TACE treatment group and targeted drug + ICIs + TACE treatment group. The TAP model can be used as a new method to assess the risk of liver injury above grade 2 in patients treated with targeted immunotherapy combined with TACE.

DTL is a Novel Downstream Gene of E2F1 that Promotes the Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), one of the world's most prevalent malignancies, accounts for 90% of primary liver cancer cases. Recent studies have shown an increased expression of denticles E3 ubiquitin protein ligase homolog (DTL) in several different tumor types, but its function and regulatory mechanisms remain unclear. This study aimed to investigate the expressions of the Cullin4 (CUL4) complex in HCC and elucidate the roles of DTL in HCC cells. The relative expression of the CUL4 complex and its clinical significance were analyzed with The Cancer Genome Atlas (TCGA) data, and the level of DTL was confirmed by immunohistochemistry. The functions of DTL1 and upstream E2F1 were evaluated by a Western blot, MTT, transwell, and xenograft in HCC cell lines. The elevated mRNA expression of the CUL4 complex, including CUL4B, DDB1 (Damage Specific DNA Binding Protein 1), and DTL, was associated with the overall survival of HCC patients. We also found that the DTL protein was elevated in HCC tissues, and patients with highly expressed DTL and nucleus-located DTL had a poorer survival time. DTL knockdown significantly inhibited cancer proliferation, migration, and invasion. Further experiments showed that E2F1 was an upstream regulatory molecule of DTL, which was bound to the promoter of DTL, promoting the expression of DTL. The study results demonstrate that E2F1-DTL signaling promotes the growth, migration, and invasion of HCC cells, which provides new insights and a potential biological target for future HCC therapies.

Circulating small extracellular vesicle-derived splicing factor 3b subunit 4 as a non-invasive diagnostic biomarker of early hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer cases and related deaths. The purpose of this study was to assess the diagnostic value of splicing factor 3b subunit 4 (SF3B4) as a novel non-invasive biomarker for HCC and determine the association between SF3B4 expression and immune cell infiltration.MethodsAn enzyme-linked immunosorbent assay (ELISA) was used to detect SF3B4 levels in plasma samples obtained from healthy controls (HCs) and patients with chronic hepatitis, liver cirrhosis, and HCC. The expression levels of autoantibodies that detect SF3B4 in the plasma samples of each group of patients were measured. Small extracellular vesicles (EVs) were isolated from patient sera, and the expression levels of EV-SF3B4 were measured using quantitative reverse transcription PCR.ResultsELISA results confirmed that the expression levels of SF3B4 proteins and autoantibodies in the plasma of patients with HCC were higher than those in HCs. However, their diagnostic performance was not better than that of alpha-fetoprotein (AFP). The mRNA expression of SF3B4 in serum EV increased but not in the buffy coat or serum of patients with HCC. Serum EV-SF3B4 displayed better diagnostic power than AFP for all stages of HCC (AUC = 0.968 vs. 0.816), including early-stage HCC (AUC = 0.960 vs. 0.842), and this was consistent in the external cohort. Single-cell RNA sequencing indicated that SF3B4 expression was correlated with myeloid-derived suppressor cells. The Tumor Immune Estimation Resource database reconfirmed the correlation between SF3B4 expression and immune cell infiltration in HCC.ConclusionsSF3B4 may be associated with tumor immune infiltration in HCC, and EV-SF3B4 shows potential as a novel non-invasive diagnostic biomarker of HCC.

Visceral and ectopic fat are more predictively associated with primary liver cancer than overall obesity from genetic sights: A Mendelian randomization study.

Several observational studies have reported an association between obesity and primary liver cancer (PLC), while the causality behind this association and the comparison of the risk effects of different obesity indicators on PLC remain unclear. In this study, we performed two-sample Mendelian randomization (MR) analyses to assess the associations of genetically determined liver fat, visceral adipose tissue (VAT), and body mass index (BMI) with the risk of PLC. The summary statistics of exposures were obtained from two genome-wide association studies (GWASs) based on the UK Biobank (UKB) imaging cohort and the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. GWAS summary statistics for PLC were obtained from FinnGen consortium R7 release data, including 304 PLC cases and 218 488 controls. Inverse-variance weighted (IVW) was used as the primary analysis, and a series of sensitivity analyses were performed to further verify the robustness of these findings. IVW analysis highlighted a significant association of genetically determined liver fat (OR per SD increase: 7.14; 95% CI: 5.10-9.99; P = 2.35E-30) and VAT (OR per SD increase: 5.70; 95% CI: 1.32-24.72; P = .020) with PLC but not of BMI with PLC. The findings were further confirmed by a series of MR methods. No evidence of horizontal pleiotropy between these associations existed. Our study suggested that genetically determined liver fat and VAT rather than BMI were associated with an increased risk of PLC, which suggested that visceral fat distribution is more predictive of the clinical risk of PLC than common in vitro measures.

Incidence trends of primary liver cancer in different geographical regions of China from 1978 to 2012 and projections to 2032: An age-period-cohort analysis.

China accounted for 45.3% of new cases of primary liver cancer (PLC) worldwide in 2020. While variations in PLC incidence between different regions of China and decreasing incidence in overall China have been reported, incidence patterns have not been thoroughly explored by region. We examined the nearly status and temporal trends of PLC incidence in different geographical regions in China and project future trends. The age-standardized incidence rate (ASR) was estimated for 1978 to 2012 by different geographical regions and gender in China. Age-period-cohort model was adopted to evaluate age and birth cohort effects on the temporal trend of five registries of China (Hong Kong, Shanghai, Jiashan, Harbin and Zhongshan), Bayesian age-period-cohort model was adopted to project future trends for 2013 to 2032. PLC incidence in China exhibits marked geographical disparity, with the highest incidence in Southwest China, and gender differences being particularly pronounced in South China. While other registries exhibited decreasing trend, Zhongshan exhibited an increasing trend, with the cohort effect showing a marked upward trend for females born in 1916 to 1949 and males born in 1916 to 1962. During 2013 to 2032, the ASR appears to increase by 86.9% for men and 40.0% for women in Zhongshan, while the remaining registries will decline by around 50%. Since the high incidence of hepatitis B virus infection in early birth cohort, recent rise of nonviral risk factors and the severe aging of the Chinese population, it may be critical to tailor future prevention and control strategies for PLC to the distribution of risk factors in different geographical regions.

New Era of Immune-Based Therapy in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10-15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC.

Association of dietary insulinemic and inflammatory potential with risk of liver cancer and chronic liver disease mortality in postmenopausal women: a prospective cohort study

BackgroundLow diet quality, diabetes, and chronic inflammation are risk factors of liver cancer and chronic liver disease (CLD), but the extent to which insulinemic and inflammatory diets are independently associated with risk of liver cancer and CLD mortality is unknown. MethodsWe conducted a prospective cohort analysis among 78,356 postmenopausal women in the Women’s Health Initiative Observational Study. Two validated dietary indices, the empirical dietary index for hyperinsulinemia (EDIH) and the empirical dietary inflammation pattern (EDIP), were estimated from a food-frequency questionnaire. Incident cases of liver cancer and CLD mortality were adjudicated via review of medical records and linkage to National Death Index. Multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards models, adjusted for age, diabetes, body mass index, and other covariates. ResultsDuring a median 22.1 y of follow-up, we documented 176 primary liver cancer cases and 156 CLD mortality cases. EDIH was positively associated with incident liver cancer (HRQuartile 4 vs. Quartile 1 = 1.68; 95% CI: 1.00, 2.83; P-trend = 0.05) and CLD mortality (HRQ4 vs. Q1 = 2.28; 95% CI: 1.25, 4.15; P-trend = 0.02) in the multivariable model. EDIP was also positively associated with liver cancer (HRQ4 vs. Q1 = 1.88; 95% CI: 1.17, 3.03; P-trend = 0.009) and CLD mortality (HRQ4 vs. Q1 = 1.85; 95% CI: 1.09, 3.15; P-trend = 0.007). Estimates remained significant and robust in sensitivity analyses. Further analyses indicated positive associations for refined grains, processed meat, sugary beverages, and eggs, and inverse associations for coffee/tea and poultry. ConclusionsDietary insulinemic and inflammatory potentials were independently associated with higher risk of liver cancer and CLD mortality in U.S. postmenopausal women. These findings suggest a potential role for diet modification to reduce risk of liver cancer and CLD.

Abstract 6456: Association of dietary inflammatory and insulinemic potential with risk of liver cancer and chronic liver disease mortality

Abstract Background: Increasing burdens of liver cancer and chronic liver disease (CLD) urge investigation of modifiable risk factors for primary prevention. Despite strong experimental evidence showing the role of chronic insulin resistance/hyperinsulinemia and inflammation in liver cancer and CLD, whether the insulinemic and inflammatory potential of diet are independently associated with higher risk of these outcomes requires further investigation. Methods: We conducted a prospective cohort study among 78,356 postmenopausal women in the Women’s Health Initiative Observational Study. Two validated dietary indices that predict circulating C-peptide or biomarkers of inflammation, namely, the empirical dietary index for hyperinsulinemia (EDIH) and the empirical dietary inflammation pattern (EDIP), were estimated from a food frequency questionnaire. Incident cases of liver cancer and CLD mortality were ascertained via review of medical records and linkage to national registries. Multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazard models, adjusted for age, diabetes, body mass index (BMI), and other covariates. Results: During a median 22.1 years of follow-up, we documented 176 primary liver cancer cases and 156 CLD mortality cases. The EDIH was positively associated with incident liver cancer risk (HRQuartile4 vs. Quartile1 = 1.70; 95% CI: 1.03, 2.81; p-trend = 0.03) and CLD mortality risk (HRQ4 vs. Q1 = 2.75; 95% CI: 1.54, 4.93; p-trend = 0.01) in the multivariable adjusted model, including diabetes and BMI as covariates. The EDIP was also positively associated with liver cancer (HRQ4 vs. Q1 = 1.93; 95% CI: 1.21, 3.09; p-trend &amp;lt;0.001) and CLD mortality risk (HRQ4 vs. Q1 = 2.09; 95% CI: 1.24, 3.52; p-trend &amp;lt;0.001) in the multivariable adjusted model. The estimates remained significant and robust in sensitivity analyses, after exclusion of cases in the first 2 years of follow-up or with liver disease history. There was no additive effect between the two dietary indices. Further analyses of individual food groups and liver outcomes indicated positive associations with refined grains, processed meat, butter, and eggs, and inverse associations with coffee, poultry, green leafy vegetables, and dark yellow vegetables. Conclusions: Dietary insulinemic and inflammatory potential were independently associated with higher risk of liver cancer and CLD mortality in US postmenopausal women. Monitoring dietary patterns to reduce chronic hyperinsulinemia and inflammation may contribute to the primary prevention of liver cancer and CLD mortality. Citation Format: Xinyuan Zhang, Longgang Zhao, Cami Christopher, Fred K. Tabung, Wei Bao, David O. Garcia, Marian L. Neuhouser, Aladdin H. Shadyab, Nazmus Saquib, Lesley Tinker, Xuehong Zhang. Association of dietary inflammatory and insulinemic potential with risk of liver cancer and chronic liver disease mortality. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6456.

Abstract 35: Development of novel human hepatocellular carcinoma models using genetically modified human hepatocytes in FSRG humanized liver mice

Abstract The incidence of liver cancer is growing worldwide, and it is estimated that by 2025, over 1 million individuals will be affected by liver cancer every year. Hepatocellular carcinoma (HCC) accounts for about 90% of primary liver cancer cases and is one of the leading causes of death from cancer worldwide. Establishing animal models that faithfully replicate the human disease is critical to improve our understanding of HCC pathogenesis and to test new therapeutic strategies. Here, we describe a novel human HCC model using genetically modified human hepatocytes in a humanized liver mouse. Primary human hepatocytes (PHH) were modified ex vivo through lentivirus or Lipid Nanoparticle (LNP)-mediated delivery of CRISPR/Cas9 components, resulting in over-expression of oncogenes or inactivation of tumor suppressor genes. These genetically engineered PHH were engrafted into the livers of FSRG (FAH−/−, SIRPahu/hu, RAG2−/−, IL2Rg−/−) mice, developed by Regeneron VelociGene technology, in which mouse liver parenchyma can be replaced with human hepatocytes. Tumor formation was validated in livers engrafted with human hepatocytes after different combinations of genetic modification, including over-expression of cMYC plus HRASv12, and cMYC over-expression together with p53 KO. Tumor progression could be monitored by measuring human Alpha Fetoprotein (AFP) in serum of engrafted mice. Liver tumors were positive for fumarylacetoacetate hydrolase (FAH) and human Asialoglycoprotein Receptor 1 (ASGR1), confirming their human origin, as well as the proliferation marker, Ki67, and Glypican-3 (GPC3), which is frequently over-expressed in HCC and a potential therapeutic target. In these studies, mice were engrafted with a mix of lentivirus-transduced and non-transduced hepatocytes, resulting in humanized livers with both normal and transformed human hepatocytes, providing an ideal system to recapitulate neoplastic transformation and clonal expansion of human hepatocytes carrying oncogenic mutations as well as to test the specificity of novel therapies. By combining genetic manipulation of human hepatocytes with the FSRG humanized liver mouse platform, we have established a flexible system to model clinically relevant combinations of HCC mutations for both new target discovery and therapeutic testing. Citation Format: Marisa Carbonaro, Ciro Bonetti, Hui Huang, Kehui Wang, Mathieu Desclaux, Guochun Gong, John C. Lin, Christopher Daly, Gavin Thurston, Zhe Li. Development of novel human hepatocellular carcinoma models using genetically modified human hepatocytes in FSRG humanized liver mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 35.

Site-Specifically Conjugated Single-Domain Antibody Successfully Identifies Glypican-3-Expressing Liver Cancer by Immuno-PET.

Primary liver cancer is the third leading cause of cancer-related deaths, and its incidence and mortality are increasing worldwide. Hepatocellular carcinoma (HCC) accounts for 80% of primary liver cancer cases. Glypican-3 (GPC3) is a heparan sulfate proteoglycan that histopathologically defines HCC and represents an attractive tumor-selective marker for radiopharmaceutical imaging and therapy for this disease. Single-domain antibodies are a promising scaffold for imaging because of their favorable pharmacokinetic properties, good tumor penetration, and renal clearance. Although conventional lysine-directed bioconjugation can be used to yield conjugates for radiolabeling full-length antibodies, this stochastic approach risks negatively affecting target binding of the smaller single-domain antibodies. To address this challenge, site-specific approaches have been explored. Here, we used conventional and sortase-based site-specific conjugation methods to engineer GPC3-specific human single-domain antibody (HN3) PET probes. Methods: Bifunctional deferoxamine (DFO) isothiocyanate was used to synthesize native HN3 (nHN3)-DFO. Site-specifically modified HN3 (ssHN3)-DFO was engineered using sortase-mediated conjugation of triglycine-DFO chelator and HN3 containing an LPETG C-terminal tag. Both conjugates were radiolabeled with 89Zr, and their binding affinity invitro and target engagement of GPC3-positive (GPC3+) tumors invivo were determined. Results: Both 89Zr-ssHN3 and 89Zr-nHN3 displayed nanomolar affinity for GPC3 invitro. Biodistribution and PET/CT image analysis in mice bearing isogenic A431 and A431-GPC3+ xenografts, as well as in HepG2 liver cancer xenografts, showed that both conjugates specifically identify GPC3+ tumors. 89Zr-ssHN3 exhibited more favorable biodistribution and pharmacokinetic properties, including higher tumor uptake and lower liver accumulation. Comparative PET/CT studies on mice imaged with both 18F-FDG and 89Zr-ssHN3 showed more consistent tumor accumulation for the single-domain antibody conjugate, further establishing its potential for PET imaging. Conclusion: 89Zr-ssHN3 showed clear advantages in tumor uptake and tumor-to-liver signal ratio over the conventionally modified 89Zr-nHN3 in xenograft models. Our results establish the potential of HN3-based single-domain antibody probes for GPC3-directed PET imaging of liver cancers.

Hepatogastric fistula formation after liver chemoembolization in a patient with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for 75% to 95% of all cases of primary liver cancer. The number of cases of newly diagnosed hepatocellular cancer (HCC) in the Russian Federation in 2019 accounted to 9324. Currently, the method of transarterial chemoembolization (TACE) is widely used for the treatment of patients with malignant liver tumors. Various methods of transarterial embolization of the liver are used, including selective or superselective catheterization and the use of various chemotherapeutic and embolizing agents. In recent years, calibrated synthetic microspheres loaded with a chemotherapeutic agent have been developed. They ensure uniform and prolonged release of the drug and the achievement of high concentrations of the chemotherapeutic agent in tumor cells. The method of transarterial embolization of the liver using grains containing the drug is known as DEB‑TACE (Drug‑eluting bead transarterial chemoembolization). The traditional TACE (conventional transarterial chemoembolization), technique is also widely used, in which a chemotherapeutic drug is administered together with lipiodol, and then with occlusive material. When comparing the techniques, no differences were found in their safety profiles. Despite the fact that transarterial embolization of the liver is considered a safe procedure, it is not without the risk of complications, the most common of which are acute cholecystitis and leukopenia. Also, a frequent undesirable phenomenon after transarterial chemoembolization of the liver is postembolization syndrome, which includes abdominal pain, hyperthermia up to 38 ° C and nausea. One of the rare complications occurring in less than 1% of cases is a complication of liver TACE – the development of a liver abscess against the background of tumor necrosis. It is believed that the formation of an abscess can lead to the formation of fistulas: hepaticobronchial, hepaticoduodenal, hepaticogastric, etc. Our article presents a rare clinical case of hepatogastric fistula formation after liver TACE.

Pre-diagnostic anti-EBV antibodies and primary liver cancer risk: a population-based nested case-control study in southern China

BackgroundWe aimed to investigate associations between pre-diagnostic anti-Epstein-Barr virus (EBV) antibodies, including interactions with hepatitis B virus (HBV), and risk of primary liver cancer in southern China.MethodsIn a population-based nested case-control study, we measured pre-diagnostic immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA) in 125 primary liver cancer cases and 2077 matched controls. We also explored the interaction between HBV surface antigen (HBsAg) and anti-EBV antibodies.ResultsParticipants with positive EBNA1-IgA, positive VCA-IgA or single-positive anti-EBV antibodies had two-fold odds of developing liver cancer, compared with seronegative subjects. The odds ratios (ORs) between the relative optical density of EBNA1-IgA and VCA-IgA and primary cancer, controlling for age and HBsAg, were 1.59 (95% confidence interval (CI): 1.17, 2.14) and 1.60 (95% CI: 1.07, 2.41), respectively. Subjects with both HBsAg and anti-EBV antibody seropositivity were at 50-fold increased risk compared with those negative for both biomarkers (OR: 50.67, 95% CI: 18.28, 140.46), yielding a relative excess risk due to interaction of 30.81 (95% CI: 3.42, 114.93).ConclusionPre-diagnostic seropositivity for EBNA1-IgA and/or VCA-IgA was positively associated with primary liver cancer risk, especially in combination with HBsAg positivity. EBV may interact with HBV in the development of primary liver cancer, and anti-EBV antibodies might be potential biomarkers for primary liver cancer in this high-risk population.