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1.
World J Gastroenterol ; 30(19): 2488-2495, 2024 May 21.
Article En | MEDLINE | ID: mdl-38817660

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality. This particular type of cancer has the distinctive characteristic of mostly happening in individuals with an underlying liver disease. This makes the management of patients more challenging, since physicians must take into consideration two different conditions, the chronic liver disease and the tumor. The underlying liver disease has several implications in clinical practice, because different kinds of chronic liver disease can lead to varying degrees of risk of developing HCC, obstacles in surveillance, and differences in the efficacy of the treatment against HCC. A shift in the prevalence of liver diseases has been evident over the last few years, with viral hepatitis gradually losing the leading position as cause of HCC and metabolic dysfunction-associated steatotic liver disease gaining importance. Therefore, in an era of personalized medicine, it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and its impact in the management of their tumors.


Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Liver Neoplasms/epidemiology , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/epidemiology , Risk Factors , Prevalence , Precision Medicine/methods , Liver Diseases/epidemiology , Liver Diseases/therapy , Liver Diseases/diagnosis , Liver/pathology
2.
World J Gastroenterol ; 30(19): 2512-2522, 2024 May 21.
Article En | MEDLINE | ID: mdl-38817666

Hepatocellular carcinoma (HCC) is a high mortality neoplasm which usually appears on a cirrhotic liver. The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis. Notwithstanding the current deployment of treatments with curative intent (liver resection/local ablation and liver transplantation) in early and intermediate stages, a high rate of HCC recurrence persists, underscoring a pivotal clinical challenge. Emergent systemic therapies (ST), particularly immunotherapy, have demonstrate promising outcomes in terms of increase overall survival, but they are currently bound to the advanced stage of HCC. This review provides a comprehensive analysis of the literature, encompassing studies up to March 10, 2024, evaluating the impact of novel ST in the early and intermediate HCC stages, specially focusing on the findings of neoadjuvant and adjuvant regimens, aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent. We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent. Finally, we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.


Carcinoma, Hepatocellular , Liver Neoplasms , Neoadjuvant Therapy , Neoplasm Staging , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/mortality , Humans , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Liver Neoplasms/mortality , Neoadjuvant Therapy/methods , Neoadjuvant Therapy/trends , Neoplasm Recurrence, Local , Immunotherapy/methods , Hepatectomy , Liver Transplantation , Treatment Outcome , Chemotherapy, Adjuvant/methods , Prognosis
3.
Front Immunol ; 15: 1397541, 2024.
Article En | MEDLINE | ID: mdl-38774870

Aim: Despite the significant therapeutic outcomes achieved in systemic treatments for liver hepatocellular carcinoma (LIHC), it is an objective reality that only a low proportion of patients exhibit an improved objective response rate (ORR) to current immunotherapies. Antibody-dependent cellular phagocytosis (ADCP) immunotherapy is considered the new engine for precision immunotherapy. Based on this, we aim to develop an ADCP-based LIHC risk stratification system and screen for relevant targets. Method: Utilizing a combination of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, we screened for ADCP modulating factors in LIHC and identified differentially expressed genes along with their involved functional pathways. A risk scoring model was established by identifying ADCP-related genes with prognostic value through LASSO Cox regression analysis. The risk scoring model was then subjected to evaluations of immune infiltration and immunotherapy relevance, with pan-cancer analysis and in vitro experimental studies conducted on key targets. Results: Building on the research by Kamber RA et al., we identified GYPA, CLDN18, and IRX5 as potential key target genes regulating ADCP in LIHC. These genes demonstrated significant correlations with immune infiltration cells, such as M1-type macrophages, and the effectiveness of immunotherapy in LIHC, as well as a close association with clinical pathological staging and patient prognosis. Pan-cancer analysis revealed that CLDN18 was prognostically and immunologically relevant across multiple types of cancer. Validation through tissue and cell samples confirmed that GYPA and CLDN18 were upregulated in liver cancer tissues and cells. Furthermore, in vitro knockdown of CLDN18 inhibited the malignancy capabilities of liver cancer cells. Conclusion: We have identified an ADCP signature in LIHC comprising three genes. Analysis based on a risk scoring model derived from these three genes, coupled with subsequent experimental validation, confirmed the pivotal role of M1-type macrophages in ADCP within LIHC, establishing CLDN18 as a critical ADCP regulatory target in LIHC.


Carcinoma, Hepatocellular , Liver Neoplasms , RNA-Seq , Humans , Liver Neoplasms/genetics , Liver Neoplasms/immunology , Liver Neoplasms/therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/therapy , Prognosis , Immunotherapy/methods , Gene Expression Regulation, Neoplastic , Biomarkers, Tumor/genetics , Single-Cell Analysis , Phagocytosis/genetics , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Gene Expression Profiling , Male , Claudins/genetics , Female , Single-Cell Gene Expression Analysis
4.
J Nippon Med Sch ; 91(2): 180-189, 2024.
Article En | MEDLINE | ID: mdl-38777781

BACKGROUND: The incidence of alcoholic liver cirrhosis (ALC) is increasing. However, few reports have focused on ALC-derived esophageal varices (EV). We retrospectively examined differences in overall survival (OS) and EV recurrence rate in patients after endoscopic injection sclerotherapy (EIS) for ALC and hepatic B/C virus liver cirrhosis (B/C-LC). METHODS: We analyzed data from 215 patients (B/C-LC, 147; ALC, 68) who underwent EIS. The primary endpoints were OS and EV recurrence in patients with unsuccessful abstinence ALC and those with uncontrolled B/C-LC, before and after propensity score matching (PSM) to unify the patients' background. The secondary endpoints were predictors associated with these factors, as determined by multivariate analysis. RESULTS: The observation period was 1,430 ± 1,363 days. In the analysis of all patients, OS was significantly higher in the ALC group than in the B/C-LC group (p = 0.039); however, there was no difference in EV recurrence rate (p = 0.502). Ascites and history of hepatocellular carcinoma (HCC) (p = 0.019 and p < 0.001, respectively) predicted OS, whereas age and EV size predicted recurrence (p = 0.011 and 0.024, respectively). In total, 96 patients without an HCC history were matched by PSM, and there was no significant difference in OS or EV recurrence rate (p = 0.508 and 0.246, respectively). CONCLUSION: When limited to patients without a history of HCC, OS and the EV recurrence rate were comparable in patients with ALC who continued to consume alcohol and those with B/C-LC without viral control.


Esophageal and Gastric Varices , Liver Cirrhosis, Alcoholic , Liver Cirrhosis , Recurrence , Sclerotherapy , Humans , Esophageal and Gastric Varices/etiology , Esophageal and Gastric Varices/therapy , Male , Female , Middle Aged , Retrospective Studies , Sclerotherapy/methods , Liver Cirrhosis, Alcoholic/complications , Liver Cirrhosis/complications , Treatment Outcome , Aged , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Adult , Propensity Score
5.
Int J Nanomedicine ; 19: 3827-3846, 2024.
Article En | MEDLINE | ID: mdl-38708180

Background: New treatment modalities for hepatocellular carcinoma (HCC) are desperately critically needed, given the lack of specificity, severe side effects, and drug resistance with single chemotherapy. Engineered bacteria can target and accumulate in tumor tissues, induce an immune response, and act as drug delivery vehicles. However, conventional bacterial therapy has limitations, such as drug loading capacity and difficult cargo release, resulting in inadequate therapeutic outcomes. Synthetic biotechnology can enhance the precision and efficacy of bacteria-based delivery systems. This enables the selective release of therapeutic payloads in vivo. Methods: In this study, we constructed a non-pathogenic Escherichia coli (E. coli) with a synchronized lysis circuit as both a drug/gene delivery vehicle and an in-situ (hepatitis B surface antigen) Ag (ASEc) producer. Polyethylene glycol (CHO-PEG2000-CHO)-poly(ethyleneimine) (PEI25k)-citraconic anhydride (CA)-doxorubicin (DOX) nanoparticles loaded with plasmid encoded human sulfatase 1 (hsulf-1) enzyme (PNPs) were anchored on the surface of ASEc (ASEc@PNPs). The composites were synthesized and characterized. The in vitro and in vivo anti-tumor effect of ASEc@PNPs was tested in HepG2 cell lines and a mouse subcutaneous tumor model. Results: The results demonstrated that upon intravenous injection into tumor-bearing mice, ASEc can actively target and colonise tumor sites. The lytic genes to achieve blast and concentrated release of Ag significantly increased cytokine secretion and the intratumoral infiltration of CD4/CD8+T cells, initiated a specific immune response. Simultaneously, the PNPs system releases hsulf-1 and DOX into the tumor cell resulting in rapid tumor regression and metastasis prevention. Conclusion: The novel drug delivery system significantly suppressed HCC in vivo with reduced side effects, indicating a potential strategy for clinical HCC therapy.


Carcinoma, Hepatocellular , Doxorubicin , Escherichia coli , Liver Neoplasms , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/drug therapy , Liver Neoplasms/therapy , Humans , Doxorubicin/pharmacology , Doxorubicin/chemistry , Doxorubicin/administration & dosage , Hep G2 Cells , Mice , Escherichia coli/drug effects , Hepatitis B Surface Antigens , Sulfotransferases/genetics , Nanoparticles/chemistry , Mice, Inbred BALB C , Drug Delivery Systems/methods , Xenograft Model Antitumor Assays
7.
Gulf J Oncolog ; 1(45): 75-90, 2024 May.
Article En | MEDLINE | ID: mdl-38774936

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common primary liver tumor. It is considered a global public health problem given its incidence and high mortality rate. Epidemiological studies on hepatocellular carcinoma in our Moroccan and North African contexts are rare. Hence, our study aims to determine the epidemiological, clinical, paraclinical, etiological and therapeutic aspects of this pathology in our context. MATERIALS AND METHODS: We conducted a descriptive retrospective study on patients with HCC treated by the Hepato-gastroenterology department of the university hospital of Mohammed VI in Marrakech over a period of 7 years spread between 01/01/2015 and 31/12/2021. The epidemiological characteristics, diagnostic methods and therapeutic management of HCC in these patients have been described and analyzed. RESULTS: 100 patients with HCC were identified and included in our study. The average age was 63.3 ± 12.63 years with a male predominance. The predominant etiology was cirrhosis (87% of cases) then viral hepatitis C (35%) and B (27%) and of unknown origin in 29% of cases. HCC revealed cirrhosis in 41% and was diagnosed during cirrhosis surveillance in 36% of cases. The functional signs were dominated by abdominal pain (68%), deterioration of general condition (58%) and abdominal distension (43%). Alfa-fetoprotein was elevated in 73% of cases and was above 400ng/ml in 41% of cases. The diagnosis was mainly radiological in 92% and histological in 8% of cases. The radiological aspects of HCC were dominated by mononodular form (58%), a right lobar location (80%), a diameter greater than 5 cm (58%), a typical vascular aspect (86%) with portal thrombosis in 24% and metastases in 36% of cases, especially in lymph nodes. The majority of cirrhosis in our series was classified as Child-Pugh stage B (46%) at the time of diagnosis and most patients had an advanced stage of HCC with 31% at BCLC C and 28% at BCLC D. 72% of patients received palliative treatment, and only 6% received curative treatment. At the end of the study, 48% of patients had died with an overall survival of 6.5 months. CONCLUSION: Our study achieved its main objective by providing a snapshot of HCC in our context and confirmed that HCC remains with poor prognosis since its diagnosis is often late, limiting the therapeutic choices with a very short median survival. It also noted that the viral etiology remains the main cause of HCC in our population. Therefore, prevention remains the best therapeutic approach against HCC and the need for a national or at least a regional HCC registry in our country is essential in order to develop targeted preventive measures adapted to our context and to improve the diagnostic and therapeutic approaches for our patients.


Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/diagnosis , Liver Neoplasms/therapy , Liver Neoplasms/epidemiology , Liver Neoplasms/pathology , Liver Neoplasms/diagnosis , Male , Morocco/epidemiology , Female , Middle Aged , Retrospective Studies , Aged
9.
Int J Oncol ; 64(6)2024 06.
Article En | MEDLINE | ID: mdl-38757345

Hepatocellular carcinoma (HCC), one of the leading causes of cancer­related mortality worldwide, is challenging to identify in its early stages and prone to metastasis, and the prognosis of patients with this disease is poor. Treatment options for HCC are limited, with even radical treatments being associated with a risk of recurrence or transformation in the short term. Furthermore, the multi­tyrosine kinase inhibitors approved for first­line therapy have marked drawbacks, including drug resistance and side effects. The rise and breakthrough of immune checkpoint inhibitors (ICIs) have provided a novel direction for HCC immunotherapy but these have the drawback of low response rates. Since avoiding apoptosis is a universal feature of cancer, the induction of non­apoptotic regulatory cell death (NARCD) is a novel strategy for HCC immunotherapy. At present, NARCD pathways, including ferroptosis, pyroptosis and necroptosis, are novel potential forms of immunogenic cell death, which have synergistic effects with antitumor immunity, transforming immune 'cold' tumors into immune 'hot' tumors and exerting antitumor effects. Therefore, these pathways may be targeted as a novel treatment strategy for HCC. In the present review, the roles of ferroptosis, pyroptosis and necroptosis in antitumor immunity in HCC are discussed, and the relevant targets and signaling pathways, and the current status of combined therapy with ICIs are summarized. The prospects of targeting ferroptosis, pyroptosis and necroptosis in HCC immunotherapy are also considered.


Carcinoma, Hepatocellular , Ferroptosis , Immunotherapy , Liver Neoplasms , Necroptosis , Pyroptosis , Humans , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/immunology , Liver Neoplasms/drug therapy , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Pyroptosis/drug effects , Pyroptosis/immunology , Ferroptosis/drug effects , Necroptosis/immunology , Necroptosis/drug effects , Immunotherapy/methods , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Signal Transduction/drug effects , Animals
10.
World J Gastroenterol ; 30(18): 2387-2390, 2024 May 14.
Article En | MEDLINE | ID: mdl-38764762

Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes. The redefinition of NAFLD in 2023 marked a significant reposition in terminology, emphasizing a broader understanding of liver steatosis and its associated risks. MASLD is now recognized as a major risk factor for liver cirrhosis, hepatocellular carcinoma, and systemic complications such as cardiovascular diseases or systemic inflammation. Diagnostic challenges arise, particularly in identifying MASLD in lean individuals, necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools. Therapeutically, there is an urgent need for effective treatments targeting MASLD, with emerging pharmacological options focusing on, among others, carbohydrate and lipid metabolism. Additionally, understanding the roles of bile acid metabolism, the microbiome, and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches. There is a strong need to emphasize the importance of collaborative efforts in understanding, diagnosing, and managing MASLD to improve physicians' approaches and patient outcomes.


Non-alcoholic Fatty Liver Disease , Terminology as Topic , Humans , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/therapy , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Risk Factors , Lipid Metabolism , Liver/pathology , Liver/metabolism , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/therapy , Liver Neoplasms/diagnosis , Liver Neoplasms/pathology , Liver Neoplasms/genetics , Liver Cirrhosis/diagnosis , Liver Cirrhosis/therapy , Liver Cirrhosis/pathology , Bile Acids and Salts/metabolism
11.
World J Gastroenterol ; 30(18): 2479-2481, 2024 May 14.
Article En | MEDLINE | ID: mdl-38764761

In the study by Wu et al, patients with unresectable hepatocellular carcinoma were subjected to transarterial chemoembolization (TACE) as a conversion therapy in order to render their tumors suitable for resection. A nomogram was devised and shown to be effective in predicting the survival of these patients. Generalization of the results, however, is questionable since the study subjects consisted of patients who had resection after TACE while excluding patients with the same disease but not suitable for TACE. Immunotherapy can be considered to be an option for conversion therapy. However, markers for determining responses to a conversion therapy and for guiding the decision between TACE and sequential immunotherapy have been lacking. The question of whether effective conversion therapy can truly enhance overall survival remains unanswered.


Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Humans , Liver Neoplasms/therapy , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Chemoembolization, Therapeutic/methods , Chemoembolization, Therapeutic/mortality , Treatment Outcome , Hepatectomy , Nomograms , Immunotherapy/methods
12.
Medicine (Baltimore) ; 103(19): e38138, 2024 May 10.
Article En | MEDLINE | ID: mdl-38728500

INTRODUCTION: Systemic therapy is recommended for patients with advanced hepatocellular carcinoma (aHCC). However, drug resistance occurs over time when patients receive systemic therapy, resulting in cancer progression. Due to the lack of relevant clinical trials, optimizing subsequent treatments after cancer progression remains elusive. PATIENT CONCERNS: A 52-year-old male patient presented with epigastric discomfort and fatigue for almost 1 month with a past history of chronic hepatitis B virus infection for 30 years. DIAGNOSIS: Based on the patient's performance status, tumor status assessed by computed tomography, liver function, he was diagnosed with HCC at BCLC stage C. INTERVENTIONS AND OUTCOMES: He first received transarterial chemoembolization (TACE) combined with sintilimab and lenvatinib as first-line treatment and experienced 10-month progression-free survival. After cancer progression, the patient participated in a clinical trial of ABSK-011, a novel fibroblast growth factor receptor 4 inhibitor, with a frustrating result. Then, the patient underwent TACE and received sintilimab plus lenvatinib again. Surprisingly, the tumor had a partial response, and the patient's serum alpha-fetoprotein returned to normal. LESSONS: The combined treatment of TACE plus systemic therapy might be an appropriate subsequent treatment.


Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Disease Progression , Liver Neoplasms , Phenylurea Compounds , Quinolines , Humans , Male , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/therapy , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Middle Aged , Quinolines/therapeutic use , Chemoembolization, Therapeutic/methods , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
13.
Zhonghua Gan Zang Bing Za Zhi ; 32(4): 332-339, 2024 Apr 20.
Article Zh | MEDLINE | ID: mdl-38733188

Objective: To evaluate the long-term efficacy of percutaneous microwave ablation (MWA) therapy for hepatocellular carcinoma. Methods: 2054 cases with Barcelona Clinic Liver Cancer (BCLC) stage 0~B at the Fifth Medical Center of the Chinese People's Liberation Army General Hospital from January 2006 to September 2020 were retrospectively collected. All patients were followed up for at least 2 years. The primary endpoint of overall survival and secondary endpoints (tumor-related survival, disease-free survival, and postoperative complications) of patients treated with ultrasound-guided percutaneous MWA were analyzed. Kaplan-Meier method was used for stratified survival rate analysis. Fine-and-Gray competing risk model was used to analyze overall survival. Results: A total of 5 503 HCC nodules [mean tumor diameter (2.6±1.6) cm] underwent 3 908 MWAs between January 2006 and September 2020, with a median follow-up time of 45.6 (24.0 -79.2) months.The technical effectiveness rate of 5 375 tumor nodules was 97.5%. The overall survival rates at 5, 10, and 15-years were 61.6%, 38.8%, and 27.0%, respectively. The tumor-specific survival rates were 67.1%, 47.2%, and 37.7%, respectively. The free tumor survival rates were 25.8%, 15.7%, and 9.9%, respectively. The incidence rate of severe complications was 2.8% (108/3 908). Further analysis showed that the technical effectiveness and survival rate over the passing three time periods from January 2006-2010, 2011-2015, and 2016-September 2020 were significantly increased, with P < 0.001, especially for liver cancer 3.1~5.0 cm (P < 0.001). Conclusion: Microwave ablation therapy is a safe and effective method for BCLC stage 0-B, with significantly enhanced technical efficacy and survival rate over time.


Carcinoma, Hepatocellular , Liver Neoplasms , Microwaves , Humans , Liver Neoplasms/surgery , Liver Neoplasms/therapy , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/surgery , Microwaves/therapeutic use , Retrospective Studies , Survival Rate , Treatment Outcome , Disease-Free Survival , Catheter Ablation/methods , Female , Postoperative Complications/epidemiology , Male , Middle Aged
14.
Zhonghua Gan Zang Bing Za Zhi ; 32(4): 370-374, 2024 Apr 20.
Article Zh | MEDLINE | ID: mdl-38733194

Authoritative guidelines at home and abroad typically classify chronic hepatitis B virus (HBV) infection into four stages. However, in clinical practice, a considerable number of patients do not meet the guidelines for staging and are called "indeterminate phase" chronic HBV- infected patients. Studies have shown that patients in the indeterminate phase account for about 30%-50% of chronic HBV infection, have significant liver histological changes or even cirrhosis in a large proportion, and are at a higher risk of HCC and death if they do not receive antiviral therapy. Preliminary research shows that patients in the indeterminate phase who receive antiviral treatment have a good virological response and a remarkable reduced HCC risk. To this end, the 2022 publication "Expert Opinions on Expanding Antiviral Treatment for Chronic Hepatitis B" recommends aggressive treatment for patients with an indeterminate phase who have undergone more than a year of follow-up. However, there is still a lack of unified standards to refine the classification, as well as a lack of effective and rapid non-invasive diagnostic methods to identify patients in the indeterminate phase who are at risk for disease progression. This article aims to review the researches on the proportion, clinical characteristics, disease progression, and treatment benefits to further explore how to better manage indeterminate-phase chronic HBV-infected patients.


Antiviral Agents , Hepatitis B virus , Hepatitis B, Chronic , Humans , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/drug therapy , Antiviral Agents/therapeutic use , Hepatitis B virus/genetics , Disease Progression , Liver Cirrhosis/diagnosis , Liver Cirrhosis/etiology , Liver Neoplasms/diagnosis , Liver Neoplasms/therapy , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/therapy
15.
Zhonghua Gan Zang Bing Za Zhi ; 32(4): 306-311, 2024 Apr 20.
Article Zh | MEDLINE | ID: mdl-38733184

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is a global health challenge. Radical surgical resection is the most effective method to achieve long-term survival for HCC. Regrettably, the vast majority of HCC patients lose the opportunity for radical resection at the time of diagnosis due to advanced tumors or poor liver reserve capacity. HCC is resistant to conventional chemotherapy, and in the past, there have been no definite and effective systemic therapeutic drugs. Fortunately, over the last decade, the research and development of molecular targeted therapy and immunotherapy drugs for HCC have made rapid progress, and a variety of drugs and combination therapy regimens have been successively approved for clinical use. However, the overall therapeutic effect is still not ideal and needs further improvement.


Carcinoma, Hepatocellular , Immunotherapy , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Immunotherapy/methods , Drug Development , Molecular Targeted Therapy , Antineoplastic Agents/therapeutic use
16.
Sci Rep ; 14(1): 10896, 2024 05 13.
Article En | MEDLINE | ID: mdl-38740983

Development of subclassification of intermediate-stage hepatocellular carcinoma (HCC) by treatment suitability is in demand. We aimed to identify predictors that define treatment refractoriness against locoregional(transarterial chemoembolization(TACE) or thermal ablation) and surgical therapy. This multicenter retrospective study enrolled 1167 HCC patients between 2015 and 2021. Of those, 209 patients were initially diagnosed with intermediate-stage HCC. Treatment refractoriness was defined as clinical settings that meets the following untreatable progressive conditions by TACE (1) 25% increase of intrahepatic tumor, (2) transient deterioration to Child-Pugh class C, (3) macrovascular invasion or extrahepatic spread, within one year. We then analyzed factors contributing to treatment refractoriness. The Child-Pugh score/class, number of tumors, infiltrative radiological type, and recurrence were significant factors. Focusing on recurrence as a predictor, median time to untreatable progression (TTUP) was 17.2 months in the recurrence subgroup whereas 35.5 months in the initial occurrence subgroup (HR, 2.06; 95% CI, 1.44-2.96; P = 0.001). Median TTUP decreased in cases with more later times of recurrence (3-5 recurrences, 17.3 months; ≥ 6 recurrences, 7.7 months). Recurrence, even more at later times, leads to increased treatment refractoriness. Early introduction of multidisciplinary treatment should be considered against HCC patients after multiple recurrent episodes.


Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Neoplasm Recurrence, Local , Humans , Carcinoma, Hepatocellular/surgery , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Liver Neoplasms/therapy , Male , Female , Neoplasm Recurrence, Local/pathology , Middle Aged , Aged , Retrospective Studies , Chemoembolization, Therapeutic/methods , Neoplasm Staging , Adult
18.
Front Immunol ; 15: 1244392, 2024.
Article En | MEDLINE | ID: mdl-38694506

Objective: Significant advancements have been made in hepatocellular carcinoma (HCC) therapeutics, such as immunotherapy for treating patients with HCC. However, there is a lack of reliable biomarkers for predicting the response of patients to therapy, which continues to be challenging. Cancer stem cells (CSCs) are involved in the oncogenesis, drug resistance, and invasion, as well as metastasis of HCC cells. Therefore, in this study, we aimed to create an mRNA expression-based stemness index (mRNAsi) model to predict the response of patients with HCC to immunotherapy. Methods: We retrieved gene expression and clinical data of patients with HCC from the GSE14520 dataset and the Cancer Genome Atlas (TCGA) database. Next, we used the "one-class logistic regression (OCLR)" algorithm to obtain the mRNAsi of patients with HCC. We performed "unsupervised consensus clustering" to classify patients with HCC based on the mRNAsi scores and stemness subtypes. The relationships between the mRNAsi model, clinicopathological features, and genetic profiles of patients were compared using various bioinformatic methods. We screened for differentially expressed genes to establish a stemness-based classifier for predicting the patient's prognosis. Next, we determined the effect of risk scores on the tumor immune microenvironment (TIME) and the response of patients to immune checkpoint blockade (ICB). Finally, we used qRT-PCR to investigate gene expression in patients with HCC. Results: We screened CSC-related genes using various bioinformatics tools in patients from the TCGA-LIHC cohort. We constructed a stemness classifier based on a nine-gene (PPARGC1A, FTCD, CFHR3, MAGEA6, CXCL8, CABYR, EPO, HMMR, and UCK2) signature for predicting the patient's prognosis and response to ICBs. Further, the model was validated in an independent GSE14520 dataset and performed well. Our model could predict the status of TIME, immunogenomic expressions, congenic pathway, and response to chemotherapy drugs. Furthermore, a significant increase in the proportion of infiltrating macrophages, Treg cells, and immune checkpoints was observed in patients in the high-risk group. In addition, tumor cells in patients with high mRNAsi scores could escape immune surveillance. Finally, we observed that the constructed model had a good expression in the clinical samples. The HCC tumor size and UCK2 genes expression were significantly alleviated and decreased, respectively, by treatments of anti-PD1 antibody. We also found knockdown UCK2 changed expressions of immune genes in HCC cell lines. Conclusion: The novel stemness-related model could predict the prognosis of patients and aid in creating personalized immuno- and targeted therapy for patients in HCC.


Biomarkers, Tumor , Carcinoma, Hepatocellular , Computational Biology , Immunotherapy , Liver Neoplasms , Machine Learning , Neoplastic Stem Cells , Tumor Microenvironment , Humans , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/immunology , Liver Neoplasms/genetics , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Computational Biology/methods , Prognosis , Biomarkers, Tumor/genetics , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Immunotherapy/methods , Male , Gene Expression Regulation, Neoplastic , Female , Gene Expression Profiling , Middle Aged , Predictive Value of Tests
19.
Cancer Med ; 13(9): e7236, 2024 May.
Article En | MEDLINE | ID: mdl-38716585

INTRODUCTION: Regorafenib remains the standard and widely used second-line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large-scale multicenter real-world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second-line therapy for advanced HCC under real-world circumstances. PATIENTS AND METHODS: The study included 208 patients from five medical facilities. One hundred forty-three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. RESULTS: The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p < 0.001) compared to the regorafenib monotherapy group based on mRECIST criteria. Median progression-free survival (7.9 vs. 3.2 months, after PSM, p < 0.001) and overall survival (25.6 vs. 16.4 months, p = 0.010, after PSM) were also considerably longer in the regorafenib plus ICI group. The incidence of Grades 3-4 treatment-related adverse events (TRAEs) was marginally greater in the regorafenib plus ICI group than in the regorafenib group (23.8% vs. 20.0%, p = 0.546). Notably, there were no instances of treatment-related mortality or emergence of new TRAEs in any treatment group. CONCLUSION: The combination of regorafenib and ICI shows potential as a viable second-line treatment for advanced HCC, exhibiting favorable efficacy while maintaining a tolerable safety profile in contrast to regorafenib monotherapy.


Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Hepatocellular , Liver Neoplasms , Phenylurea Compounds , Pyridines , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Pyridines/therapeutic use , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Female , Male , Middle Aged , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Retrospective Studies , Adult , Immunotherapy/methods
20.
Ren Fail ; 46(1): 2347461, 2024 Dec.
Article En | MEDLINE | ID: mdl-38700058

End-stage renal disease (ESRD) coexisted with cirrhosis, ascites, and primary liver cancer represents an extraordinarily rare clinical condition that typically occurs in very late-stage decompensated cirrhosis and is associated with an extremely poor prognosis. We present a case of a 68-year-old male patient with ESRD who experienced various decompensated complications of liver cirrhosis, particularly massive ascites and hepatic space-occupying lesions. Peritoneal dialysis (PD) catheter insertion and continuous ambulatory peritoneal dialysis (CAPD) treatment were successfully performed. During meticulous follow-up, the patient survived for one year but ultimately succumbed to complications related to liver cancer. PD can serve as an efficacious therapeutic approach for such late-stage patients afflicted together with severe cirrhosis, massive ascites and primary liver cancer.


Ascites , Kidney Failure, Chronic , Liver Cirrhosis , Liver Neoplasms , Humans , Male , Aged , Kidney Failure, Chronic/therapy , Kidney Failure, Chronic/complications , Ascites/etiology , Ascites/therapy , Liver Neoplasms/complications , Liver Neoplasms/therapy , Liver Cirrhosis/complications , Fatal Outcome , Peritoneal Dialysis, Continuous Ambulatory/adverse effects , Peritoneal Dialysis/adverse effects
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