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Cancer Medicine Jun 2024Radical surgery, the first-line treatment for patients with hepatocellular cancer (HCC), faces the dilemma of high early recurrence rates and the inability to predict...
PURPOSE
Radical surgery, the first-line treatment for patients with hepatocellular cancer (HCC), faces the dilemma of high early recurrence rates and the inability to predict effectively. We aim to develop and validate a multimodal model combining clinical, radiomics, and pathomics features to predict the risk of early recurrence.
MATERIALS AND METHODS
We recruited HCC patients who underwent radical surgery and collected their preoperative clinical information, enhanced computed tomography (CT) images, and whole slide images (WSI) of hematoxylin and eosin (H & E) stained biopsy sections. After feature screening analysis, independent clinical, radiomics, and pathomics features closely associated with early recurrence were identified. Next, we built 16 models using four combination data composed of three type features, four machine learning algorithms, and 5-fold cross-validation to assess the performance and predictive power of the comparative models.
RESULTS
Between January 2016 and December 2020, we recruited 107 HCC patients, of whom 45.8% (49/107) experienced early recurrence. After analysis, we identified two clinical features, two radiomics features, and three pathomics features associated with early recurrence. Multimodal machine learning models showed better predictive performance than bimodal models. Moreover, the SVM algorithm showed the best prediction results among the multimodal models. The average area under the curve (AUC), accuracy (ACC), sensitivity, and specificity were 0.863, 0.784, 0.731, and 0.826, respectively. Finally, we constructed a comprehensive nomogram using clinical features, a radiomics score and a pathomics score to provide a reference for predicting the risk of early recurrence.
CONCLUSIONS
The multimodal models can be used as a primary tool for oncologists to predict the risk of early recurrence after radical HCC surgery, which will help optimize and personalize treatment strategies.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Male; Female; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Tomography, X-Ray Computed; Machine Learning; Aged; Hepatectomy; Adult; Radiomics
PubMed: 38864473
DOI: 10.1002/cam4.7374 -
Frontiers in Immunology 2024Hepatocellular carcinoma (HCC) ranks as the sixth most common malignancy globally, with the majority of patients presenting at the initial diagnosis with locally... (Review)
Review
Transarterial chemoembolization combined with atezolizumab plus bevacizumab conversion therapy for intermediate-stage hepatocellular carcinoma: a case report and literature review.
Hepatocellular carcinoma (HCC) ranks as the sixth most common malignancy globally, with the majority of patients presenting at the initial diagnosis with locally advanced or metastatic disease, precluding the opportunity for curative surgical intervention. With the exploration and advancement of locoregional treatments, novel molecular-targeted therapies, anti-angiogenic agents, and immunomodulatory drugs, the management of HCC has seen an increase in objective response rates and prolonged duration of response significantly enhancing the potential for conversion to resectable disease in intermediate and advanced-stage unresectable HCC. Herein, we present a case of Barcelona Clinic Liver Cancer stage B unresectable HCC, where after two courses of treatment with transarterial chemoembolization combined with atezolizumab plus bevacizumab significant tumor reduction was achieved. Per Response Evaluation Criteria in Solid Tumors 1.1, partial response culminated in successful curative surgical resection. No drug-related adverse reactions occurred during hospitalization, and there has been no recurrence during the 11-month postoperative follow-up. For patients with Barcelona Clinic Liver Cancer stage B (intermediate-stage) unresectable HCC, the transarterial chemoembolization combined with atezolizumab plus bevacizumab regimen may offer improved therapeutic outcomes leading to a higher success rate of conversion therapy and, thus, improved survival.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Bevacizumab; Chemoembolization, Therapeutic; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Male; Neoplasm Staging; Middle Aged; Treatment Outcome; Combined Modality Therapy
PubMed: 38863699
DOI: 10.3389/fimmu.2024.1358602 -
Frontiers in Immunology 2024This study aimed to develop a prognostic nomogram for predicting the recurrence-free survival (RFS) of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)...
Machine learning-based model for predicting tumor recurrence after interventional therapy in HBV-related hepatocellular carcinoma patients with low preoperative platelet-albumin-bilirubin score.
INTRODUCTION
This study aimed to develop a prognostic nomogram for predicting the recurrence-free survival (RFS) of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients with low preoperative platelet-albumin-bilirubin (PALBI) scores after transarterial chemoembolization (TACE) combined with local ablation treatment.
METHODS
We gathered clinical data from 632 HBV-related HCC patients who received the combination treatment at Beijing You'an Hospital, affiliated with Capital Medical University, from January 2014 to January 2020. The patients were divided into two groups based on their PALBI scores: low PALBI group (n=247) and high PALBI group (n=385). The low PALBI group was then divided into two cohorts: training cohort (n=172) and validation cohort (n=75). We utilized eXtreme Gradient Boosting (XGBoost), random survival forest (RSF), and multivariate Cox analysis to pinpoint the risk factors for RFS. Then, we developed a nomogram based on the screened factors and assessed its risk stratification capabilities and predictive performance.
RESULTS
The study finally identified age, aspartate aminotransferase (AST), and prothrombin time activity (PTA) as key predictors. The three variables were included to develop the nomogram for predicting the 1-, 3-, and 5-year RFS of HCC patients. We confirmed the nomogram's ability to effectively discern high and low risk patients, as evidenced by Kaplan-Meier curves. We further corroborated the excellent discrimination, consistency, and clinical utility of the nomogram through assessments using the C-index, area under the curve (AUC), calibration curve, and decision curve analysis (DCA).
CONCLUSION
Our study successfully constructed a robust nomogram, effectively predicting 1-, 3-, and 5-year RFS for HBV-related HCC patients with low preoperative PALBI scores after TACE combined with local ablation therapy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Male; Female; Middle Aged; Machine Learning; Bilirubin; Neoplasm Recurrence, Local; Nomograms; Hepatitis B virus; Chemoembolization, Therapeutic; Prognosis; Blood Platelets; Hepatitis B; Adult; Serum Albumin; Retrospective Studies; Platelet Count
PubMed: 38863693
DOI: 10.3389/fimmu.2024.1409443 -
BMC Cancer Jun 2024To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined Lenvatinib plus Camrelizumab (TLC) in unresectable hepatocellular... (Comparative Study)
Comparative Study
BACKGROUNDS
To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined Lenvatinib plus Camrelizumab (TLC) in unresectable hepatocellular carcinoma (uHCC) with those of TACE alone .
METHODS
A retrospective analysis was performed on 222 patients with uHCC who were treated between September 2013 and Jun 2023. One group received TACE + lenvatinib + camrelizumab (TLC) (n = 97) and another group received TACE alone (n = 151). Efficacy and safety were compared after propensity score matching between the TLC and TACE groups.
RESULTS
After propensity matching, the TLC group had higher objective response rate (ORR) (88.6% vs. 28.6%, P < 0.001), disease control rate (DCR) (94.3%% vs. 72.9%, P < 0.001), and conversion rates before and after propensity matching were 44.1% and 41.4%, respectively, compared with the TACE group. The median progression free survival (PFS) was longer in the TLC group than in the TACE group (12.7 vs. 6.1 months, P = 0.005). The median overall survival (OS) was longer in the TLC group than in the TACE group (19.4 vs. 13.0 months, P = 0.023). Cox multivariate analysis with different modes of adjustment showed that treatment was an independent influencing factor of PFS and OS. The interaction analysis showed that cirrhosis and Child-Pugh stage an interactive role in the PFS of different treatment. Decreased AFP after treatment portends higher ORR and DCR.
CONCLUSION
TACE combined Lenvatinib plus Camrelizumab regimen was safe and superior to TACE alone in improving PFS, OS, and tumor response rates for unresectable recurrent HCC patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Quinolines; Male; Female; Chemoembolization, Therapeutic; Middle Aged; Retrospective Studies; Propensity Score; Antibodies, Monoclonal, Humanized; Phenylurea Compounds; Aged; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Combined Modality Therapy; Adult
PubMed: 38862932
DOI: 10.1186/s12885-024-12484-3 -
Nature Communications Jun 2024RNF214 is an understudied ubiquitin ligase with little knowledge of its biological functions or protein substrates. Here we show that the TEAD transcription factors in...
RNF214 is an understudied ubiquitin ligase with little knowledge of its biological functions or protein substrates. Here we show that the TEAD transcription factors in the Hippo pathway are substrates of RNF214. RNF214 induces non-proteolytic ubiquitylation at a conserved lysine residue of TEADs, enhances interactions between TEADs and YAP, and promotes transactivation of the downstream genes of the Hippo signaling. Moreover, YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, RNF214 is overexpressed in hepatocellular carcinoma (HCC) and inversely correlates with differentiation status and patient survival. Consistently, RNF214 promotes tumor cell proliferation, migration, and invasion, and HCC tumorigenesis in mice. Collectively, our data reveal RNF214 as a critical component in the Hippo pathway by forming a signaling axis of RNF214-TEAD-YAP and suggest that RNF214 is an oncogene of HCC and could be a potential drug target of HCC therapy.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Ubiquitination; Animals; Transcription Factors; Signal Transduction; Mice; DNA-Binding Proteins; Cell Proliferation; YAP-Signaling Proteins; Cell Line, Tumor; TEA Domain Transcription Factors; Adaptor Proteins, Signal Transducing; Disease Progression; Mice, Nude; Cell Movement; Male; Gene Expression Regulation, Neoplastic; Hippo Signaling Pathway; HEK293 Cells; Ubiquitin-Protein Ligases; Female; Nuclear Proteins
PubMed: 38862474
DOI: 10.1038/s41467-024-49045-y -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To investigate the prognostic value of M2 macrophage-related genes (MRG) in hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC).
OBJECTIVE
To investigate the prognostic value of M2 macrophage-related genes (MRG) in hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC).
METHODS
The transcriptome data of 73 patients with HBV-related HCC were obtained from TCGA database, and the MRG modules were identified by WGCNA. The MRG-based risk scoring model was constructed by LASSO regression analysis and validated using an external dataset. The correlation of the risk score with immune cell infiltration and drug sensitivity of HCC were analyzed with CIBERSORT and R. pRRophetic. The signaling pathways of the differential genes between the high- and low-risk groups were investigated using GSVA and GSEA enrichment analyses, and MRG expressions at the single cell level were validated using R.Seurat. The cell interaction intensity was analyzed by R.Cellchat to identify important cell types related to HCC progression. MRG expression levels were detected by RT-qPCR in THP-1 cells with HCC-conditioned medium-induced M2 polarization and in HBV-positive HCC cells.
RESULTS
A high M2 macrophage infiltration level was significantly correlated with a poor prognosis of HCC, and 5 hub MRG (VTN, GCLC, PARVB, TRIM27, and GMPR) were identified. The overall survival of HCC patients was significantly lower in the high-risk than in the low-risk group. The high- and the low-risk groups showed significant enrichment of M2 macrophages and na?ve B cells, respectively, and were sensitive to BI. 2536 and to AG. 014699, AKT. inhibitor. Ⅷ, AZD. 0530, AZD7762, and BMS. 708163, respectively. The proliferation-related and metabolism-related pathways were enriched in the high-risk group, where monocytes showed the most active cell interactions during HCC progression. VTN was significantly upregulated in HCC cell lines, while GCLC, PARVB, TRIM27, and GMPR were upregulated in M2 THP-1 cells.
CONCLUSION
The MRG-based risk scoring model can accurately predict the prognosis of HBV-related HCC and reveal the differences in tumor microenvironment to guide precision treatment of the patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Macrophages; Hepatitis B virus; Transcriptome; Hepatitis B; Gene Expression Regulation, Neoplastic; Tumor Microenvironment
PubMed: 38862440
DOI: 10.12122/j.issn.1673-4254.2024.05.04 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To investigate the effects of an adeno-associated virus (AAV2) vector expressing secretory transforming growth factor-β (TGF-β) type Ⅱ receptor (sTβRⅡ)...
[A recombinant adeno-associated virus expressing secretory TGF-β type Ⅱ receptor inhibits triple-negative murine breast cancer 4T1 cell proliferation and lung metastasis in mice].
OBJECTIVE
To investigate the effects of an adeno-associated virus (AAV2) vector expressing secretory transforming growth factor-β (TGF-β) type Ⅱ receptor (sTβRⅡ) extracellular domain-IgG2a Fc fusion protein (sTβRⅡ-Fc) on proliferation and migration of triple-negative murine breast cancer 4T1 cells in mice.
METHODS
The pAAV-sTβRⅡ-Fc vector expressing sTβRⅡ-Fc fusion protein constructed by molecular cloning, the capsid protein-expressing vector pAAV2 and the helper vector were co-transfected into HEK 293T cells to prepare the recombinant AAV2-sTβRⅡ virus, which was purified by density gradient centrifugation with iodixanol. Western blotting was used to examine the effects of AAV-sTβRⅡ virus on Smad2/3 phosphorylation in 4T1 cells and on expression levels of E-cadherin, vimentin and p-Smad2/3 in 4T1 cell xenografts in mice. BALB/c mice bearing subcutaneous xenografts of luciferase-expressing 4T1 cells received intravenous injections of AAV-sTβRⅡ virus, AAV-GFP virus or PBS (=6) through the tail vein, and the proliferation and migration of 4T1 cells were analyzed with in vivo imaging. Ki67 expression in the tumor tissues and sTβRⅡ protein expressions in mouse livers were detected with immunohistochemistry and immunofluorescence staining, and tumor metastases in the vital organs were examined with HE staining.
RESULTS
The recombinant pAAV-sTβRⅡ-Fc vector successfully expressed sTβRⅡ in HEK 293T cells. Infection with AAV2-sTβRⅡ virus significantly reduced TGF-β1-induced Smad2/3 phosphorylation in 4T1 cells and effectively inhibited proliferation and lung metastasis of 4T1 xenografts in mice (<0.05). In the tumor-bearing mice, intravenous injection of AAV-sTβRⅡ virus significantly increased E-cadherin expression, reduced vimentin and Ki67 protein expressions and Smad2/3 phosphorylation level in the tumor tissues (<0.05 or 0.01), and induced liver-specific sTβRⅡ expression without causing body weight loss or heart, liver, spleen or kidney pathologies.
CONCLUSION
The recombinant AVV2 vector encoding sTβRⅡ extracellular domain is capable of blocking the TGF-β signaling pathway to inhibit the proliferation and lung metastasis of 4T1 cells in mice.
Topics: Animals; Mice; Dependovirus; Cell Proliferation; Mice, Inbred BALB C; Humans; HEK293 Cells; Genetic Vectors; Lung Neoplasms; Female; Receptor, Transforming Growth Factor-beta Type II; Cell Line, Tumor; Triple Negative Breast Neoplasms; Cadherins; Smad3 Protein; Cell Movement; Smad2 Protein
PubMed: 38862439
DOI: 10.12122/j.issn.1673-4254.2024.05.03 -
Redox Report : Communications in Free... Dec 2024Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We...
Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We aim to assess the anticancer activity of emodin against hepatocellular carcinoma (HCC) in rat models using the proliferation, invasion, and angiogenesis biomarkers. After induction of HCC, assessment of the liver impairment and the histopathology of liver sections were investigated. Hepatic expression of both mRNA and protein of the oxidative stress biomarkers, HO-1, Nrf2; the mitogenic activation biomarkers, ERK5, PKCδ; the tissue destruction biomarker, ADAMTS4; the tissue homeostasis biomarker, aggregan; the cellular fibrinolytic biomarker, MMP3; and of the cellular angiogenesis biomarker, VEGF were measured. Emodin increased the survival percentage and reduced the number of hepatic nodules compared to the HCC group. Besides, emodin reduced the elevated expression of both mRNA and proteins of all PKC, ERK5, ADAMTS4, MMP3, and VEGF compared with the HCC group. On the other hand, emodin increased the expression of mRNA and proteins of Nrf2, HO-1, and aggrecan compared with the HCC group. Therefore, emodin is a promising anticancer agent against HCC preventing the cancer prognosis and infiltration. It works through many mechanisms of action, such as blocking oxidative stress, proliferation, invasion, and angiogenesis.
Topics: Animals; Emodin; Carcinoma, Hepatocellular; Rats; Thioacetamide; Liver Neoplasms; Antioxidants; ADAMTS4 Protein; Male; Protein Kinase C; Oxidative Stress; Antineoplastic Agents; Signal Transduction; Cell Proliferation
PubMed: 38861483
DOI: 10.1080/13510002.2024.2365590 -
Journal of Cancer Research and Clinical... Jun 2024Human MARCH5 is a mitochondria-localized E3 ubiquitin-protein ligase that is essential for the regulation of mitochondrial dynamics. A large body of evidence suggests...
BACKGROUND
Human MARCH5 is a mitochondria-localized E3 ubiquitin-protein ligase that is essential for the regulation of mitochondrial dynamics. A large body of evidence suggests that imbalances in mitochondrial dynamics are strongly associated with cancer. However, the expression, biological function and prognostic significance of MARCH5 in hepatocellular carcinoma (HCC) have not been determined.
MATERIALS AND METHODS
The mRNA and protein expression of MARCH5 in HCC cell lines and tumor tissues was assessed by real-time quantitative PCR, Western blot analysis and immunohistochemistry. The clinical prognostic significance of MARCH5 was evaluated in 135 HCC patients. Knockdown or overexpression of MARCH5 in HCC cells was determined by in vitro cell proliferation, migration and invasion assays, and in vivo tumor growth and metastasis assays. In addition, the intrinsic mechanisms by which MARCH5 regulates HCC cell growth and metastasis were explored.
RESULTS
MARCH5 was significantly overexpressed in HCC cells and was closely associated with patients' poor postoperative prognosis. In vivo and in vitro experiments revealed that MARCH5 significantly promoted the increase and invasive and migratory ability of hepatocellular carcinoma cells, which was mainly due to the promotion of autophagy by MARCH5. Mechanistic studies revealed that MARCH5 promoted autophagy through ubiquitination degradation of p53 leading to malignant progression of hepatocellular carcinoma.
CONCLUSION
Our findings suggest that MARCH5 plays a critical oncogenic role in HCC cells, which provides experimental evidence for the use of MARCH5 as a potential target for HCC therapy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Ubiquitination; Ubiquitin-Protein Ligases; Tumor Suppressor Protein p53; Disease Progression; Male; Animals; Mice; Female; Prognosis; Mice, Nude; Cell Proliferation; Middle Aged; Cell Line, Tumor; Mice, Inbred BALB C; Cell Movement
PubMed: 38861187
DOI: 10.1007/s00432-024-05782-7 -
Technology in Cancer Research &... 2024To compare the ability of gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA) and gadobenate dimeglumine (Gd-BOPTA) to display the 3 major features recommended by the... (Comparative Study)
Comparative Study
Comparison of the Ability of Gadobenate Dimeglumine and Gadolinium Ethoxybenzyl Dimeglumine to Display the major Features for Noninvasively Diagnosing Hepatocellular Carcinoma According to the LI-RADS 2018v.
OBJECTIVE
To compare the ability of gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA) and gadobenate dimeglumine (Gd-BOPTA) to display the 3 major features recommended by the Liver Imaging Reporting and Data System (LI-RADS 2018v) for diagnosing hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
In this retrospective study, we included 98 HCC lesions that were scanned with either Gd-EOB-DTPA-MR or Gd-BOPTA-M.For each lesion, we collected multiple variables, including size and enhancement pattern in the arterial phase (AP), portal venous phase (PVP), transitional phase (TP), delayed phase (DP), and hepatobiliary phase (HBP). The lesion-to-liver contrast (LLC) was measured and calculated for each phase and then compared between the 2 contrast agents. A value < .05 was considered statistically significant. The display efficiency of the LLC between Gd-BOPTA and Gd-EOB-DTPA for HCC features was evaluated by receiver operating characteristic (ROC) curve analysis.
RESULTS
Between Gd-BOPTA and Gd-EOB-DTPA, significant differences were observed regarding the display efficiency for capsule enhancement and the LLC in the AP/PVP/DP ( < .05), but there was no significant difference regarding the LLC in the TP/HBP. Both Gd-BOPTA and Gd-EOB-DTPA had good display efficiency in each phase (AUC> 0.750). When conducting a total evaluation of the combined data across the 5 phases, the display efficiency was excellent (AUC > 0.950).
CONCLUSION
Gd-BOPTA and Gd-EOB-DTPA are liver-specific contrast agents widely used in clinical practice. They have their own characteristics in displaying the 3 main signs of HCC. For accurate noninvasive diagnosis, the choice of agent should be made according to the specific situation.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Contrast Media; Magnetic Resonance Imaging; Male; Organometallic Compounds; Gadolinium DTPA; Female; Meglumine; Middle Aged; Aged; Retrospective Studies; ROC Curve; Adult; Image Enhancement; Aged, 80 and over
PubMed: 38860337
DOI: 10.1177/15330338241260331