Management Of Hepatocellular Carcinoma Patients Research Articles

Impact of red blood cell distribution width (RDW) on postoperative outcomes in hepatocellular carcinoma (HCC) patients.

This study examines the relationship between red blood cell distribution width (RDW) and the prognosis of patients undergoing hepatectomy for hepatocellular carcinoma (HCC). Additionally, it explores the potential effect of RDW for the early identification of high-risk patients after surgery, advocating for timely interventions to improve outcomes. A comprehensive literature search was conducted on May 16, 2022, across PubMed (23 studies), Embase (45 studies), the Cochrane Library (1 study), and CNKI (17 studies), resulting in 6 relevant articles after screening. This analysis primarily focused on the postoperative outcomes of patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled to assess prognosis, with survival indicators including overall survival (OS) and disease-free survival (DFS). All 6 studies reported on OS, and 2 addressed DFS. A total of 1645 patients from 6 studies were included. The pooled analysis revealed that RDW is an independent prognostic factor for both OS (HR = 1.50, I² = 84%, 95% CI = 1.23-1.77, P < .01) and DFS (HR = 2.06, I² = 15%, 95% CI = 1.51-2.82, P < .01). Patients in the high RDW group exhibited significantly poorer OS and DFS compared to those in the low RDW group. RDW is a prognostic factor for HCC patients after surgery. Elevated RDW levels are associated with a poorer prognosis, adversely affecting both OS and DFS. RDW may serve as a valuable marker for stratifying risk and guiding intervention strategies in the postoperative management of HCC patients.

Use of integrated multi-omics analysis to determine antitumor efficacy of donafenib in combination with FADS2 inhibition in hepatocellular carcinoma.

e15083 Background: Pharmacotherapy remains a pivotal treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Donafenib, globally the first targeted therapy proven to offer superior survival benefits and safety over sorafenib in a large-scale phase III clinical trial with head-to-head comparison, has been adopted for first-line treatment of advanced HCC. Given the limited basic research on Donafenib both domestically and internationally, and its constrained clinical efficacy, this study aims to explore combination drug therapy for HCC in an attempt to achieve further breakthroughs and enhance the anticancer activity of Donafenib. Methods: A xenograft tumor model in nude mice was established to observe the in vivo antitumor effects of Donafenib. Transcriptomics and proteomics were employed to characterize the gene expression changes in HCC cell lines after Donafenib intervention and to screen for key molecules. A series of assays, including the Cell Counting Kit-8 (CCK8), flow cytometry, scratch assays, Transwell assays, Western blotting, and in vivo tumorigenicity in nude mice, were conducted to determine the impact of the hub gene on the malignant behavior of HCC and to evaluate the combined antitumor effects of the molecular inhibition and Donafenib treatment in HCC. Results: Treatment with Donafenib significantly slowed tumor growth in a nude mouse xenograft model, resulting in a marked reduction in final tumor volumes compared to control subjects. Proteomic analyses post-Donafenib treatment identified FADS2 as the protein with the highest absolute log2 fold change among all differentially expressed proteins in HCC cells. This finding was corroborated by transcriptomic data, which indicated a concurrent downregulation of FADS2 at the mRNA level. Subsequent in vitro and in vivo assays validated the inhibitory effect of FADS2 blockade on the malignant biological behaviors of HCC cells. Importantly, the concomitant administration of Donafenib and the FADS2 inhibitor SC-26196 exhibited a synergistic antitumor action, significantly enhancing therapeutic efficacy in both HCC cell lines and xenografted tumors in nude mice. Conclusions: Combination therapy, a prevalent approach in clinical oncology, has the potential to augment treatment efficacy while simultaneously diminishing toxicity. This study employed an extensive multi-omics approach complemented by a range of both in vitro and in vivo experiments. It revealed that the synergistic use of Donafenib and SC-26196 markedly enhances Donafenib-induced the inhibition of cancer cell growth and metastasis, demonstrating a significant synergistic antitumor effect. These findings from our preclinical investigations may offer a promising new combinational drug regimen for the therapeutic management of HCC patients.

The Deterioration of Sarcopenia Post-Transarterial Radioembolization with Holmium-166 Serves as a Predictor for Disease Progression at 3 Months in Patients with Advanced Hepatocellular Carcinoma: A Pilot Study.

The aim of this pilot study is to explore the relationship between changes in sarcopenia before and after one to three months of Transarterial Radioembolization (TARE) treatment with Holmium-166 (166Ho) and its effect on the rate of local response. Our primary objective is to assess whether the worsening of sarcopenia can function as an early indicator of a subgroup of patients at increased risk of disease progression in cases of hepatocellular carcinoma (HCC). A single-center retrospective analysis was performed on 25 patients with HCC who underwent 166Ho-TARE. Sarcopenia status was defined according to the measurement of the psoas muscle index (PMI) at baseline, one month, and three months after TARE. Radiological response according to mRECIST criteria was assessed and patients were grouped into responders and non-responders. The loco-regional response rate was evaluated for all patients before and after treatment, and was compared with sarcopenia status to identify any potential correlation. A total of 20 patients were analyzed. According to the sarcopenia status at 1 month and 3 months, two groups were defined as follows: patients in which the deltaPMI was stable or increased (No-Sarcopenia group; n = 12) vs. patients in which the deltaPMI decreased (Sarcopenia group; n = 8). Three months after TARE, a significant difference in sarcopenia status was noted (p = 0.041) between the responders and non-responders, with the non-responder group showing a decrease in the sarcopenia values with a median deltaPMI of -0.57, compared to a median deltaPMI of 0.12 in the responder group. Therefore, deltaPMI measured three months post-TARE can be considered as a predictive biomarker for the local response rate (p = 0.028). Lastly, a minor deltaPMI variation (>-0.293) was found to be indicative of positive treatment outcomes (p = 0.0001). The decline in sarcopenia three months post-TARE with Holmium-166 is a reliable predictor of worse loco-regional response rate, as evaluated radiologically, in patients with HCC. Sarcopenia measurement has the potential to be a valuable assessment tool in the management of HCC patients undergoing TARE. However, further prospective and randomized studies involving larger cohorts are necessary to confirm and validate these findings.

Biosensing of Alpha-Fetoprotein: A Key Direction toward the Early Detection and Management of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is currently one of the most prevalent cancers worldwide. Associated risk factors include, but are not limited to, cirrhosis and underlying liver diseases, including chronic hepatitis B or C infections, excessive alcohol consumption, nonalcoholic fatty liver disease (NAFLD), and exposure to chemical carcinogens. It is crucial to detect this disease early on before it metastasizes to adjoining parts of the body, worsening the prognosis. Serum biomarkers have proven to be a more accurate diagnostic tool compared to imaging. Among various markers such as nucleic acids, circulating genetic material, proteins, enzymes, and other metabolites, alpha-fetoprotein (AFP) is a protein marker primarily used to diagnose HCC. However, current methods need a large sample and carry a high cost, among other challenges, which can be improved using biosensing technology. Early and accurate detection of AFP can prevent severe progression of the disease and ensure better management of HCC patients. This review sheds light on HCC development in the human body. Afterward, we outline various types of biosensors (optical, electrochemical, and mass-based), as well as the most relevant studies of biosensing modalities for non-invasive monitoring of AFP. The review also explains these sensing platforms, detection substrates, surface modification agents, and fluorescent probes used to develop such biosensors. Finally, the challenges and future trends in routine clinical analysis are discussed to motivate further developments.

Curcumin, Piperine and Taurine Combination Enhances the Efficacy of Transarterial Chemoembolization Therapy in patients with Intermediate Stage Hepatocellular Carcinoma: A Pilot Study.

Diagnosis of the majority of hepatocellular carcinoma (HCC) patients occurs at intermediate to advanced stages, with a few curative therapeutic options being available. It is therefore strongly urgent to discover additional adjuvant therapy for this lethal malignancy. This study aimed to assess the effectiveness of curcumin (C), piperine (P) and taurine (T) combination as adjuvant agents on serum levels of IFN-γ, immunophenotypic and molecular characterization of mononuclear leukocytes (MNLs) in HCC patients treated with Transarterial chemoembolization (TACE). Serum and MNLs were collected from 20 TACE-treated HCC patients before (baseline-control samples) and after treatment with 5 g curcumin capsules , 10 mg piperine and 0.5 mg taurine taken daily for three consecutive months. Immunophenotypic and molecular characterization of MNLs were determined by flow cytometry and quantitative real time PCR, respectively. In addition, serum IFN-γ level was quantified by ELISA. After receiving treatment with CPT combination, there was a highly significant increase in IFN- γ levels in the sera of patients when compared to basal line control samples. Additionally, the group receiving combined therapy demonstrated a downregulation in the expression levels of PD-1, in MNLs as compared to controls. MNLs' immunophenotyping revealed a significant decline in CD4+CD25+cells (regulatory T lymphocytes). Furthermore, clinicopathological characteristics revealed a highly significant impact of CPT combination on aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and alpha feto protein (AFP) levels. This study introduces a promising adjuvant CPT combined treatment as natural agents to enhance the management of HCC patients who are candidates to TACE treatment.

A Novel Cholesterol Metabolism-Related lncRNA Signature Predicts the Prognosis of Patients with Hepatocellular Carcinoma and Their Response to Immunotherapy.

The survival rate of hepatocellular carcinoma (HCC) is low and the prognosis is poor. Metabolic reprogramming is still an emerging hallmark of cancer, and reprogramming of cholesterol metabolism plays a crucial action in tumor pathogenesis. Increasing evidence suggests that cholesterol metabolism affects the cell proliferation, invasion, migration, and resistance to chemotherapy of HCC. To date, no long noncoding RNA (lncRNA) signature associated with cholesterol metabolism has been developed to predict the outcome of patients with HCC. The RNA-seq data as well as the prognostic and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We conducted univariate and multivariate analyses to assess cholesterol metabolism-related lncRNAs correlated with the prognosis of patients with HCC in order to construct a prognostic signature. Functional differences between low- and high-risk groups were investigated using genomic enrichment analysis (GSEA). Kaplan-Meier (KM) curves were applied to explore the overall survival (OS) of the low- and high-risk groups. Single-sample genomic enrichment analysis (ssGSEA) was applied to investigate the association between this predictive signature and immune function. We subsequently examined how this signature relates to treatment response in HCC patients. A prognostic signature comprising six lncRNAs related to cholesterol metabolism was constructed (AC124798.1, AL031985.3, AC103760.1, NRAV, WAC-AS1 and AC022613.1). We found that low-risk groups showed a better prognosis than high-risk groups. In HCC patients, the cholesterol metabolism-related lncRNA signature may be served as an independent prognostic factor. Cholesterol metabolism-related lncRNA signature had higher diagnostic efficiency compared to clinicopathologic variables. After stratifying patients according to different clinicopathological variables, patients with low-risk had a longer OS compared with high-risk patients. The ssGSEA demonstrated that this signature was closely related to the immune status of HCC patients. GSEA analysis demonstrated that immune- and tumor-related pathways were predominantly enriched in the high-risk group. High-risk patients were more responsive to immune checkpoint inhibitors (ICIs) and conventional chemotherapeutic agents. This cholesterol metabolism-related lncRNA signature can predict the prognosis of HCC patients and guide the clinical management of HCC patients, including immunotherapy.

Role of Biobran (Arabinoxylan Rice Bran) on Patients with Advanced Stage Hepatocellular Carcinoma.

Carcinoma of liver - renowned, has taken third position in world ranking, comparing to other causes for cancer-related death, however, curative treatment of hepatocellular carcinoma (HCC) is largely absent and even proper management of HCC patients is extremely difficult. The situation becomes more complex when HCC patients are attended by physicians in their terminal state. Arabinoxylan rice bran (biobran) is an inherent product and hemicellulose which is denatured, as well as gained by hemicellulose including a number of hydrolyzing enzymes of carbohydrate from Shiitake mushrooms. It enhances activities of different immune cells and may exert some effects in cancer patients. In this observation study, the implication of biobran was assessed in a small group of 52 HCC patients. One halves of the patient received biobran and the other halves received best supportive care (BSC). Baseline parameters in two groups were mostly comparable. During observation after 30, 60, and 90 days, a total of six, one, and one patient were alive in biobran group, respectively. The survival of cancer patients of the BSC group was comparable at these time points (6, 1, and 0, respectively) with no statistical significance. After 30 days of treatment, those who were survived in biobran group, the mean CP score was 11.00 ± 1.55 and 10.50 ± 0.84 at pretreatment and posttreatment, respectively, (p = 0.20). Biobran may be of some benefit for terminal HCC, however, more studies are warranted to optimize dose and duration of therapy. Ashrafujjaman M, Mahtab MA, Noor-E-Alam SM, et al. Role of Biobran (Arabinoxylan Rice Bran) on Patients with Advanced Stage Hepatocellular Carcinoma. Euroasian J Hepato-Gastroenterol 2023;13(2):84-88.

Demographic, Clinical and Treatment Characteristics of Patients with Hepatocellular Cancer: 10 Years of Experience of a Single Center

Primary cancers of the liver are in the 3rd place in cancer-related deaths. Hepatocellular carcinoma (HCC) accounts for approximately 80% of primary hepatic malignancies. The Barcelona Clinic Liver Cancer (BCLC) classification divides HCC into 5 stages and allocates treatments. The aim of this study is to examine the initial treatments of HCC patients in our center and compare them with the approaches in the guidelines. The data of patients diagnosed with HCC between 2006 and 2016 were recruited retrospectively. Age, gender, etiology, Child-Pugh score, BCLC stage, model for end-stage liver disease score, alpha-fetoprotein level, tumor characteristics, type of first treatment and survival time were evaluated. There were 228 men and 33 women. The mean age was 61±10.5. Of the 130 patients 77 were found on BCLC stage C. The first treatment according to BCLC stage were sorafenib in 22, resection in 16, TACE in 15, Ytrium-90 in 14, systemic chemotherapy other than sorafenib in 14, transplantation in 11, palliative treatment in 8, and ablation in 4 patients. The median survival time was 11.9 (8.1-15.9) months. One-year survival was 32%, three-year survival was 19%, and five-year survival was 16%. The management of HCC patients was performed according to more than just BCLC guidelines in our center. The high number of patients who did not receive treatment may indicate that we need to show sufficient clinical attention to Stage D patients.

Construction and validation of 3-genes hypoxia-related prognostic signature to predict the prognosis and therapeutic response of hepatocellular carcinoma patients.

Previous studies have shown that the hypoxia microenvironment significantly impacted tumor progression. However, the clinical prognostic value of hypoxia-related risk signatures and their effects on the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains hazy. This study aimed to conduct novel hypoxia-related prognostic signatures and improve HCC prognosis and treatment. Differentially expressed hypoxia-related genes (HGs) were identified with the gene set enrichment analysis (GSEA). Univariate Cox regression was utilized to generate the tumor hypoxia-related prognostic signature, which consists of 3 HGs, based on the least absolute shrinkage and selection operator (LASSO) algorithm. Then the risk score for each patient was performed. The prognostic signature's independent prognostic usefulness was confirmed, and systematic analyses were done on the relationships between the prognostic signature and immune cell infiltration, somatic cell mutation, medication sensitivity, and putative immunological checkpoints. A prognostic risk model of four HGs (FDPS, SRM, and NDRG1) was constructed and validated in the training, testing, and validation datasets. To determine the model's performance in patients with HCC, Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves analysis was implemented. According to immune infiltration analysis, the high-risk group had a significant infiltration of CD4+ T cells, M0 macrophages, and dendritic cells (DCs) than those of the low-risk subtype. In addition, the presence of TP53 mutations in the high-risk group was higher, in which LY317615, PF-562271, Pyrimethamine, and Sunitinib were more sensitive. The CD86, LAIR1, and LGALS9 expression were upregulated in the high-risk subtype. The hypoxia-related risk signature is a reliable predictive model for better clinical management of HCC patients and offers clinicians a holistic viewpoint when determining the diagnosis and course of HCC treatment.

Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review

The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10-20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients' survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.

Novel Nomograms Based on Gamma-Glutamyl Transpeptidase-to-Lymphocyte Ratio Predict Prognosis of Hepatocellular Carcinoma Patients After Hepatectomy.

The prediction of prognosis of hepatocellular carcinoma (HCC) is of great significance in improving disease outcome and optimizing clinical management, while reliable prognostic indicators are lacking. This study was conducted to develop readily-to-use nomograms for prognosis prediction of HCC after hepatectomy. Data of eligible patients were collected and analyzed retrospectively. Independent prognostic factors were identified by Cox regression, and nomograms for the prediction of disease-free survival (DFS) and overall survival (OS) were developed. The performance of the nomograms was evaluated by receiver operating characteristics (ROC) curves, C-indexes and calibration curves and was verified by the validation cohort. The predictive value of the nomograms was also compared with the 8th edition of American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) and the Barcelona Clinic Liver Cancer (BCLC) staging systems. In total, 599 patients were enrolled in the analysis: 420 in the training cohort and 179 in the validation cohort. The optimal cut-off value of Gamma-Glutamyl Transpeptidase-to-Lymphocyte Ratio (GLR) was 19.5. GLR contributed significantly to the nomograms with good predictive power. In ROC analyses, the areas under curve (AUCs) of the nomograms for 1-, 3- and 5-year DFS and OS prediction were 0.758, 0.756, 0.734 and 0.810, 0.799, 0.758, respectively. The C-indexes of the DFS nomogram were 0.697 (95% CI 0.665-0.729) in the training cohort and 0.710 (95% CI 0.664-0.756) in the validation cohort. For OS prediction, the C-indexes were 0.741 (95% CI 0.704-0.778) and 0.758 (95% CI 0.705-0.811) in the training and validation cohorts, respectively. The calibration curves demonstrated satisfactory agreement between nomogram predictions and actual observations. The nomograms demonstrated superior predictive performance to the TNM and the BCLC staging systems. Our novel nomograms showed adequate performance in the prediction of HCC prognosis after hepatectomy, which may facilitate the risk stratification and individualized management of HCC patients.

Advances in multidisciplinary team-based collaborative care models in the nutritional management of patients with hepatocellular carcinoma

Liver cancer is a common and highly prevalent malignancy in China, and is a high prevalence of malnutrition. With the continuous innovation of medical technology and nursing model, the multidisciplinary teamwork nursing model has become inevitable for the care of liver cancer patients. This study reviews the concept of MDT nursing model, its development status at home and abroad and its application in the postoperative nutritional management of hepatocellular carcinoma patients, aiming to provide a basis for clinical hepatocellular carcinoma nutritional management.

Role of CA 19.9 and CEA in predicting diagnosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is responsible for 90% of cases of primary liver cancer and is also responsible for the fourth most common cause of cancer death worldwide. To improve the current scenario for the early diagnosis and management of HCC patients, a better understanding of HCC is required. Hence, serum tumor biomarkers such as CA 19-9 (cancer antigen), CEA (carcinoembryonic antigen), and AFP (alpha-fetoprotein) show promising future, when it comes to early diagnosis of primary liver cancer (PHC), liver cirrhosis, and metastasis. It was a retrospective cross-sectional analysis of patients diagnosed with primary hepatocellular carcinoma, data were collected from the hospital database and included a total of 245 patients of HCC attending the out-patient department and some were admitted for treatment at our institution. Out of 245 patients, 68 patients were selected for the study. We have collected information related to the patient's demographic profile, pathological diagnosis, biochemical profile, and even radiological diagnosis. The sensitivity and specificity of CA 19-9 and CEA were also done. Adenocarcinoma is the most common type of liver cancer followed by HCC. We have shown a weak correlation between tumor markers CA 19-9 and CEA for the diagnosis of liver carcinoma. Further our study shows that the sensitivity of tumor marker CA 19-9 for the diagnosis of liver carcinoma is 64.28% and that of CEA is 83.67%. The search for a novel biomarker of early liver carcinoma requires further research. The authors declare that they have no competing interests.

Predictive machine learning model for microvascular invasion identification in hepatocellular carcinoma based on the LI-RADS system.

This study aimed to establish a predictive model of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) by contrast-enhanced computed tomography (CT), which relied on a combination of machine learning approach and imaging features covering Liver Imaging and Reporting and Data System (LI-RADS) features. The retrospective study included 279 patients with surgery who underwent preoperative enhanced CT. They were randomly allocated to training set, validation set, and test set (167 patients vs. 56 patients vs. 56 patients, respectively). Significant imaging findings for predicting MVI were identified through the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression method. Predictive models were performed by machine learning algorithm, support vector machine (SVM), in the training set and validation set, and evaluated in the test set. Further, a combined model adding clinical findings to the radiologic model was developed. Based on the LI-RADS category, subgroup analyses were conducted. We included 116 patients with MVI which were diagnosed through pathological confirmation. Six imaging features were selected about MVI prediction: four LI-RADS features (corona enhancement, enhancing capsule, non-rim aterial phase hyperehancement, tumor size) and two non-LI-RADS features (internal arteries, non-smooth tumor margin). The radiological feature with the best accuracy was corona enhancement followed by internal arteries and tumor size. The accuracies of the radiological model and combined model were 0.725-0.714 and 0.802-0.732 in the training set, validation set, and test set, respectively. In the LR-4/5 subgroup, a sensitivity of 100% and an NPV of 100% were obtained by the high-sensitivity threshold. A specificity of 100% anda PPV of 100% were acquired through the high specificity threshold in the LR-M subgroup. A combination of LI-RADS features and non-LI-RADS features and serum alpha-fetoprotein value could be applied as a preoperative biomarker for predicting MVI by the machine learning approach. Furthermore, its good performance in the subgroup by LI-RADS category may help optimize the management of HCC patients.

Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation.

Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients.

Development and validation of an ECM-related prognostic signature to predict the immune landscape of human hepatocellular carcinoma

BackgroundThe global burden of hepatocellular carcinoma (HCC) is increasing, negatively impacting social health and economies. The discovery of novel and valuable biomarkers for the early diagnosis and therapeutic guidance of HCC is urgently needed.MethodsExtracellular matrix (ECM)-related gene sets, transcriptome data and mutation profiles were downloaded from the Matrisome Project and The Cancer Genome Atlas (TCGA)-LIHC datasets. Coexpression analysis was initially performed with the aim of identifying ECM-related lncRNAs (r > 0.4, p < 0.001). The screened lncRNAs were subjected to univariate analysis to obtain a series of prognosis-related lncRNA sets, which were incorporated into least absolute selection and shrinkage operator (LASSO) regression for signature establishment. Following the grouping of LIHC samples according to risk score, the correlations between the signature and clinicopathological, tumour immune infiltration, and mutational characteristics as well as therapeutic response were also analysed. lncRNA expression levels used for modelling were finally examined at the cellular and tissue levels by real-time PCR. All analyses were based on R software.ResultsAL031985.3 and MKLN1-AS were ultimately identified as signature-related lncRNAs, and both were significantly upregulated in HCC tissue samples and cell lines. The prognostic value of the signature reflected by the AUC value was superior to that of age, sex, grade and stage. Correlation analysis results demonstrated that high-risk groups exhibited significant enrichment of immune cells (DCs, macrophages and Tregs) and increased expression levels of all immune checkpoint genes. Prominent differences in clinicopathological profiles, immune functions, tumour mutation burden (TMB) and drug sensitivity were noted between the two risk groups.ConclusionsOur signature represents a valuable predictive tool in the prognostic management of HCC patients. Further validation of the mechanisms involved is needed.

Laparoscopic surgical management of hepatocellular carcinoma patients with diaphragmatic involvement.

Hepatocellular carcinoma (HCC) is a common malignancy of the digestive system with high morbidity and high mortality worldwide. Currently, surgical resection is considered the most effective treatment for HCC. Laparoscopic surgery is a major trend in contemporary minimally invasive surgery. However, is laparoscopic resection suitable for HCC patients with diaphragmatic involvement? If so, then what is the preferred resection method, and how safe and effective is this treatment? Are there any factors that require special attention? Clinical data of 17 patients who underwent laparoscopic surgery in the Second Affiliated Hospital, Third Military Medical University (Army Medical University) from January 2018 to February 2021 were retrospectively analyzed. The mean age was 48.9 ± 14.0years; mean operation time, 186.00 ± 18.3min; median blood loss, 170.0ml (140.8-207.5ml); and median length of hospital stay, 8.0days (7.0-9.5days). There was no case of open conversion. Pathologic findings revealed all cases of HCC. Intraoperative frozen pathology and postoperative pathology showed free surgical margins. Six patients had pathologically confirmed diaphragmatic invasion (DI), and eleven was confirmed as having diaphragmatic fibrous adhesion (DFA) only. Post-operative complications included liver section effusion, pleural effusion, pneumonia and bile leak. All the complications responded well to conservative treatment. No other abnormality was noted during outpatient follow-up examination. Sixteen patients survived tumor-free; one patient with HCC developed intrahepatic metastasis 1year after surgery, and this patient survived with tumor after treatment. Our experience initially provides valuable support for the laparoscopic surgical treatment of HCC patients with diaphragmatic involvement.

Nationwide database analysis of insomnia, depression, and sleeping pill prescriptions in hepatocellular carcinoma patients

Objective To clarify the status of insomnia and depression and the prescription of sleeping pills in hepatocellular carcinoma (HCC) patients before and after HCC diagnosis and treatment. Methods Patients’ data from a Japanese health insurance claims database were analyzed retrospectively to determine the incidence of insomnia and depression and their association with sleeping pill prescriptions during the 6 months before and after HCC diagnosis and treatment. Results A total of 9,109 HCC patients (median age at diagnosis = 71.5 years, 68.1% male) were analyzed. The incidences of insomnia and depression increased significantly after HCC diagnosis. Insomnia was reported in 15.0% of patients before diagnosis, and it increased to 27.6% after diagnosis. Similarly, depression was reported in 6.3% and 11.3% before and after diagnosis, respectively. The incidences of insomnia and depression before diagnosis were higher in patients with concomitant liver diseases including hepatitis, cirrhosis, and hepatic encephalopathy. However, the rate of sleeping pill prescription was significantly lower in patients with concomitant liver diseases after diagnosis. The incidence of fracture was higher in insomnia or depression patients than others and in patients treated with sleeping pills than without before and after diagnosis. Conclusions HCC patients had increased risks of insomnia and depression after diagnosis. The high risk of fracture in HCC patients with insomnia and depression and treated with sleeping pills suggests that it is difficult to optimize the management of HCC patients, especially those with concomitant liver diseases.

Monitoring One-carbon metabolism by mass spectrometry for early diagnosis of cirrhosis and HCC

Introduction: Liver cancer represents one of the most frequent causes of death by cancer, ranked as the sixth most prevalent and the second in lethality. Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and presents an increasing incidence during the last years. Late diagnosis is one of the reasons explaining the low survival rate of HCC patients (5 years survival after diagnosis below 20%). Remarkably, 80% of HCC cases develop in cirrhotic tissue (1). Main risk factors for HCC are well known and include hepatitis B and C viral infections or abusive alcohol consumption. However, the underlying molecular mechanisms remain unknown and its research will lead to the characterization of new biomolecular markers for the early diagnosis, prognosis and therapy of HCC. Metabolic remodeling is a common feature among several hepatic disorders, from steatosis to HCC (2). Tumoral hepatocytes modify their metabolism to satisfy cancer’s proliferative requirements. One-carbon metabolism (OCM) plays a fundamental role maintaining the differentiation and quiescent state of hepatocytes, and is recognized as the link between intermediate metabolism and epigenetic regulation. Owing to these reasons, it might be a potential source of biomarkers for early diagnosis and prognosis of HCC. Accordingly, it has been demonstrated that some OCM enzymes are differentially expressed in murine HCC models (3). Materials and methods: We have developed a robust targeted mass spectrometry-based method, using SRM mode (Selected Reaction Monitoring), for the systematic quantification of 13 enzymes that participate in OCM. For this purpose, purified synthetic heavy standard peptides, as well as OCM recombinant proteins have been used. Sixty-four human liver samples, including 28 control samples, 21 tumoral samples and15 cirrhotic samples have been used. Results and conclusions: We have demonstrated that there is a profound remodeling of the OCM cycle in HCC versus control samples, while cirrhotic samples tend to show intermediate expression levels between both physiological situations. Machine learning- based analysis of our results suggests that monitoring a panel of functionally related proteins might be useful for future clinical developments and improve the management of HCC patients. However, further experiments with larger cohorts are required to confirm these findings. References 1) Ryerson, A. B., et al (2016). Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer, 122(9), 1312-1337. 2) Vander Heiden, et al (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324(5930), 1029-1033 3) Mora, M. I., Corrales, F. J., et al (2017). Prioritizing popular proteins in liver cancer: remodelling one-carbon metabolism. Journal of proteome research, 16(12), 4506-4514.

Construction of a Necroptosis-Related miRNA Signature for Predicting the Prognosis of Patients With Hepatocellular Carcinoma.

Background: Many miRNAs have been demonstrated to be associated with the prognosis of hepatocellular carcinoma (HCC). However, how to combine necroptosis-related miRNAs to achieve the best predictive effect in estimating HCC patient survival has not been explored. Methods: The mRNA and miRNA expression profile were downloaded from a public database (TCGA-LIHC cohort). Necroptosis-related genes were obtained from previous references, and necroptosis-related miRNAs were identified using Pearson analysis. Subsequently, differential expression miRNAs (DEms) were identified in HCC and paracancer normal samples based on necroptosis-related miRNA expression. The whole set with HCC was randomized into a training set and testing set (1:1). LASSO-Cox regression analysis was used to construct an miRNA signature. Multiple statistical methods were used to validate the clinical benefit of signature in HCC patients, including receiver operator characteristic (ROC) curves, Kaplan–Meier survival analyses, and decision curve analysis (DCA). The downstream target genes of miRNAs were obtained from different online tools, and the potential pathways involved in miRNAs were explored. Finally, we conducted RT-qPCR in SK-HEP-1, THLE-3, and HUH-7 cell lines for miRNAs involved in the signature. Results: The results showed that a total of eight specific necroptosis-related miRNAs were screened between HCC and adjacent tissues in the training set. Subsequently, based on the aforementioned miRNAs, 5-miRNA signature (miR-139-5p, hsa-miR-326, miR-10b-5p, miR-500a-3p, and miR-592) was generated by LASSO-Cox regression analysis. Multivariate Cox regression analysis showed that the risk scores were independent prognostic indicators in each set. The area under curves (AUCs) of 1 year, 3 years, 5 years, and 7 years were high in each set (AUC >0.7). DCA analysis also revealed that the risk score had a potential benefit than other clinical characteristics. Meanwhile, survival analysis showed that the high-risk group showed low survival probabilities. Moreover, the results of enrichment analysis showed that specific miRNAs were mainly enriched in the cAMP signaling pathway and TNF signaling pathway. Finally, the results of RT-qPCR were consistent with the prediction results in public databases. Conclusion: Our study establishes a robust tool based on 5-necroptosis-related miRNAs for the prognostic management of HCC patients.