Integration of network pharmacology, metabolomics and lipidomics for clarifying the role of sphingolipid metabolism in the treatment of liver cancer by regorafenib.

AIMS: Regorafenib, an FDA-approved drug for advanced primary liver cancer (PLC), could provide survival benefits for patients. However, markers for its therapeutic sensitivity are lacking. This study seeks to identify sensitive targets of regorafenib in PLC from the perspective of small molecular metabolites. MATERIALS AND METHODS: Initiated with network pharmacology (NP) to map regorafenib's target landscape and metabolic regulatory network in liver cancer. Subsequently, regorafenib's impact on hepatoma cells was evaluated by flow cytometry, western blotting (WB) and cell viability assay. Advanced metabolomics and lipidomics were employed to elucidate regorafenib's metabolic reprogramming effects in liver cancer. Metabolic enzyme expression was assessed by WB, immunohistochemical and immunofluorescence assays. Ultimately, mendelian randomization (MR) analysis was utilized to investigate the potential causality of sphingolipid metabolism in hepatic cancer. KEY FINDINGS: Regorafenib was observed to inhibit hepatoma cell proliferation and cell cycle progression at G0/G1 phase, resulting in significant alterations in sphingolipid levels. It promoted the significant accumulation of 16:0 dihydroceramide (16:0 dhCer) by upregulating ceramide synthase 6 (CERS6) expression and inhibiting dihydroceramide desaturase 1 (DEGS1) activity. The MR analysis revealed that DEGS1 was a risk factor for the development and progression of liver cancer, while cumulative 16:0 dhCer was a protective factor. SIGNIFICANCE: Sphingolipids, particularly dhCer and regulatory enzymes, may be potential sensitive markers of regorafenib in the treatment of liver cancer, providing new insights for enhancing the treated efficacy of regorafenib in liver cancer.

Leveraging Patient-Derived Organoids for Personalized Liver Cancer Treatment.

Primary liver cancer (PLC) is a primary cause of cancer-related death worldwide, and novel treatments are needed due to the limited options available for treatment and tumor heterogeneity. 66 surgically removed PLC samples were cultured using the self-developed 2:2 method, and the final success rate for organoid culture was 40.9%. Organoid performance has been evaluated using comprehensive molecular measurements, such as whole-exome and RNA sequencing, as well as anticancer drug testing. Multiple organoids and their corresponding tumor tissues contained several of the same mutations, with all pairs sharing conventional TP53 mutations. Regarding copy number variations and gene expression, significant correlations were observed between the organoids and their corresponding parental tumor tissues. Comparisons at the molecular level provided us with an assessment of organoid-to-tumor concordance, which, in combination with drug sensitivity testing provided direct guidance for treatment selection. Finally, we were able to determine an appropriate pharmacological regimen for a patient with ICC, demonstrating the clinical practicality in tailoring patient-specific drug regimens. Our study provides an organoid culture technology that can cultivate models that retain most of the molecular characteristics of tumors and can be used for drug sensitivity testing, demonstrating the broad potential application of organoid technology in precision medicine for liver cancer treatment.

Analysis of alkaline phosphatase and γ-glutamyltransferase after radiofrequency ablation of primary liver cancer: A retrospective study.

BACKGROUND: Changes in alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) levels in patients with primary liver cancer (PLC) after radiofrequency ablation (RFA). Hepatocellular carcinoma is a malignant tumor with high incidence worldwide. As a common local treatment, RFA has attracted much attention for its efficacy and influence on liver function. AIM: To investigate the effect of serum ALP and GGT levels on the prognosis of patients with PLC treated by RFA. METHODS: The preoperative clinical data of 165 patients who were pathologically or clinically diagnosed with PLC and who received RFA in our hospital between October 2018 and June 2023 were collected. The chi-square test was used to compare the data between groups. The Kaplan-Meier method and Cox regression were used to analyze the associations between serum ALP and GGT levels and overall survival, progression-free survival (PFS) and clinical characteristics of patients before treatment. RESULTS: The 1-year survival rates of patients with normal (≤ 135 U/L) and abnormal (> 135 U/L) serum ALP before treatment were 91% and 79%, respectively; the 2-year survival rates were 90% and 68%, respectively; and the 5-year survival rates were 35% and 18%, respectively. The difference between the two groups was statistically significant (P = 0.01). Before treatment, the 1-year survival rates of patients with normal serum GGT levels (≤ 45 U/L) and abnormal serum GGT levels (> 45 U/L) were 95% and 87%, the 2-year survival rates were 85% and 71%, and the 5-year survival rates were 37% and 21%, respectively. The difference between the two groups was statistically significant (P < 0.001). Serum ALP [hazard ratio (HR) = 1.766, 95% confidence interval (95%CI): 1.068-2.921, P = 0.027] and GGT (HR = 2. 312, 95%CI: 1.367-3.912, P = 0.002) is closely related to the overall survival of PLC patients after RF ablation and is an independent prognostic factor. The 1-year PFS rates were 72% and 50%, the 2-year PFS rates were 52% and 21%, and the 5-year PFS rates were 14% and 3%, respectively. The difference between the two groups was statistically significant (P < 0001). The 1-year PFS rates were 81% and 56% in patients with normal and abnormal serum GGT levels before treatment, respectively; the 2-year PFS rates were 62% and 35%, respectively; and the 5-year PFS rates were 18% and 7%, respectively, with statistical significance between the two groups (P < 0.001). The serum ALP concentration (HR = 1. 653, 95%CI: 1.001-2.729, P = 0.049) and GGT (HR = 1.949, 95%CI: 1.296-2.930, P = 0.001) was closely associated with PFS after RFA in patients with PLC. The proportion of male patients with abnormal ALP levels is high, the Child-Pugh grade of liver function is poor, and the incidence of ascites is high. Among GGT-abnormal patients, the Child-Pugh grade of liver function was poor, the tumor stage was late, the proportion of patients with tumors ≥ 5 cm was high, and the incidence of hepatic encephalopathy was high. CONCLUSION: Serum ALP and GGT levels before treatment can be used to predict the prognosis of patients with PLC after RFA, and they have certain guiding significance for the long-term survival of patients with PLC after radiofrequency therapy.

Diagnostic value of serum vascular endothelial growth factor and interleukin-17 in primary hepatocellular carcinoma.

BACKGROUND: Despite significant advancements in the medical treatment of primary hepatocellular carcinoma (PHC) in recent years, enhancing therapeutic effects and improving prognosis remain substantial challenges worldwide. AIM: To investigate the expression levels of serum vascular endothelial growth factor (VEGF) and interleukin (IL)-17 in patients with PHC and evaluate their diagnostic value while exploring their relationship with patients' clinical characteristics. METHODS: The study included 50 patients with confirmed PHC who visited Wuhan Hanyang Hospital from January 2021 to January 2022, and 50 healthy individuals from the same period served as the control group. Serum VEGF and IL-17 levels in both groups were measured by Enzyme-Linked Immunosorbent Assay, and their diagnostic value was assessed using receiver operating characteristic (ROC) curves. Pearson correlation analysis was performed to examine the relationship between serum VEGF and IL-17 levels. Pathological data of the PHC patients were analyzed to determine the relationship between serum VEGF and IL-17 levels and pathological characteristics. RESULTS: Serum VEGF and IL-17 levels were significantly higher in the study group compared to the control group (P < 0.05). No significant association was observed between serum VEGF and IL-17 levels and gender, age, combined cirrhosis, tumor diameter, or degree of differentiation (P > 0.05). However, there was a significant relationship between clinical TNM stage, tumor metastasis, and serum VEGF and IL-17 levels (P < 0.05). Correlation analysis revealed a positive correlation between serum VEGF and IL-17 (P < 0.05). ROC analysis demonstrated that both serum VEGF and IL-17 had good diagnostic efficacy for PHC. CONCLUSION: Serum VEGF and IL-17 levels were significantly higher in PHC patients compared to healthy individuals. Their levels were closely related to pathological features such as tumor metastasis and clinical TNM stage, and there was a significant positive correlation between VEGF and IL-17. These biomarkers may serve as valuable reference indicators for the early diagnosis and treatment guidance of PHC.

Prognostic value of AFP-L3 and Des-γ-carboxy prothrombin in advanced primary liver cancer treated with Sorafenib and transarterial chemoembolization.

OBJECTIVE: To evaluate the prognostic value of serum alpha-fetoprotein (AFP-L3) and Des-γ-carboxy prothrombin (DCP) in advanced primary liver cancer (PLC) undergoing combined treatment with Sorafenib and transarterial chemoembolization (TACE). METHODS: This retrospective analysis included 82 patients with advanced PLC treated at the Second Affiliated Hospital, Guangzhou Medical University from January 2018 to January 2020. The patients were divided into an observation group (41 cases) and a control group (41 cases) based on their treatment method. The control group received TACE, while the observation group received a combination of Sorafenib and TACE. Both groups were evaluated after 12 weeks of treatment. Serum AFP-L3 and DCP levels were measured using a chemiluminescence immunoassay with magnetic particles. Short-term efficacy was compared between the two groups after 12 weeks of treatment. Additionally, Karnofsky Performance Status (KPS) scores, serum AFP-L3 and DCP levels before and after 12 weeks of treatment, and the survival rate after 2 years of follow-up were recorded. Serum AFP-L3 and DCP levels were compared between surviving and deceased patients. RESULTS: The objective response rate in the observation group (68.29%) was higher than in the control group (46.34%) (P<0.05). KPS scores in both groups were significantly higher 12 weeks post-treatment compared to pre-treatment (P<0.05); the observation group had higher post-treatment KPS scores than the control group (P<0.05). Serum AFP-L3 and DCP levels were reduced in both groups after 12 weeks of treatment compared to pre-treatment levels (P<0.05). However, post-treatment serum AFP-L3 and DCP levels were lower in the observation group compared to the control group (both P<0.05). After 2 years of follow-up, the survival rate was higher in the observation group compared to the control group (P<0.05). AFP-L3 and DCP levels were higher in deceased patients compared to surviving patients after 2 years of follow-up (both P<0.05). CONCLUSION: Combination therapy with Sorafenib and TACE is effective for patients with advanced PLC, reducing AFP-L3 and DCP levels and improving patient survival rates. Additionally, higher levels of serum AFP-L3 and DCP are associated with poor prognosis.

Predictive models and treatment efficacy for liver cancer patients with bone metastases: A comprehensive analysis of prognostic factors and nomogram development.

Background: Bone metastasis considerably undermines the prognosis of advanced primary liver cancer patients. Though its impact is well-recognized, the clinical field still lacks robust predictive models that can accurately forecast patient outcomes and aid in treatment effectiveness evaluation. Addressing this gap is paramount for improving patient management and survival. Materials and methods: We conducted an extensive analysis using data from the SEER database (2010-2020). COX regression analysis was applied to identify prognostic factors for primary liver cancer with bone metastasis (PLCBM). Nomograms were developed and validated to predict survival outcomes in PLCBM patients. Additionally, propensity score matching and Kaplan-Meier survival analyses lent additional insight by dissecting the survival advantage conferred by various treatment strategies. Results: A total of 470 patients with PLCBM were included in our study. The median overall survival (OS) and cancer-specific survival (CSS) for these patients were both 5 months. We unveiled several independent prognosticators for OS and CSS, spanning demographic to therapeutic parameters like marital status, cancer grade, histological type, and treatments received. This discovery enabled the formulation of two novel nomograms-now verified to eclipse the predictive prowess of the traditional TNM staging system regarding discrimination and clinical utility. Additionally, propensity score matching analysis showed the effectiveness of surgeries, radiotherapy, and chemotherapy in improving OS and CSS outcomes for PLCBM patients. Conclusions: Our investigation stands out by introducing pioneering nomograms for prognostic evaluation in PLCBM, a leap forward compared to existing tools. Far exceeding mere academic exercise, these nomograms hold immense clinical value, serving as a foundation for nuanced risk stratification systems and delivering dynamic, interactive guides, allowing healthcare professionals and patients to assess individual bone metastasis survival probabilities and personalize treatment selection.

Relative contribution of hepatitis B and C viruses in primary liver cancer in China: A systematic review and meta-analysis.

OBJECTIVES: China, which has the largest number of patients with primary liver cancer (PLCs), lacks data on the overall prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in PLCs. We aimed to comprehensively assess the seroprevalence of HBV and HCV among PLCs in China. METHODS: We included and pooled observational studies reporting seroprevalence of HBsAg and anti-HCV antibodies among PLCs in China by searching PubMed, Web of Science, Cochrane, Scopus, Embase, CNKI, Wanfang, and CBM. Multivariate meta-regression and subgroup analyses were used to explore sources of heterogeneity, and publication bias was assessed by funnel plots and Egger's test. PROSPERO registration number is CRD42023450382. RESULTS: A total of 217 eligible studies were included in the meta-analysis. The estimated seroprevalence of HBV and HCV in PLCs was 75.09% (95% CI 73.12-77.02) and 11.82% (95% CI 9.79-14.00), respectively. After stratifying and analysing subgroups by region and study period, we found geographic differences in HBV and HCV prevalence among PLCs, with an overall increasing trend in the proportion of HBV and a decreasing trend in the proportion of HCV as well as co-infections in the last 40 years. CONCLUSIONS: HBV and HCV infections still account for a high proportion of PLCs in China.

Tumor Resection in Hepatic Carcinomas Restores Circulating T Regulatory Cells.

Background/Objectives: Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) represent major primary liver cancers, affecting one of the most vital organs in the human body. T regulatory (Treg) cells play an important role in liver cancers through the immunosuppression of antitumor immune responses. The current study focuses on the characterization of circulating natural killer (NK) cells and T cell subsets, including Treg cells, in CCA and HCC patients, before and after surgical tumor resection, in order to understand the effect of tumor resection on the homeostasis of peripheral blood NK cells and T cells. Methods: Whole blood assays were performed to monitor immune alterations and the functional competence of circulating lymphocytes in a group of ten healthy individuals, eight CCA patients, and twenty HCC patients, before and one month after the surgical procedure, using flow cytometry, cell sorting, and qRT-PCR. Results: Before tumor resection, both HCC and CCA patients display increased percentages of CD8+ Treg cells and decreased frequencies of circulating CD4+ Treg cells. Notwithstanding, no functional impairment was detected on circulating CD4+ Treg cells, neither in CCA nor in HCC patients. Interestingly, the frequency of peripheral CD4+ Treg cells increased from 0.55% ± 0.49 and 0.71% ± 0.54 (in CCA and HCC, respectively) at T0 to 0.99% ± 0.91 and 1.17% ± 0.33 (in CCA and HCC, respectively) at T1, following tumor resection. Conclusions: Our results suggest mechanisms of immune modulation induced by tumor resection.

Primary liver cancer organoids and their application to research and therapy.

Primary liver cancer is a leading cause of death worldwide. To create advanced treatments for primary liver cancer, studies have utilized models such as 2D cell culture and in vivo animal models. Recent developments in cancer organoids have created the possibility for 3D in vitro cultures that recapitulates the cancer cell structure and operation as well as the tumor microenvironment (TME). However, before organoids can be directly translated to clinical use, tissue processing and culture medium must be standardized with unified protocols to decrease variability in results. Herein, we present the wide variety of published methodologies used to derive liver cancer organoids from patient tumor tissues. Additionally, we summarize validation methodologies for organoids in terms of marker expression levels with immunohistochemistry as well as the presence of mutations and variants through RNA-sequencing. Primary liver cancer organoids have exciting applications allowing for faster drug testing at a larger scale. Primary liver cancer organoids also assisit in uncovering new mechanisms. Through the coculture of different immune cells and cancer organoids, organoids are now better able to recapitulate the liver cancer TME. In addition, it further aids in the investigation of drug development and drug resistance. Lastly, we posit that the usage of liver cancer organoids in animal models provides researchers a methodology to overcome the current limitations of culture systems.

A nomogram predicting venous thromboembolism risk in primary liver cancer patients.

Cancer frequently causes venous thromboembolism (VTE), a leading cause of cancer-related mortality. Primary liver cancer (PLC) is prevalent and highly fatal, with an increased risk of venous thrombotic complications. Thus, we aimed to develop a nomogram model for predicting VTE in patients with PLC. We retrospectively analyzed 1,565 patients diagnosed with PLC between January 2018 and December 2022 at Chongqing University Cancer Hospital. Univariate logistic analysis and multivariate logistic regression identified eight significant risk factors: activated partial thromboplastin time (APTT) ≤ 32.20 s, D-dimer > 1.44 mg/L, lymphocyte count (LYM) ≤ 1.18 × 109/L, monocyte count (MONO) > 0.42 × 109/L, transarterial chemoembolization (TACE), surgical intervention, immunotherapy, and ß2-microglobulin. The nomogram model exhibited strong discriminatory power, with C indices of 0.753 and 0.710 for the training and validation cohorts, respectively. The calibration curve showed a strong correlation between predicted and actual probabilities. Additionally, decision curve analysis (DCA) and clinical impact curves (CIC) confirmed the model's clinical utility. This nomogram facilitates the identification of high-risk PLC patients, allowing for timely preventive and therapeutic interventions to reduce the risk of thrombosis.

Efficacy of hepatic arterial infusion chemotherapy in patients with primary liver cancer with portal vein tumor thrombosis: a comparative analysis of different perfusion chemotherapeutic regimens.

BACKGROUND: Portal vein tumor thrombosis (PVTT) commonly occurs in patients with primary liver cancer (PLC). Transarterial chemoembolization (TACE) is a treatment for patients with PLC and PVTT. Some studies have shown that combining TACE therapy with hepatic arterial infusion chemotherapy (HAIC) might improve the survival rate of PLC patients with PVTT. However, few studies have compared the different regimens of PLC with PVTT. We aimed to compare the differences between the oxaliplatin + raltetrexed regimen and FOLFOX regimen. METHODS: We divided the 248 patients into two groups. There were 60 patients in the oxaliplatin + ratitetrexed group and 74 patients in the FOLFOX group. The primary endpoints were OS and PFS. The secondary endpoints were ORR and adverse events. We used SPSS software, the Kaplan-Meier method, the t test, and the rank sum test to compare the differences between the two groups. RESULTS: The median OS was 10.82 months in the oxaliplatin + raltitrexed group and 8.67 months in the FOLFOX group. The median PFS time was greater in the oxaliplatin + raltitrexed group (10.0 months) than that in the FOLFOX group (7.1 months). The ORR was greater in the oxaliplatin + raltitrexed group than that in the FOLFOX group (18.3% vs. 13.5%; P = 0.445). The DCR in the oxaliplatin + raltitrexed group was higher than that in the FOLFOX group (70.0% vs. 64.8%; P = 0.529). However, in the subgroup analysis, the difference between them was more significant in the type II PVTT subgroup. The OS was 12.08 months in the oxaliplatin + raltitrexed group and 7.26 months in the FOLFOX group (P = 0.008). The PFS was 11.68 months in the oxaliplatin + raltitrexed group and 6.26 months in the FOLFOX group (P = 0.014). In the right branch of type II PVTT, the OS was 13.54 months in the oxaliplatin + raltitrexed group and 6.89 months in the FOLFOX group (P = 0.015), and the PFS was 13.35 months in the oxaliplatin + raltitrexed group and 6.27 months in the FOLFOX group (P = 0.030). The incidence of adverse reactions was similar between the two groups. CONCLUSIONS: Compared with the FOLFOX regimen, the oxaliplatin + raltitrexed chemoembolization regimen had longer OS, PFS time and ORR and DCR and it was safe and tolerable.

Association of Hospital Volume With Quality Care Outcomes Following Minor and Major Hepatectomy for Primary Liver Cancer.

INTRODUCTION: Regionalizing hepatic resections to high-volume hospitals (HVH) has improved outcomes, yet widened disparities in access. We sought to evaluate the association of hospital volume with quality care outcomes and overall survival (OS) between minor and major hepatectomy for primary liver cancer. METHODS: The National Cancer Database identified patients with primary liver cancer who underwent minor/major hepatectomy (2009-2019). HVHs were defined by the top quartile in annual case volume (vs. the bottom three quartiles). Quality care outcomes (time to resection, margin status, length of stay, 30-day readmission, 30-day mortality, 90-day mortality) and OS were assessed using multivariable regression. RESULTS: Overall, 6,988 patients underwent minor hepatectomy and 4880 major hepatectomy. No differences in quality care outcomes or OS based on hospital volume for minor hepatectomy were observed (all p > 0.05). Treatment at HVHs for major hepatectomy was associated with decreased odds of 30-day and 90-day mortality events (all p < 0.05). Median OS was 40.2 months [IQR 21.7-66.6] at HVHs versus 33.5 [IQR 17.0-58.7] at low-volume hospitals which remained independently predictive of improved OS on multivariable analysis (HR 0.86, 95% CI 0.79-0.93). CONCLUSION: These results support regionalization to HVHs for major hepatectomy; however, minor hepatectomy can be safely performed at hospitals regardless of volume.

Feasibility and safety of transarterial chemoembolization in patients with liver cancer via the distal radial approach: a single-center retrospective cohort study.

Background: The femoral artery is the standard route for transarterial chemoembolization (TACE); however, it is negatively associated with the quality of life of patients, and carries an increased risk of deep vein thrombosis in the lower limbs. We employed the distal radial approach to TACE to assess its feasibility and safety. Methods: We conducted a retrospective study at the First Hospital of Jilin University from August 1, 2020 to October 31, 2023. To be eligible for inclusion in the study, the patients had to meet the following main inclusion criteria: (I) have undergone a preoperative imaging (abdominal computed tomography enhancement or magnetic resonance dynamic enhancement) examination, or have a pathologically confirmed diagnosis of primary liver cancer, and a Child-Pugh score of A or B; and (II) have undergone distal radial artery puncture. The primary endpoint of this study was the success rate of distal radial artery puncture. The secondary endpoints were complications and the duration of the puncture. Results: Among the 343 patients with primary liver cancer (of whom 236 were male and 107 were female), a total of 1,315 distal radial artery punctures were attempted. The success rate was remarkably high at 95.13% (1,251/1,315), with only 64 cases requiring an alternative approach due to failed puncture. The average puncture duration was 20±7.43 minutes. No bleeding and hematoma, no arterial dissection and pseudoaneurysm formation were observed on ultrasound, and the radial pulse was palpable in all patients, highlighting the safety of the procedure. Further, no adverse events of vascular occlusion were observed among the 12 patients who received 6 or more punctures, indicating the sustainability of the distal radial artery access under the premise of adequate vascular protection. The development of this technique requires a learning curve of at least 50 cases to break through the learning baseline and be proficient in distal radial artery blind puncture. This may be the reason why many interventional physicians are reluctant to perform this procedure, adapting to the femoral approach with a shorter learning curve. Conclusions: The distal radial artery approach is feasible and safe in hepatic arterial chemoembolization, and should be widely promoted in TACE.

Nomogram predicting the prognosis of primary liver cancer after radiofrequency ablation combined with transcatheter arterial chemoembolization.

BACKGROUND: The incidence and mortality rates of primary hepatocellular carcinoma (HCC) are high, and the conventional treatment is radiofrequency ablation (RFA) with transcatheter arterial chemoembolization (TACE); however, the 3-year survival rate is still low. Further, there are no visual methods to effectively predict their prognosis. AIM: To explore the factors influencing the prognosis of HCC after RFA and TACE and develop a nomogram prediction model. METHODS: Clinical and follow-up information of 150 patients with HCC treated using RFA and TACE in the Hangzhou Linping Hospital of Traditional Chinese Medicine from May 2020 to December 2022 was retrospectively collected and recorded. We examined their prognostic factors using multivariate logistic regression and created a nomogram prognosis prediction model using the R software (version 4.1.2). Internal verification was performed using the bootstrapping technique. The prognostic efficacy of the nomogram prediction model was evaluated using the concordance index (CI), calibration curve, and receiver operating characteristic curve. RESULTS: Of the 150 patients treated with RFA and TACE, 92 (61.33%) developed recurrence and metastasis. Logistic regression analysis identified six variables, and a predictive model was created. The internal validation results of the model showed a CI of 0.882. The correction curve trend of the prognosis prediction model was always near the diagonal, and the mean absolute error before and after internal validation was 0.021. The area under the curve of the prediction model after internal verification was 0.882 [95% confidence interval (95%CI): 0.820-0.945], with a specificity of 0.828 and sensitivity of 0.656. According to the Hosmer-Lemeshow test, χ 2 = 3.552 and P = 0.895. The predictive model demonstrated a satisfactory calibration, and the decision curve analysis demonstrated its clinical applicability. CONCLUSION: The prognosis of patients with HCC after RFA and TACE is affected by several factors. The developed prediction model based on the influencing parameters shows a good prognosis predictive efficacy.

Network Pharmacology to Reveal the Mechanism of Fufang Banmao Capsule for Treating Unresectable Primary Liver Cancer and Clinical Data Validation.

INTRODUCTION: Fufang Banmao capsule (FFBM), a traditional Chinese medicine, has been used to treat primary liver cancer (PLC) for several years. However, the bioactive ingredients, and mechanism of FFBM for treating PLC remains unclear. Our objective is to utilize network pharmacology to investigate these aspects and subsequently validate their effectiveness through clinical data. MATERIALS AND METHODS: The FFBM ingredients were obtained from the HERB database and screened for bioactive ingredients using the SwissTargetPrediction database. The PharmMapper and GEO database were used to acquire targets and differentially expressed genes (DEGs) for FFBM and PLC, respectively. Common targets were identified using Venn diagrams, followed by enrichment and protein-protein interaction (PPI) analysis. Furthermore, the Cytoscape software was utilized to identify Hub genes and construct the ingredienttarget- pathway network. Subsequently, patients diagnosed with unresectable PLC who underwent transcatheter arterial chemoembolization (TACE) at our hospital between January 2008 and December 2019 were retrospectively collected. Finally, Cox analysis was conducted to reveal the role of FFBM in the treatment of unresectable PLC. RESULTS: FFBM had 232 targets, and PLC had 1582 DEGs. HSP90AA1 and SRC were identified as crucial targets. Alpha-santalol, glycyrrhizin, and morroniside were identified as the top three bioactive ingredients. Enrichment analysis revealed a significant connection between FFBM utilization for treating PLC and multiple pathways, such as chemical carcinogenesis, PI3K-AKT, Rap1, FoxO, MAPK, and VEGF pathway. Clinical data revealed that consuming FFBM significantly improved the prognosis of unresectable PLC with a hazard ratio of 0.69. CONCLUSION: Our study identified the bioactive ingredients of FFBM and its potential mechanisms for treating PLC. Additionally, we validated the effectiveness through clinical data.

Clinical effect of hepatic artery interventional embolization and chemotherapy and its influence on P16 protein expression in patients with liver cancer.

OBJECTIVE: To investigate clinical effects of hepatic artery interventional embolization chemotherapy (TACE) for primary hepatocellular carcinoma (PHC). METHODS: 73 patients with PHC in our hospital from January 2017 to January 2018 were selected and divided into 37 cases in study group and 36 cases in control group by random number table method. The control group received only ultrasound-guided microwave ablation treatment, and the study group received TACE treatment again before surgery based on control group. The expression levels of cancer antigen 125 (CA125), alpha-fetoprotein (AFP), multiple tumor suppressors 1 (P16) proteins, and cancer antigen 19-9 (CA19-9) were compared between the two groups at different time periods after treatment, and the remission rate (ORR), control rate (DCR), complication rate at 3 months after treatment and survival rate at 3 years after treatment were compared. RESULTS: After 1 year of treatment, ORR, DCR, and P16 protein levels in the study group were higher than those in the control group (P < 0.05), and differences were statistically significant; CA125, CA19-9, and AFP levels in study group were lower than those in the control group (P < 0.05), and differences were statistically significant. The regression equation showed that long-term survival rate of both groups showed decreasing trend over time, while long-term survival rate of study group was always higher than that of the control group. CONCLUSION: Comprehensive intervention for hepatic artery interventional chemoembolization in patients with primary hepatocellular carcinoma is more effective, which can effectively reduce incidence of complications and adverse effects in patients and help shorten treatment time of hepatic artery interventional chemoembolization in patients.

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

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

Organoid as a promising tool for primary liver cancer research: a comprehensive review.

Primary liver cancer (PLC) is one of the most common malignant gastrointestinal tumors worldwide. Limited by the shortage of liver transplantation donors and the heterogeneity of tumors, patients with liver cancer lack effective treatment options, which leads to rapid progression and metastasis. Currently, preclinical models of PLC fall short of clinical reality and are limited in their response to disease progression and the effectiveness of drug therapy. Organoids are in vitro three-dimensional cultured preclinical models with a high degree of heterogeneity that preserve the histomorphological and genomic features of primary tumors. Liver cancer organoids have been widely used for drug screening, new target discovery, and precision medicine; thus representing a promising tool to study PLC. Here, we summarize the progress of research on liver cancer organoids and their potential application as disease models. This review provides a comprehensive introduction to this emerging technology and offers new ideas for researchers to explore in the field of precision medicine.

Prognostic analysis of systemic antitumor therapy in young patients with advanced liver cancer: A cohort study.

Advanced liver cancer is the most common malignant tumor in the elderly, but it also occurs in young people in areas where hepatitis B virus is prevalent. The aim of the present study was to assess the efficacy of systemic antitumor therapy in young patients with advanced liver cancer and investigate the influencing factors. The baseline demographic and clinical data of 38 young patients (≤35 years old) with liver cancer were collected as group A and that of 79 elderly patients (≥55 years old) with liver cancer were collected as group B. There were no significant between-group differences regarding the proportion of patients with increased serum aspartate aminotransferase, low serum albumin, increased α-fetoprotein (AFP) and high Child-Pugh score. The median (m)PFS time in groups A and B was 3.9 and 8.3 months, respectively [hazard ratio (HR), 1.702; P=0.009]. The mOS in group A (17.6 months) was 12.4 months shorter than that in group B (HR, 1.799; P=0.010). In the subgroup analysis, male sex [HR, 1.73; 95% confidence interval (CI), 1.07-2.79], pathological diagnosis (HR, 1.79; 95% CI, 1.10-2.91), previous surgical treatment (HR, 2.16; 95% CI, 1.18-3.95), no tumor thrombus (HR, 2.45; 95% CI, 1.22-4.93), increased alanine aminotransferase (HR, 2.23; 95% CI, 1.07-4.65), increased aspartate aminotransferase (HR, 3.22; 95% CI, 1.62-6.39), normal total bilirubin (HR, 1.77; 95% CI, 1.09-2.87) and increased AFP (HR, 2.02; 95% CI, 1.19-3.41) were associated with shorter survival time in group A compared with those in group B (P<0.05). Group A also had a higher incidence of hyper-progressive disease (HPD) (31.6 vs. 3.8%; P<0.001). HPD was a risk factor for advanced liver cancer (HR, 4.530; 95% CI, 2.251-9.115; P<0.001]. In conclusion, the efficacy of systemic antitumor therapy in young patients was poorer compared with that in elderly patients. Young patients with liver cancer had a high HBV infection rate and were prone to HPD.

Research progress of ferroptosis regulating lipid peroxidation and metabolism in occurrence and development of primary liver cancer.

As a highly aggressive tumor, the pathophysiological mechanism of primary liver cancer has attracted much attention. In recent years, factors such as ferroptosis regulation, lipid peroxidation and metabolic abnormalities have emerged in the study of liver cancer, providing a new perspective for understanding the development of liver cancer. Ferroptosis regulation, lipid peroxidation and metabolic abnormalities play important roles in the occurrence and development of liver cancer. The regulation of ferroptosis is involved in apoptosis and necrosis, affecting cell survival and death. Lipid peroxidation promotes oxidative damage and promotes the invasion of liver cancer cells. Metabolic abnormalities, especially the disorders of glucose and lipid metabolism, directly affect the proliferation and growth of liver cancer cells. Studies of ferroptosis regulation and lipid peroxidation may help to discover new therapeutic targets and improve therapeutic outcomes. The understanding of metabolic abnormalities can provide new ideas for the prevention of liver cancer, and reduce the risk of disease by adjusting the metabolic process. This review focuses on the key roles of ferroptosis regulation, lipid peroxidation and metabolic abnormalities in this process.