Liver Cancer Cases Research Articles

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.

Antidepressants and Risk of Liver Cancer: A Systematic Review and Meta-Analysis.

Previous results regarding the association between the antidepressants use and risk of liver cancer are controversial. This study aimed to assess whether antidepressants use increases liver cancer risk. We systematically searched several English and Chinese databases, including the Cochrane Library, MEDLINE, Embase, PsycINFO, Web of Science, CNKI, CQVIP database, Wanfang database, and SinoMed, and 3 clinical trial registration platforms through May 2022. Observational studies evaluating liver cancer risk in patients on antidepressants use were included, and the quality of studies was assessed using the Newcastle-Ottawa scale. A random-effects model was used to calculate the pooled effect estimates and 95% confidence intervals (CIs). We included 11 studies with a total of 132 396 liver cancer cases. The meta-relative risk (RR) for liver cancer associated with antidepressants use was 0.72 (95% CI 0.59-0.86). In subgroup analyses, only selective serotonin reuptake inhibitors were negatively correlated with risk of liver cancer (RR 0.64, 95% CI 0.51-0.79); both dose subgroups ≤365cDDD (RR 0.77, 95% CI 0.69-0.85) and >365cDDD (RR 0.57, 95% CI 0.40-0.81) were associated with lower liver cancer risk; only in patients with chronic viral hepatitis, the use of antidepressants reduced liver cancer risk (RR 0.70, 95% CI 0.54-0.90). The result of the current meta-analysis shows antidepressants use is not associated with increased risk of liver cancer and appears to be correlated with decreased risk. However, the observed association needs to be verified by more powerful evidence from prospective, methodologically rigorous studies.

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.

Lifespan and medical expenditure prognosis for cancer metastasis - a simulation modeling using semi-Markov process

Background and objectiveA key reason of high mortality of cancers is attributed to the metastasized cancer, whereas, the medical expense for the treatment of cancer metastases generates heavily financial burden. The population size of metastases cases is small and comprehensive inferencing and prognosis is hard to conduct. MethodsBecause metastases and finance state can develop dynamic transitions over time, this study proposes a semi-Markov model to perform risk and economic evaluation associated to major cancer metastasis (i.e., lung, brain, liver and lymphoma cancer) against rare cases. A nationwide medical database in Taiwan was employed to derive a baseline study population and costs data. The time until development of metastasis and survivability from metastasis, as well as the medical costs were estimated through a semi-Markov based Monte Carlo simulation. ResultsIn terms of the survivability and risk associated to metastatic cancer patients, 80% lung and liver cancer cases are tended to metastasize to other part of the body. The highest cost is generated by brain cancer-liver metastasis patients. The survivors group generated approximately 5 times more costs, in average, than the non-survivors group. ConclusionsThe proposed model provides a healthcare decision-support tool to evaluate the survivability and expenditure of major cancer metastases.

Hepatocellular carcinoma progression promoted by 5-lipoxygenase activity in CD163(+) tumor-associated macrophages

Arachidonic acid 5-lipoxygenase (5-LOX), an enzyme that synthesizes leukotrienes (LTs), is involved in cancer development including proliferation, invasion, metastasis and drug resistance. However, the functional role of 5-LOX in hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we analyzed the contribution of 5-LOX in HCC progression and investigated the potential of targeted therapy. Analysis of 86 resected HCC specimens and the clinical data of 362 cases of liver cancer from The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, showed that 5-LOX expression was associated with postoperative survival. The cancer proliferative and stem cell potential were correlated with the levels of 5-LOX in CD163(+) tumor-associated macrophages (TAMs). In an HCC mouse model, CD163(+) TAMs expressed 5-LOX and produced LTB4 and LTC/D/E4; the 5-LOX inhibitor, zileuton, suppressed HCC progression. LTB4 and LTC/D/E4 promoted cancer proliferation and stem cell capacity via phosphorylation of extracellular signal-regulated kinase 1/2 and stem cell-associated genes. Taken together, we identified a novel mechanism of HCC progression in which CD163(+) TAMs express 5-LOX and produce LTB4 and LTC/D/E4, thereby enhancing the proliferative and stem cell potential of HCC cells. Furthermore, inhibition of 5-LOX activity regulates HCC progression, suggesting it has potential as a new therapeutic target.

Expression and clinical significance of plasma methylated SEPT 9 gene in patients with primary liver cancer

Objective: To investigate the expression and clinical significance of plasma methylated SEPT9 (mSEPT9) gene in patients with primary liver cancer. Methods: 393 cases who visited our hospital from May 2016 to October 2018 were selected. Among them, 75 cases were in the primary liver cancer (PLC) group, 50 cases were in the liver cirrhosis (LC) group, and 268 cases were in the healthy control group (HC). The three groups' positive rates of mSEPT9 expression in the peripheral plasma were detected by the polymerase chain reaction (PCR) fluorescent probe method. The correlational clinical features of liver cancer were analyzed. At the same time, the electrochemiluminescence detection method was used to compare the AFP positive rate. Statistical analysis was conducted using chi-square tests or continuity-corrected chi-square tests. Results: 367 cases actually had valid samples. There were 64, 42, and 64 cases in the liver cancer group, cirrhosis group, and healthy control group, respectively. Among them, 34 cases of liver cancer were verified from pathological tissues. The positive rate of plasma mSEPT9 was significantly higher in the liver cancer group than that in the liver cirrhosis and healthy control groups [76.6% (49/64), 35.7% (15/42), and 3.8% (10/261), respectively], and the differences were statistically significant (χ (2) = 176.017, P < 0.001). The sensitivity of plasma mSEPT9 detection (76.6%) was significantly better in liver cancer (76.6%) than that of AFP patients (54.7%), and the difference was statistically significant (χ (2) = 6.788, P < 0.01). Compared with the single detection, the sensitivity and specificity of plasma mSEPT9 combined with AFP were significantly improved (89.7% vs. 96.3%, respectively). Patients with liver cancer aged≥50 years, with clinical stage II or above, and those with pathological signs of moderate to low differentiation had higher levels of plasma mSEPT9 positive expression, and the differences were statistically significant (χ (2) = 6.41, 9.279, 6.332, P < 0.05). During the follow-up period, the survival time of liver cancer patients with positive plasma mSEPT9 expression was significantly shorter than that of those with negative expression (310 ± 26 days vs. 487 ± 59 days, respectively), with statistically significant differences (Log Rank P = 0.039). Conclusion: In China, the positive rate of plasma mSEPT9 detection in liver cancer patients is higher than that of AFP in relation to age, clinical stage, and degree of tissue differentiation; additionally, it has certain survival predictive values. As a result, detecting this gene has important clinical significance and potential clinical application value in the non-invasive diagnosis and prognosis assessment of patients with primary liver cancer.

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.

Anterior gradient 2 induces resistance to sorafenib via endoplasmic reticulum stress regulation in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) accounts for almost 80% of all liver cancer cases and is the sixth most common cancer and the second most common cause of cancer-related death worldwide. The survival rate of sorafenib-treated advanced HCC patients is still unsatisfactory. Unfortunately, no useful biomarkers have been verified to predict sorafenib efficacy in HCC.ResultsWe assessed a sorafenib resistance-related microarray dataset and found that anterior gradient 2 (AGR2) is highly associated with overall and recurrence-free survival and with several clinical parameters in HCC. However, the mechanisms underlying the role of AGR2 in sorafenib resistance and HCC progression remain unknown. We found that sorafenib induces AGR2 secretion via posttranslational modification and that AGR2 plays a critical role in sorafenib-regulated cell viability and endoplasmic reticulum (ER) stress and induces apoptosis in sorafenib-sensitive cells. In sorafenib-sensitive cells, sorafenib downregulates intracellular AGR2 and conversely induces AGR2 secretion, which suppresses its regulation of ER stress and cell survival. In contrast, AGR2 is highly intracellularly expressed in sorafenib-resistant cells, which supports ER homeostasis and cell survival. We suggest that AGR2 regulates ER stress to influence HCC progression and sorafenib resistance.ConclusionsThis is the first study to report that AGR2 can modulate ER homeostasis via the IRE1α-XBP1 cascade to regulate HCC progression and sorafenib resistance. Elucidation of the predictive value of AGR2 and its molecular and cellular mechanisms in sorafenib resistance could provide additional options for HCC treatment.

Management of Hepatocellular Carcinoma in Decompensated Cirrhotic Patients: A Comprehensive Overview.

Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for 75% of primary liver cancer cases, mostly on the basis of cirrhosis. However, the data and therapeutic options for the treatment of HCC in patients with decompensated cirrhosis are rather limited. This patient category is often considered to be in a terminal stage without the possibility of a specific treatment except liver transplantation, which is restricted by several criteria and liver donor shortages. Systemic treatments may provide a solution for patients with Child Pugh class B or C since they are less invasive. Although most of the existing trials have excluded patients with decompensated cirrhosis, there are increasing data from real-life settings that show acceptable tolerability and satisfying efficacy in terms of response. The data on the administration of locoregional treatments in such patients are also limited, but the overall survival seems to be potentially prolonged when patients are carefully selected, and close adverse event monitoring is applied. The aim of this review is to analyze the existing data regarding the administration of treatments in decompensated patients with HCC, evaluate the effect of therapy on overall survival and highlight the potential risks in terms of tolerability.

Affinely adjustable robust optimization for radiation therapy under evolving data uncertainty via semi-definite programming

Static robust optimization has played an important role in radiotherapy, where the decisions aim to safeguard against all possible realizations of uncertainty. However, it may lead to overly conservative decisions or too expensive treatment plans, such as delivering significantly more dose than necessary. Motivated by the success of adjustable robust optimization in reducing highly conservative decision-making of static robust optimization in applications, in this paper, we present an affinely adjustable robust optimization (AARO) model for hypoxia-based radiation treatment planning in the face of evolving data uncertainty. We establish an exact semi-definite program reformulation of the model under a so-called affine decision rule and evaluate our model and approach on a liver cancer case as a proof-of-concept. Our AARO model incorporates uncertainties both in dose influence matrix and re-oxygenation data as well as inexactness of the revealed (re-oxygenation) data. Our numerical experiments demonstrate that the adjustable model successfully handles uncertainty in both re-oxygenation and the dose matrix. They also show that, by utilizing information halfway through the treatment plan, the adjustable solutions of the AARO model outperform a static method while maintaining a similar total dose.

Immune landscape and immunotherapy of hepatocellular carcinoma: focus on innate and adaptive immune cells.

Hepatocellular carcinoma (HCC) is responsible for roughly 90% of all cases of primary liver cancer, and the cases are on the rise. The treatment of advanced HCC is a serious challenge. Immune checkpoint inhibitor (ICI) therapy has marked a watershed moment in the history of HCC systemic treatment. Atezolizumab in combination with bevacizumab has been approved as a first-line treatment for advanced HCC since 2020; however, the combination therapy is only effective in a limited percentage of patients. Considering that the tumor immune microenvironment (TIME) has a great impact on immunotherapies for HCC, an in-depth understanding of the immune landscape in tumors and the current immunotherapeutic approaches is extremely necessary. We elaborate on the features, functions, and cross talk of the innate and adaptive immune cells in HCC and highlight the benefits and drawbacks of various immunotherapies for advanced HCC, as well as future projections. HCC consists of a heterogeneous group of cancers with distinct etiologies and immune microenvironments. Almost all the components of innate and adaptive immune cells in HCC have altered, showing a decreasing trend in the number of tumor suppressor cells and an increasing trend in the pro-cancer cells, and there is also cross talk between various cell types. Various immunotherapies for HCC have also shown promising efficacy and application prospect. There are multilayered interwoven webs among various immune cell types in HCC, and emerging evidence demonstrates the promising prospect of immunotherapeutic approaches for HCC.

Silencing proline-rich coiled-coil 2C inhibit the proliferation and metastasis of liver cancer cells.

Proline-rich coiled-coil 2C (PRRC2C) is located in the chromosome region lq where hepatocellular carcinoma (HCC) frequently undergoes genomic fragment amplification, but its role in HCC is unknown. In this study, we aimed to explore the correlation of PRRC2C with HCC diagnosis and progression, as well as its influence on the biological behavior of HCC cells. The Cancer Genome Atlas (TCGA) RNA-sequencing datasets of 371 cases of primary liver cancer and 50 normal liver tissue specimens were obtained to analyze correlation between PRRC2C expression and HCC staging, grades, and overall survival. After confirming expression of PRRC2C in HCC cells, PRRC2C silencing was performed. Celigo cell counting, cell clone formation, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and Flow cytometry were used to detect the cell proliferation and apoptosis; wound healing and Transwell assays were used to detect the invasion abilities of cells. Xenograft transplantation in nude mice was performed to investigate the impact of PRRC2C knockdown on tumorigenic capabilities. In addition, the expression levels of EMT (epithelial-mesenchymal transition)-related genes, including E-cadherin, N-cadherin, Twistl, Snail, Slug, and Smad2/3/4, were detected. Analysis of TCGA data sets revealed that patients with high PRRC2C expression had significantly shorter overall survival. PRRC2C was abundantly expressed in four human hepatocarcinoma cell lines. After knockdown PRRC2C, the proliferation of HCC cells were suppressed and the numbers of apoptotic cells increased. Migration and invasion ability of HCC cells were inhibited by PRRC2C knockdown. Meanwhile, PRRC2C silencing inhibited the tumor formation (indicated by reduced tumor volume and weight compared to the control group) in BALB/c (Bagg Albino Laboratory-bred strain) nude mice. The expressions of EMT-related genes N-cadherin and Vimentin were significantly lower in the PRRC2C knockdown group than in the control group. PRRC2C promotes the proliferation and metastasis of liver cancer cells and inhibited apoptosis, potentially through upregulation of EMT related N-cadherin and Vimentin.

Reveal the mechanisms of prescriptions for liver cancer' treatment based on two illustrious senior TCM physicians.

To explore the core herbs of two illustrious senior Traditional Chinese Medicine (TCM) Physicians for the treatment of liver cancer, and to further clarify the gene targets and pathway mechanisms of liver cancer that the core prescription (CP) may regulate. We used the patient information of two illustrious senior TCM physicians from the Affiliated Hospital of Shandong University of Traditional Chinese Medicine and the Affiliated Hospital of Capital Medical University as the database. The CP was analyzed using the community network algorithm. The pathway mechanism was analyzed using network pharmacology method. And the prognostic survival genes were identified using Single factor cox regression analysis. Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine (TCMIP), Herb, Online Mendelian Inheritance in Man (OMIM), Genecards, Kyoto Encyclopedia of Genes and Genomes (KEGG), Genomic Data Commons (GDC), The Cancer Genome Atlas (TCGA), Gephi and R were used to mine CP, building a pathway network diagram. All the analyses were visualized. We found that the CP consistes of Huangqi (), Danshen (), Shuihonghuazi (), Baihuasheshecao (), Banzhilian (), and Ezhu (), which were attributed to the two physicians respectively. The CP played an anti-cancer role through such pathways as signal transduction, energy metabolism, immune system and other pathways, covering a total of 112 pathways and 176 herb-disease-related genes. Fourteen genes have a significant impact on the prognosis and survival of liver cancer. Based on the liver cancer cases of two illustrious senior TCM physicians, we obtained the CP through data mining. The CP may mainly exert anti-cancer effects by inhibiting inflammatory response, angiogenesis, and enhancing the body's immune response. We screened out 14 genes in the CP that may be related to the prognosis of liver cancer, and these genes may play an important regulatory role in the prognosis of liver cancer.

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma incidence between 2006 and 2015 in China: estimates based on data from 188 population-based cancer registries.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common subtypes of primary liver cancer, but nationwide incidence of both liver cancer subtypes have never been reported in China. We aimed to estimate the most recent incidence of HCC and ICC and temporal trends in China based on the most updated data from high qualified population-based cancer registries (covering 13.1% of the national population), in comparison to those in the United States at the same period. We used data from 188 Chinese population-based cancer registries covering 180.6 million population of China to estimate the nationwide incidence of HCC and ICC in 2015. And 22 population-based cancer registries' data were used to estimate the trends of HCC and ICC incidence from 2006 to 2015. Multiple imputation by chained equations method was used to impute liver cancer cases with unknown subtype (50.8%). We used data from 18 population-based registries from the Surveillance, Epidemiology, and End Results program to analyze incidence of HCC and ICC in the United States. In China, an estimated 301,500 and 61,900 newly diagnosed HCC and ICC occurred in 2015. The overall age-standardized rates (ASRs) of HCC incidence decreased by 3.9% per year. For ICC incidence, the overall ASR was relatively stable, but increased in the population of over 65 years old. Subgroup analysis by age showed that the ASR of HCC incidence had the sharpest decline in population who were less than 14 years old and received neonatally hepatitis B virus (HBV) vaccination. In the United States, though the incidence of HCC and ICC were lower than those in China, the overall HCC and ICC incidence increased by 3.3% and 9.2% per year. China still faces with a heavy burden of liver cancer incidence. Our results may further support the beneficial effect of Hepatitis B vaccination on reduction of HCC incidence. Both healthy lifestyle promotion and infection control are needed for future liver cancer control and prevention for China and the United States.

Plant-based Natural inhibitors of human liver carcinogenesis: A mechanistic overview, focusing on hepatitis B and hepatitis C viruses

Hepatitis B and C viruses can lead to serious complications such as hepatic fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC) and are therefore responsible for a significant portion of liver cancer cases worldwide, with over 1.3 million deaths annually. The mechanisms by which hepatitis viruses contribute to HCC include DNA integration into the host genome, metabolic reprogramming, induction of the cellular stress response pathway, and interference with tumour suppressors. HBV is a DNA virus from the Hepadnaviridae family, and HCV is an RNA virus from the Flaviviridae family. Both viruses are transmitted through contact with infected bodily fluids, such as blood or sexual fluids. It is important to get tested for hepatitis B and C and to seek treatment as early as possible to prevent the progression to liver cancer. While there is a vaccine available for Hepatitis B, there is currently no vaccine for Hepatitis C. But some natural medicines have demonstrated antiviral activity against the hepatitis B and C viruses. Therefore, it is important to explore natural alternatives for the treatment of this disease. This review aims to summarise the pathogenesis of hepatitis B and C and their link to hepatocellular carcinoma, as well as to highlight natural compounds with the potential to treat hepatitis through various mechanisms at different stages of infection. These natural compounds may offer an alternative to chemical-based medications in the treatment and control of hepatitis by inhibiting or disrupting the entry, activity, or replication of the virus within the host.

Glycoproteomic Analysis of Urinary Extracellular Vesicles for Biomarkers of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for the most common form of primary liver cancer cases and constitutes a major health problem worldwide. The diagnosis of HCC is still challenging due to the low sensitivity and specificity of the serum α-fetoprotein (AFP) diagnostic method. Extracellular vesicles (EVs) are heterogeneous populations of phospholipid bilayer-enclosed vesicles that can be found in many biological fluids, and have great potential as circulating biomarkers for biomarker discovery and disease diagnosis. Protein glycosylation plays crucial roles in many biological processes and aberrant glycosylation is a hallmark of cancer. Herein, we performed a comprehensive glycoproteomic profiling of urinary EVs at the intact N-glycopeptide level to screen potential biomarkers for the diagnosis of HCC. With the control of the spectrum-level false discovery rate ≤1%, 756 intact N-glycopeptides with 154 N-glycosites, 158 peptide backbones, and 107 N-glycoproteins were identified. Out of 756 intact N-glycopeptides, 344 differentially expressed intact N-glycopeptides (DEGPs) were identified, corresponding to 308 upregulated and 36 downregulated N-glycopeptides, respectively. Compared to normal control (NC), the glycoproteins LG3BP, PIGR and KNG1 are upregulated in HCC-derived EVs, while ASPP2 is downregulated. The findings demonstrated that specific site-specific glycoforms in these glycoproteins from urinary EVs could be potential and efficient non-invasive candidate biomarkers for HCC diagnosis.

The role and behaviour of mitochondrial creatine kinase in hepatocellular carcinoma and its potential use as a tumor detecting biomarker for cancer patients

Hepatocellular carcinoma (HCC) is responsible for approximately 75% of all liver cancer cases, which is the seventh most prevalent cancer and the second most common cause of cancer mortality worldwide. The prognosis of HCC depends on its stage and the severity of liver disease at the time of diagnosis, but there are still problems in detecting and treating HCC patients on time and effectively. Being unable to diagnose HCC patients at an early stage and ineffective therapies for HCC patients with advanced stages are associated with the disease's high mortality. Liver transplantation could be a treatment option If patients are diagnosed early, but unfortunately, most patients are diagnosed at an advanced stage where chemotherapy is necessary. Thus, an effective strategy for early detection of HCC is necessary since there was no effective chemotherapy for advanced HCC for a long time, and therapies such as the anti-angiogenesis pathway can only extend the median survival from 7.9 months to 10.7 months which is a step forward but not enough. In this article, we review the role of MtCK in HCC and its potential use as a marker to see if using it can be beneficial to patients.

Serum zinc levels in cancer patients are low and difficult to elevate when complicated by liver cirrhosis: A retrospective study.

In this study, we analyzed blood zinc concentration in patients with various cancer types and the degree of improvement in relation to the underlying disease following treatment with zinc preparations. Serum zinc levels of 530 cancer patients whose blood zinc levels were measured at our hospital from 2016 to 2021 were retrospectively examined in accordance with the primary disease. Changes in zinc levels were analyzed in 155 patients whose zinc levels had been measured on 2 or more occasions in accordance with whether they had received zinc preparations. In addition, the concentration course of zinc before and after zinc formulation administration in 73 patients was examined in accordance with the presence or absence of liver cirrhosis complications. Mean serum zinc levels were below normal in all carcinomas measured, and zinc levels were significantly lower in cirrhosis-hepatocarcinoma cases than in other primary disease cases. Furthermore, serum zinc levels in patients who did not receive zinc preparations decreased significantly over time. In patients who received zinc preparations, the elevated levels of zinc after treatment were significantly lower in patients with cirrhosis than in those without cirrhosis. There was a weak inverse correlation between pre-dose zinc concentration and increased zinc concentration in patients with cirrhosis. In the analysis of covariance, the presence of liver cirrhosis was predominantly correlated with elevated zinc per dose. In summary, serum zinc levels in cancer patients are low and especially low in cancer patients with liver cirrhosis compared with those without cirrhosis after the administration of zinc preparations.

How Could Different Obesity Scenarios Alter the Burden of Type 2 Diabetes and Liver Disease in Saudi Arabia?

Introduction: Obesity is a major risk factor for type 2 diabetes (T2DM) and liver disease, and obesity-attributable liver disease is a common indication for liver transplant. Obesity prevalence in Saudi Arabia (SA) has increased in recent decades. SA has committed to the WHO “halt obesity” target to shift prevalence to 2010 levels by 2025. We estimated the future benefits of reducing obesity in SA on incidence and costs of T2DM and liver disease under two policy scenarios: (1) SA meets the “halt obesity” target; (2) population body mass index (BMI) is reduced by 1% annually from 2020 to 2040. Methods: We developed a dynamic microsimulation of working-age people (20–59 years) in SA between 2010 and 2040. Model inputs included population demographic, disease and healthcare cost data, and relative risks of diseases associated with obesity. In our two policy scenarios, we manipulated population BMI and compared predicted disease incidence and associated healthcare costs to a baseline “no change” scenario. Results: Adults <35 years are expected to meet the “halt obesity” target, but those ≥35 years are not. Obesity is set to decline for females, but to increase amongst males 35–59 years. If SA’s working-age population achieved either scenario, >1.15 million combined cases of T2DM, liver disease, and liver cancer could be avoided by 2040. Healthcare cost savings for the “halt obesity” and 1% reduction scenarios are 46.7 and 32.8 billion USD, respectively. Conclusion: SA’s younger working-age population is set to meet the “halt obesity” target, but those aged 35–59 are off track. Even a modest annual 1% BMI reduction could result in substantial future health and economic benefits. Our findings strongly support universal initiatives to reduce population-level obesity, with targeted initiatives for working-age people ≥35 years of age.