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Prognosis of Patients with Hepatocellular Carcinoma Treated with TACE: A New Score Combining Alpha-Fetoprotein and Des-γ-Carboxy Prothrombin. 接受 TACE 治疗的肝细胞癌患者的预后:结合甲胎蛋白和去γ-羧基凝血酶原的新评分方法
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-22 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S481393
Shang-Yu Lu, Han-Yao Sun, Yan Zhou, Xi Luo, Sheng Liu, Wei-Zhong Zhou, Hai-Bin Shi, Wei Yang, Wei Tian

Purpose: Hepatocellular carcinoma (HCC) represents a significant global health problem, requiring precise prognostic tools for optimal treatment stratification. This study aimed to develop a new risk prediction score, called AD score, based on the serum markers alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), to offer an objective and accurate preoperative assessment of HCC in patients undergoing transarterial chemoembolization (TACE).

Patients and methods: This was a retrospective study that included 295 HCC patients who were subjected to TACE (training set, n=147; testing set, n=148). Serum AFP and DCP levels were log-transformed to construct the AD score. Multivariate Cox regression analysis on cirrhosis subgroups validated the objectivity of the model. Performance comparison of established models (Child Pugh, BCLC, ALBI, Up-to-seven, Six-and-twelve, Four and seven, HAP score, mHAP-II, FAIL-T score), was assessed through time-dependent receiver operating characteristic (ROC) curves and risk stratification.

Results: The AD score, incorporating lgAFP and lgDCP, demonstrated superior predictive accuracy than the existing models. Time-dependent ROC curve revealed the consistent superiority of the AD score over a 5-year period. The risk stratification into low, intermediate, and high group based on the AD score showed a significant survival difference in both training and testing set.

Conclusion: For HCC patients undergoing TACE, the AD score serves as an objective and straightforward prognostic tool, enhancing predictive accuracy and showcasing its clinical utility. It demonstrates potential significance as a crucial addition to preoperative risk assessment for TACE.

目的:肝细胞癌(HCC)是一个重大的全球健康问题,需要精确的预后工具来进行最佳治疗分层。本研究旨在根据血清标志物甲胎蛋白(AFP)和去γ-羧基凝血酶原(DCP)开发一种新的风险预测评分,称为AD评分,为接受经动脉化疗栓塞术(TACE)的患者提供客观准确的HCC术前评估:这是一项回顾性研究,纳入了295名接受TACE的HCC患者(训练组,147人;测试组,148人)。血清甲胎蛋白(AFP)和二氯丙醇(DCP)水平经对数转换后得出AD评分。肝硬化亚组的多变量 Cox 回归分析验证了模型的客观性。通过时间依赖性接收器操作特征曲线(ROC)和风险分层评估了已建立模型(Child Pugh、BCLC、ALBI、Up-to-7、Six-and-12、Four and Seven、HAP评分、mHAP-II、FAIL-T评分)的性能比较:结果:与现有模型相比,包含 lgAFP 和 lgDCP 的 AD 评分显示出更高的预测准确性。随时间变化的 ROC 曲线显示,AD 评分在 5 年内始终保持优势。根据 AD 评分将风险分层为低、中、高三组,在训练集和测试集中都显示出显著的生存率差异:对于接受 TACE 的 HCC 患者来说,AD 评分是一种客观、直接的预后工具,它提高了预测的准确性,展示了其临床实用性。它作为 TACE 术前风险评估的重要补充具有潜在意义。
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引用次数: 0
Efficacy of Atezolizumab Plus Bevacizumab Combined with Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Real-World Study. 阿特珠单抗加贝伐单抗联合经导管化疗栓塞治疗不可切除肝细胞癌的疗效:一项真实世界研究
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S478604
Xiao Shen, Jin-Xing Zhang, Jin Liu, Sheng Liu, Hai-Bin Shi, Yuan Cheng, Qing-Qiao Zhang, Guo-Wen Yin, Qing-Quan Zu

Purpose: Transarterial chemoembolization (TACE), when used in combination with immunotherapy and antiangiogenic therapy, has been shown to have synergistic anticancer effects. The aim of this study was to further assess the efficacy and safety of TACE combined with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC) in the real world.

Methods: Between August 2021 and September 2023, clinical information was collected from consecutive HCC patients who received treatment via TACE-Atezo/Bev at four tertiary institutions. This study evaluated the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) as outcomes. Predictors for OS and PFS were also analyzed. Treatment-related adverse events (TRAEs) were recorded and assessed.

Results: Ninety-two patients were enrolled in this study, with a median follow-up duration of 14.1 months. The ORRs based on the modified Response Evaluation Criteria in Solid Tumors (RECIST) and RECIST 1.1 criteria were 54.3% and 41.3%, respectively. The median OS and PFS of the patients were 15.9 months [95% confidence interval (CI), 14.5-17.2 months] and 9.1 months (95% CI, 7.4-10.8 months), respectively. Multivariate analyses revealed that the Eastern Cooperative Oncology Group score and neutrophil‒lymphocyte ratio were independent risk factors for OS, whereas tumor size and extrahepatic metastasis were independent risk factors for PFS. Grade 3/4 TRAEs occurred in 16.3% (15/92) of the patients and were controlled conservatively.

Conclusion: The combination of Atezo/Bev with TACE demonstrated acceptable synergistic therapeutic effects and manageable safety profiles in patients with unresectable HCC.

目的:经动脉化疗栓塞术(TACE)与免疫疗法和抗血管生成疗法联合使用已被证明具有协同抗癌作用。本研究旨在进一步评估TACE联合阿特珠单抗和贝伐单抗治疗不可切除肝细胞癌(HCC)的疗效和安全性:在2021年8月至2023年9月期间,收集了在四家三级医院接受TACE-Atezo/Bev治疗的连续HCC患者的临床信息。本研究对客观反应率(ORR)、总生存期(OS)和无进展生存期(PFS)进行了评估。研究还分析了OS和PFS的预测因素。记录并评估了治疗相关不良事件(TRAEs):本研究共纳入 92 例患者,中位随访时间为 14.1 个月。根据改良的实体瘤反应评估标准(RECIST)和RECIST 1.1标准得出的ORR分别为54.3%和41.3%。患者的中位OS和PFS分别为15.9个月[95%置信区间(CI),14.5-17.2个月]和9.1个月(95% CI,7.4-10.8个月)。多变量分析显示,东部合作肿瘤学组评分和中性粒细胞-淋巴细胞比率是OS的独立危险因素,而肿瘤大小和肝外转移则是PFS的独立危险因素。16.3%的患者(15/92)出现了3/4级TRAE,但均得到了保守控制:结论:Atezo/Bev 与 TACE 的联合治疗在不可切除的 HCC 患者中表现出了可接受的协同治疗效果和可控的安全性。
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引用次数: 0
Efficacy and Safety of Hepatic Arterial Infusion Chemotherapy(HAIC) Combined with PD-1 Inhibitors for Advanced Hepatocellular Carcinoma with Macrovascular Invasion: A Multicenter Propensity Score Matching Analysis. 肝动脉灌注化疗(HAIC)联合PD-1抑制剂治疗晚期大血管侵犯肝细胞癌的有效性和安全性:多中心倾向评分匹配分析》。
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-16 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S483824
Fengtao Zhang, Sheng Zhong, Qiming Wei, Haiming Zhang, Honglei Hu, Bicheng Zeng, Xiang Zheng

Aim: To investigate the efficacy and safety of HAIC combined with programmed cell death protein-1 (PD1) inhibitors in MVI-positive advanced hepatocellular carcinoma(HCC).

Methods: From September 2017 to May 2019, we retrospectively collected the clinical data from three medical centers in China pertaining to patients diagnosed with BCLC C stage HCC with MVI and receiving treatment with a combination of HAIC and PD-1 inhibitors treatment or HAIC alone, and we compared the efficacy of HAIC combined with PD-1 inhibitors and HAIC monotherapy. Propensity score matching(PSM) was utilized to adjust for baseline differences between groups. Survival outcomes and tumor response rate were used to assess survival benefits, while the incidence of adverse events was used to evaluate safety.

Results: After screening for eligibility, 489 patients diagnosed with HCC and concomitant MVI were enrolled. Of these, 173 patients received treatment combining HAIC with PD-1 inhibitors, while 316 patients underwent HAIC monotherapy. After PSM adjustment, the combination therapy group demonstrate superior survival outcomes. Median overall survival(OS) and progression free survival(PFS) were 31.8 months and 10.8 months, respectively, significantly higher than those in the monotherapy group (OS: 10.0 months; PFS: 6.1 months; both P<0.0001). Moreover, ORR and DCR remained significantly elevated in the combination therapy group (ORR: 44.3% vs 20.4%, P<0.0001; DCR: 89.8% vs 82.0%, P=0.041). Safety profiles indicated no significant differences in adverse event rates between the two treatment groups, encompassing both overall and grade-specific assessments.

Conclusion: Compared to HAIC alone, the combination of HAIC with PD-1 inhibitors represents a more promising and effective approach for patients with HCC complicated by macrovascular invasion.

目的:探讨HAIC联合程序性细胞死亡蛋白-1(PD1)抑制剂治疗MVI阳性晚期肝细胞癌(HCC)的疗效和安全性:2017年9月至2019年5月,我们回顾性收集了国内3家医疗中心确诊为BCLC C期HCC伴MVI患者接受HAIC联合PD-1抑制剂治疗或单用HAIC治疗的临床数据,比较了HAIC联合PD-1抑制剂与HAIC单药治疗的疗效。我们采用倾向评分匹配法(PSM)来调整组间基线差异。生存结果和肿瘤反应率用于评估生存获益,不良反应发生率用于评估安全性:经过资格筛选,489 名确诊为 HCC 并伴有 MVI 的患者入选。其中173名患者接受了HAIC与PD-1抑制剂联合治疗,316名患者接受了HAIC单药治疗。经PSM调整后,联合治疗组的生存率更高。中位总生存期(OS)和无进展生存期(PFS)分别为31.8个月和10.8个月,明显高于单药治疗组(OS:10.0个月;PFS:6.1个月;均为PConclusion):与单用HAIC相比,HAIC与PD-1抑制剂联合治疗并发大血管侵犯的HCC患者是一种更有前景、更有效的方法。
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引用次数: 0
Incomplete Thermal Ablation-Induced FOXP4-Mediated Promotion of Malignant Progression in Liver Cancer via NDST2. 不完全热消融诱导的 FOXP4 通过 NDST2 促进肝癌恶性进展
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S476612
Weijun Wan, Yunjing Pan, Jinshu Pang, Xiumei Bai, Lipeng Li, Tong Kang, Jiamin Chen, Rong Wen, Dongyue Wen, Hong Yang, Yun He

Purpose: The explosive progression of residual hepatocellular carcinoma (HCC) following incomplete thermal ablation is challenging, and the underlying mechanisms require further exploration. We investigated the mechanism by which Forkhead box P4 (FOXP4) promotes the malignant transformation of residual HCC cells through N-deacetylase and N-sulfotransferase 2 (NDST2) after incomplete thermal ablation.

Methods: The clinical significance of FOXP4 and NDST2 in HCC was evaluated using big data analysis. FOXP4 expression was detected in clinical samples of HCC. The gene expression levels in an in vitro heat-stressed HCC cell model were determined using quantitative real-time PCR (RT-qPCR) and Western blotting. The effects of the genes on heat-stressed HCC cells were investigated using Cell Counting Kit-8 (CCK-8), scratch, Transwell migration, and invasion assays. Additionally, the regulatory relationship between FOXP4 and NDST2 was validated using the Cleavage Under Targets and Tagmentation (CUT&Tag) experiments and phenotypic assays.

Results: High FOXP4 expression was correlated with liver cancer occurrence and development. In the heat-stressed HCC cell model, downregulating FOXP4 inhibited cancer cell progression. Besides, there was a positive association between FOXP4 and NDST2 in liver cancer. Suppressing FOXP4 reduced NDST2 expression in the heat-stressed HCC cells. Furthermore, reducing NDST2 expression weakened the biological behavior of heat-stressed HCC cells.

Conclusion: FOXP4 and NDST2 are crucial in the incomplete thermal ablation of residual cancer. FOXP4 might regulate the biological progression of residual HCC after incomplete thermal ablation through NDST2.

目的:不完全热消融后残留肝细胞癌(HCC)的爆发性进展具有挑战性,其潜在机制需要进一步探索。我们研究了不完全热消融后叉头框P4(FOXP4)通过N-去乙酰化酶和N-磺基转移酶2(NDST2)促进残留HCC细胞恶性转化的机制:方法:利用大数据分析评估了FOXP4和NDST2在HCC中的临床意义。在 HCC 临床样本中检测了 FOXP4 的表达。使用实时定量 PCR(RT-qPCR)和 Western 印迹法测定了体外热应激 HCC 细胞模型中的基因表达水平。使用细胞计数试剂盒-8(CCK-8)、划痕、Transwell 迁移和侵袭试验研究了这些基因对热应激 HCC 细胞的影响。此外,还利用靶标下裂解和标记(CUT&Tag)实验和表型实验验证了 FOXP4 和 NDST2 之间的调控关系:结果:FOXP4的高表达与肝癌的发生和发展相关。在热应激 HCC 细胞模型中,下调 FOXP4 可抑制癌细胞进展。此外,肝癌中的 FOXP4 与 NDST2 呈正相关。抑制 FOXP4 可降低 NDST2 在热应激 HCC 细胞中的表达。此外,降低 NDST2 的表达会削弱热应激 HCC 细胞的生物学行为:结论:FOXP4和NDST2在残余癌细胞的不完全热消融中至关重要。结论:FOXP4 和 NDST2 在不完全热消融残留癌中至关重要,FOXP4 可能通过 NDST2 调节不完全热消融后残留 HCC 的生物学进展。
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引用次数: 0
Tumor Growth Pattern and Intra- and Peritumoral Radiomics Combined for Prediction of Initial TACE Outcome in Patients with Primary Hepatocellular Carcinoma. 结合肿瘤生长模式和瘤内及瘤周放射组学预测原发性肝细胞癌患者的初始 TACE 结果
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-09 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S480554
Jiaying Li, Minhui Zhou, Yahan Tong, Haibo Chen, Ruisi Su, Yinghui Tao, Guodong Zhang, Zhichao Sun

Purpose: Non-invasive methods are urgently needed to assess the efficacy of transarterial chemoembolization (TACE) and to identify patients with hepatocellular carcinoma (HCC) who may benefit from this procedure. This study, therefore, aimed to investigate the predictive ability of tumor growth patterns and radiomics features from contrast-enhanced magnetic resonance imaging (CE-MRI) in predicting tumor response to TACE among patients with HCC.

Patients and methods: A retrospective study was conducted on 133 patients with HCC who underwent TACE at three centers between January 2015 and April 2023. Enrolled patients were divided into training, testing, and validation cohorts. Rim arterial phase hyperenhancement (Rim APHE), tumor growth patterns, nonperipheral washout, markedly low apparent diffusion coefficient (ADC) value, intratumoral arteries, and clinical baseline features were documented for all patients. Radiomics features were extracted from the intratumoral and peritumoral regions across the three phases of CE-MRI. Seven prediction models were developed, and their performances were evaluated using receiver operating characteristic (ROC) and decision curve analysis (DCA).

Results: Tumor growth patterns and albumin-bilirubin (ALBI) score were significantly correlated with tumor response. Tumor growth patterns also showed a positive correlation with tumor burden (r = 0.634, P = 0.000). The Peritumor (AUC = 0.85, 0.71, and 0.77), Clinics_Peritumor (AUC = 0.86, 0.77, and 0.81), and Tumor_Peritumor (AUC = 0.87, 0.77, and 0.80) models significantly outperformed the Clinics and Tumor models (P < 0.05), while the Clinics_Tumor_Peritumor model (AUC = 0.88, 0.81, and 0.81) outperformed the Clinics (AUC = 0.67, 0.77, and 0.75), Tumor (AUC = 0.78, 0.72, and 0.68), and Clinics_Tumor (AUC = 0.82, 0.83, and 0.78) models (P < 0.05 or 0.053, respectively). The DCA curve demonstrated better predictive performance within a specific threshold probability range for Clinics_Tumor_Peritumor.

Conclusion: Combining tumor growth patterns, intra- and peri-tumoral radiomics features, and ALBI score could be a robust tool for non-invasive and personalized prediction of treatment response to TACE in patients with HCC.

目的:评估经动脉化疗栓塞术(TACE)的疗效以及识别可能从该手术中获益的肝细胞癌(HCC)患者急需无创方法。因此,本研究旨在探讨对比增强磁共振成像(CE-MRI)的肿瘤生长模式和放射组学特征在预测HCC患者对TACE的肿瘤反应方面的预测能力:对2015年1月至2023年4月期间在三个中心接受TACE治疗的133名HCC患者进行了回顾性研究。入组患者被分为训练组、测试组和验证组。所有患者的边缘动脉期高增强(Rim APHE)、肿瘤生长模式、非外周冲刷、明显偏低的表观弥散系数(ADC)值、瘤内动脉和临床基线特征均有记录。从CE-MRI三个阶段的瘤内和瘤周区域提取放射组学特征。建立了七个预测模型,并使用接收器操作特征(ROC)和决策曲线分析(DCA)对其性能进行了评估:结果:肿瘤生长模式和白蛋白胆红素(ALBI)评分与肿瘤反应显著相关。肿瘤生长模式与肿瘤负荷也呈正相关(r = 0.634,P = 0.000)。肿瘤周围(AUC = 0.85、0.71 和 0.77)、Clinics_Peritumor(AUC = 0.86、0.77 和 0.81)和 Tumor_Peritumor(AUC = 0.87、0.77 和 0.80)模型的表现明显优于 Clinics 和 Tumor 模型(P < 0.05),而 Clinics_Tumor_Peritumor 模型(AUC = 0.88、0.81 和 0.81)则优于 Clinics(AUC = 0.67、0.77 和 0.75)、Tumor(AUC = 0.78、0.72 和 0.68)和 Clinics_Tumor(AUC = 0.82、0.83 和 0.78)模型(P < 0.05 或 0.053)。DCA曲线在特定阈值概率范围内对Clinics_Tumor_Peritumor具有更好的预测性能:结论:结合肿瘤生长模式、瘤内和瘤周放射组学特征以及 ALBI 评分,可以成为无创和个性化预测 HCC 患者对 TACE 治疗反应的有力工具。
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引用次数: 0
A Gluconeogenesis-Related Genes Model for Predicting Prognosis, Tumor Microenvironment Infiltration, and Drug Sensitivity in Hepatocellular Carcinoma. 用于预测肝细胞癌预后、肿瘤微环境浸润和药物敏感性的糖元生成相关基因模型
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-05 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S483664
Xilong Tang, Jianjin Xue, Jie Zhang, Jiajia Zhou

Background: Hepatocellular carcinoma (HCC) is a prevalent malignancy within the digestive system, known for its poor prognosis. Gluconeogenesis, a critical metabolic pathway, is responsible for the synthesis of glucose in the normal liver. This study aimed to examine the role of gluconeogenesis-related genes (GRGs) in HCC and evaluate their impact on the tumor microenvironment infiltration and drug sensitivity in HCC.

Methods: We retrieved gene expression and clinical pathological data of HCC from The Cancer Genome Atlas (TCGA) database. This dataset was utilized to develop a prognosis model. The data from The International Cancer Genome Consortium (ICGC) served as an independent validation cohort. A least absolute shrinkage and selection operator (LASSO) regression analysis was applied to a curated panel of GRGs to construct and validate the predictive model. Furthermore, unsupervised consensus clustering, based on the expression levels of GRGs, categorized HCC patients into distinct subgroups.

Results: A four-gene prognostic model, referred to as GRGs, has been successfully developed with high accuracy and stability for the prediction of HCC patient prognosis. This model enables the stratification of patients into high or low risk groups based on individual risk scores, revealing significant differences in immune infiltration patterns and anti-tumor drug responses. Unsupervised consensus clustering analysis delineated four distinct subgroups of patients, each characterized by a unique prognosis and tumor immune microenvironment (TIME).

Conclusion: This study is the first to develop a prognostic model incorporating 4-GRGs that effectively predicts the prognosis, tumor microenvironment infiltration, and drug sensitivity in HCC patients. The model based on 4 GRGs may contribute to predict the prognosis, immunotherapy and chemotherapy response of HCC patients.

背景:肝细胞癌(HCC)是消化系统中一种常见的恶性肿瘤,以预后不良而闻名。糖元生成是一条重要的代谢途径,负责在正常肝脏中合成葡萄糖。本研究旨在探讨糖元生成相关基因(GRGs)在 HCC 中的作用,并评估其对 HCC 中肿瘤微环境浸润和药物敏感性的影响:我们从癌症基因组图谱(TCGA)数据库中检索了HCC的基因表达和临床病理数据。我们利用该数据集建立了一个预后模型。国际癌症基因组联盟(ICGC)的数据作为独立验证队列。我们将最小绝对收缩和选择算子(LASSO)回归分析应用于经过策划的GRGs面板,以构建和验证预测模型。此外,基于GRGs表达水平的无监督共识聚类将HCC患者分为不同的亚组:结果:我们成功建立了一个四基因预后模型(简称 GRGs),该模型在预测 HCC 患者预后方面具有较高的准确性和稳定性。该模型可根据个体风险评分将患者分为高风险组和低风险组,揭示了免疫浸润模式和抗肿瘤药物反应的显著差异。无监督共识聚类分析划分出四个不同的患者亚组,每个亚组都有独特的预后和肿瘤免疫微环境(TIME):本研究首次建立了一个包含 4 个 GRGs 的预后模型,该模型能有效预测 HCC 患者的预后、肿瘤微环境浸润和药物敏感性。基于4个GRGs的模型可能有助于预测HCC患者的预后、免疫治疗和化疗反应。
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引用次数: 0
Gut Microbiome and Hepatic Transcriptomic Determinants of HCC Development in Mice with Metabolic Dysfunction-Associated Steatohepatitis. 代谢功能障碍相关性脂肪性肝炎小鼠肝癌发生的肠道微生物组和肝转录组决定因素
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-03 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S485532
Lillian I Dolapchiev, Kristyn A Gonzales, Lorenzo R Cruz, Mihai Gagea, Heather L Stevenson, Suet-Ying Kwan, Laura Beretta

Purpose: Hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) is often diagnosed at a late stage, and its incidence is increasing. Predictive biomarkers are therefore needed to identify individuals at high risk of HCC. We aimed to characterize the gut microbiome and hepatic transcriptome associated with HCC development in female mice with hepatocyte-deletion of Pten (HepPten -). These mice present with large variations in HCC development, making them a powerful model for biomarker discovery.

Methods & results: Sequencing of stool 16S and hepatic RNA was performed on a first set of mice. Among all liver histology parameters measured, the strongest association with microbiome composition changes was with the number of tumors detected at necropsy, followed by inflammation. The gut microbiome of mice with more than 2 tumors was enriched with Lachnospiraceae UCG and depleted of Palleniella intestinalis and Odoribacter. In contrast, hepatic transcriptomic changes were most strongly associated with tumor burden, followed by liver fibrosis. The 840 differentially expressed genes correlating with tumor burden were enriched in leukocyte extravasation and interleukin 10 receptor A (IL10RA) pathways. In addition, the abundance of Spp1-high epithelial cells is correlated with tumor burden. Association between tumor number and depletion of Palleniella intestinalis, and between tumor burden and circulating levels of C-X-C motif chemokine ligand 13 (CXCL13) and stem cell factor (SCF), was further validated in an independent set of mice.

Conclusion: We identified microbiome components contributing to liver carcinogenesis by inducing inflammation, and changes in hepatic gene expression and hepatic cells distribution that contribute to tumor growth. Such information can be highly valuable for the development of new prevention strategies as well as of new biomarkers for risk modeling in HCC.

目的:与代谢功能障碍相关性脂肪性肝病(MASLD)有关的肝细胞癌(HCC)往往在晚期才被诊断出来,而且其发病率正在上升。因此,需要预测性生物标志物来识别 HCC 高危人群。我们的目的是描述肝细胞缺失 Pten(HepPten -)雌性小鼠肠道微生物组和肝脏转录组与 HCC 发展相关的特征。这些小鼠的 HCC 发展变化很大,是发现生物标志物的有力模型:对第一组小鼠进行了粪便 16S 和肝脏 RNA 测序。在测量的所有肝组织学参数中,与微生物组组成变化关系最密切的是尸体解剖时检测到的肿瘤数量,其次是炎症。有两个以上肿瘤的小鼠的肠道微生物组富含Lachnospiraceae UCG,而肠道Palleniella和Odoribacter则很少。相比之下,肝脏转录组变化与肿瘤负荷的关系最为密切,其次是肝纤维化。与肿瘤负荷相关的840个差异表达基因富集于白细胞外渗和白细胞介素10受体A(IL10RA)通路。此外,Spp1-高上皮细胞的丰度与肿瘤负荷相关。在一组独立的小鼠中,我们进一步验证了肿瘤数量与肠道苍白藻(Palleniella intestinalis)耗竭之间的关系,以及肿瘤负荷与循环中的C-X-C motif趋化因子配体13(CXCL13)和干细胞因子(SCF)水平之间的关系:结论:我们发现了通过诱导炎症、改变肝脏基因表达和肝细胞分布而导致肿瘤生长的微生物组成分。这些信息对于开发新的预防策略以及用于 HCC 风险建模的新生物标记物非常有价值。
{"title":"Gut Microbiome and Hepatic Transcriptomic Determinants of HCC Development in Mice with Metabolic Dysfunction-Associated Steatohepatitis.","authors":"Lillian I Dolapchiev, Kristyn A Gonzales, Lorenzo R Cruz, Mihai Gagea, Heather L Stevenson, Suet-Ying Kwan, Laura Beretta","doi":"10.2147/JHC.S485532","DOIUrl":"10.2147/JHC.S485532","url":null,"abstract":"<p><strong>Purpose: </strong>Hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) is often diagnosed at a late stage, and its incidence is increasing. Predictive biomarkers are therefore needed to identify individuals at high risk of HCC. We aimed to characterize the gut microbiome and hepatic transcriptome associated with HCC development in female mice with hepatocyte-deletion of Pten (<i>HepPten</i> <sup>-</sup>). These mice present with large variations in HCC development, making them a powerful model for biomarker discovery.</p><p><strong>Methods & results: </strong>Sequencing of stool 16S and hepatic RNA was performed on a first set of mice. Among all liver histology parameters measured, the strongest association with microbiome composition changes was with the number of tumors detected at necropsy, followed by inflammation. The gut microbiome of mice with more than 2 tumors was enriched with <i>Lachnospiraceae UCG</i> and depleted of <i>Palleniella intestinalis</i> and <i>Odoribacter</i>. In contrast, hepatic transcriptomic changes were most strongly associated with tumor burden, followed by liver fibrosis. The 840 differentially expressed genes correlating with tumor burden were enriched in leukocyte extravasation and interleukin 10 receptor A (IL10RA) pathways. In addition, the abundance of Spp1-high epithelial cells is correlated with tumor burden. Association between tumor number and depletion of <i>Palleniella intestinalis</i>, and between tumor burden and circulating levels of C-X-C motif chemokine ligand 13 (CXCL13) and stem cell factor (SCF), was further validated in an independent set of mice.</p><p><strong>Conclusion: </strong>We identified microbiome components contributing to liver carcinogenesis by inducing inflammation, and changes in hepatic gene expression and hepatic cells distribution that contribute to tumor growth. Such information can be highly valuable for the development of new prevention strategies as well as of new biomarkers for risk modeling in HCC.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"1891-1905"},"PeriodicalIF":4.2,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Absence of Survival Impact from Hepatitis During Immunotherapy in 193 Patients with Advanced Hepatocellular Carcinoma - An Observational Study from Taiwan. 193例晚期肝细胞癌患者免疫治疗期间肝炎对生存无影响--一项来自台湾的观察性研究。
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-02 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S464105
Chi-Han Lin, Yung-Chia Kuo, Hsuan-Chih Kuo, Ching-Ting Wang, Shi-Ming Lin, Alan Chao-Wei Lee, Ming-Chin Yu, Wei-Chen Lee, Cherry Chiao-Erh Chen, Jason Chia-Hsun Hsieh

Background: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear.

Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns.

Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses.

Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.

背景:肝炎通常发生在开始免疫检查点抑制剂(ICI)治疗之后。晚期肝细胞癌(aHCC)患者开始接受 ICI 治疗后出现肝炎的时间和程度以及免疫相关肝炎的预后作用仍不清楚:在这项真实世界分析中,我们招募了接受 ICI 治疗的 aHCC 患者,记录了 ICI 治疗期间/之后肝酶的最高水平,并分析了不同肝炎模式对生存的影响:结果:共招募了 103 名接受 ICI 治疗的 aHCC 患者。在 ICI 期间,88.6% 的患者出现了天冬氨酸转氨酶(AST)升高(III/IV 级:7.8%)。81.3%的患者丙氨酸转氨酶(ALT)升高(III/IV 级:3.6%),41.5%的患者胆红素升高(3/4 级:6.7%)。ICI 治疗开始后,AST、ALT 和总胆红素的中位值显著升高(均 p < 0.001),同样,排除进展期疾病后,AST、ALT 和总胆红素的中位值也显著升高(p = 0.014、p = 0.002、p < 0.001)。肝炎发生的中位时间为第 4.0 周至第 15.9 周。多变量分析显示,接受 ICIs 的患者的 AST 和总胆红素的肝酶变化规律与总生存率(OS,p = 0.009 和 0.001,分别为 0.009 和 0.001)显著相关。ICI 终止后,胆红素(p = 0.003)和谷草转氨酶(p = 0.005)升高的患者预示着生存率较低,病毒性肝炎和 ICI 反应的调整:结论:肝炎出现在开始 ICI 后的第 4 至 20 周。ICI治疗期间肝酶的变化并不直接影响OS,这意味着在有临床指征时及时使用皮质类固醇,ICI的使用是安全的。
{"title":"Absence of Survival Impact from Hepatitis During Immunotherapy in 193 Patients with Advanced Hepatocellular Carcinoma - An Observational Study from Taiwan.","authors":"Chi-Han Lin, Yung-Chia Kuo, Hsuan-Chih Kuo, Ching-Ting Wang, Shi-Ming Lin, Alan Chao-Wei Lee, Ming-Chin Yu, Wei-Chen Lee, Cherry Chiao-Erh Chen, Jason Chia-Hsun Hsieh","doi":"10.2147/JHC.S464105","DOIUrl":"10.2147/JHC.S464105","url":null,"abstract":"<p><strong>Background: </strong>Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear.</p><p><strong>Methods: </strong>In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns.</p><p><strong>Results: </strong>One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all <i>p</i> < 0.001) and, similarly, after excluding progressive disease (<i>p</i> = 0.014, <i>p</i> = 0.002, <i>p</i> < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, <i>p</i> = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (<i>p =</i> 0.003) and AST (<i>p</i> = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses.</p><p><strong>Conclusion: </strong>Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"1875-1890"},"PeriodicalIF":4.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multicenter Integration of MR Radiomics, Deep Learning, and Clinical Indicators for Predicting Hepatocellular Carcinoma Recurrence After Thermal Ablation. 多中心整合磁共振放射组学、深度学习和临床指标,预测热消融后的肝细胞癌复发。
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-02 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S482760
Yandan Wang, Yong Zhang, Jincheng Xiao, Xiang Geng, Lujun Han, Junpeng Luo

Background: To develop and validate an innovative predictive model that integrates multisequence magnetic resonance (MR) radiomics, deep learning features, and clinical indicators to accurately predict the recurrence of hepatocellular carcinoma (HCC) after thermal ablation.

Methods: This retrospective multicenter cohort study enrolled patients who were diagnosed with HCC and treated via thermal ablation. We extracted radiomic features from multisequence 3T MR images, analyzed these images using a 3D convolutional neural network (3D CNN), and incorporated clinical data into the model. Model performance was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve.

Results: The study included 535 patients from three hospitals, comprising 462 males and 43 females. The RDC model, which stands for the Radiomics-Deep Learning-Clinical data model, demonstrated high predictive accuracy, achieving AUCs of 0.794 in the training set, 0.777 in the validation set, and 0.787 in the test set. Statistical analysis confirmed the model's robustness and the significant contribution of the integrated features to its predictive capabilities.

Conclusion: The RDC model effectively predicts HCC recurrence after thermal ablation by synergistically combining advanced imaging analysis and clinical parameters. This study highlights the potential of such integrative approaches to enhance prognostic assessments in HCC patients and offers a promising tool for clinical decision-making.

背景:开发并验证一种创新的预测模型,该模型整合了多序列磁共振(MR)放射组学、深度学习特征和临床指标,可准确预测热消融术后肝细胞癌(HCC)的复发:这项回顾性多中心队列研究纳入了确诊为 HCC 并接受热消融治疗的患者。我们从多序列 3T 磁共振图像中提取了放射学特征,使用三维卷积神经网络(3D CNN)分析了这些图像,并将临床数据纳入模型。使用接收者操作特征曲线(ROC)的曲线下面积(AUC)对模型性能进行评估:研究对象包括三家医院的 535 名患者,其中男性 462 名,女性 43 名。RDC模型是放射组学-深度学习-临床数据模型的缩写,具有很高的预测准确性,训练集的AUC为0.794,验证集的AUC为0.777,测试集的AUC为0.787。统计分析证实了该模型的稳健性以及集成特征对其预测能力的显著贡献:RDC模型通过协同结合先进的成像分析和临床参数,有效预测了热消融后的HCC复发。这项研究强调了这种综合方法在加强 HCC 患者预后评估方面的潜力,并为临床决策提供了一种前景广阔的工具。
{"title":"Multicenter Integration of MR Radiomics, Deep Learning, and Clinical Indicators for Predicting Hepatocellular Carcinoma Recurrence After Thermal Ablation.","authors":"Yandan Wang, Yong Zhang, Jincheng Xiao, Xiang Geng, Lujun Han, Junpeng Luo","doi":"10.2147/JHC.S482760","DOIUrl":"10.2147/JHC.S482760","url":null,"abstract":"<p><strong>Background: </strong>To develop and validate an innovative predictive model that integrates multisequence magnetic resonance (MR) radiomics, deep learning features, and clinical indicators to accurately predict the recurrence of hepatocellular carcinoma (HCC) after thermal ablation.</p><p><strong>Methods: </strong>This retrospective multicenter cohort study enrolled patients who were diagnosed with HCC and treated via thermal ablation. We extracted radiomic features from multisequence 3T MR images, analyzed these images using a 3D convolutional neural network (3D CNN), and incorporated clinical data into the model. Model performance was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve.</p><p><strong>Results: </strong>The study included 535 patients from three hospitals, comprising 462 males and 43 females. The RDC model, which stands for the Radiomics-Deep Learning-Clinical data model, demonstrated high predictive accuracy, achieving AUCs of 0.794 in the training set, 0.777 in the validation set, and 0.787 in the test set. Statistical analysis confirmed the model's robustness and the significant contribution of the integrated features to its predictive capabilities.</p><p><strong>Conclusion: </strong>The RDC model effectively predicts HCC recurrence after thermal ablation by synergistically combining advanced imaging analysis and clinical parameters. This study highlights the potential of such integrative approaches to enhance prognostic assessments in HCC patients and offers a promising tool for clinical decision-making.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"1861-1874"},"PeriodicalIF":4.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Role of Lactate Dehydrogenase in Exploring the Immune Evasion in HCC Patients Who Underwent TACE: Implications for Clinical Application. 乳酸脱氢酶在探索接受 TACE 的 HCC 患者免疫逃避中的作用:对临床应用的启示
IF 4.2 3区 医学 Q2 ONCOLOGY Pub Date : 2024-09-29 eCollection Date: 2024-01-01 DOI: 10.2147/JHC.S480090
Yang Xie, Xiangyang Sun, Fubo Xie, Wencheng Jian, Qingliang Wang, Xiaochen Ma, Caixia Li, Kai Zhang

Purpose: To examine the relationship between lactate dehydrogenase (LDH) levels and soluble programmed cell death-ligand 1 (sPD-L1) levels in hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE).

Methods: A total of 83 hCC patients participated in this study. Patients were categorized into subgroups based on their alpha-fetoprotein (AFP) levels, presence or absence of extrahepatic metastasis, vascular invasion, Barcelona Clinic Liver Cancer (BCLC) stage, tumor response, tumor size, and number LDH and sPD-L1 levels were compared before and after TACE (3, 7, and 30 days post-TACE).

Results: LDH and sPD-L1 levels were significantly higher at 3 and 7 days post-TACE than at baseline. Positive correlations were observed between changes in LDH levels and sPD-L1 levels at 3 and 7 days post-TACE. LDH levels were higher in patients with elevated AFP compared to those in the normal AFP group at 3 and 7 days post-TACE, in the stable disease (SD) group compared to complete response (CR) and partial response (PR) groups at 7 days post-TACE, and in those with tumor > 5 cm compared with those with tumor ≤ 5 cm at 3 and 7 days after TACE (all P < 0.05). sPD-L1 levels were higher in patients with vascular invasion than those without vascular invasion at 3 and 7 days post-TACE, in the SD group compared to CR and PR groups at 3 and 7 days post-TACE, and in those with tumor > 5 cm compared to those with tumor < 5 cm at 3 and 7 days after TACE (all P < 0.05).

Conclusion: A positive correlation was found between LDH expression and sPD-L1 levels, suggesting LDH as a potential biomarker for assessing immune status in HCC patients following TACE.

目的:研究接受经动脉化疗栓塞术(TACE)的肝细胞癌(HCC)患者体内乳酸脱氢酶(LDH)水平与可溶性程序性细胞死亡配体1(sPD-L1)水平之间的关系:共有 83 名 HCC 患者参与了这项研究。根据甲胎蛋白(AFP)水平、有无肝外转移、血管侵犯、巴塞罗那临床肝癌(BCLC)分期、肿瘤反应、肿瘤大小、TACE前后(TACE后3天、7天和30天)比较LDH和sPD-L1水平,将患者分为不同的亚组:结果:TACE术后3天和7天的LDH和sPD-L1水平明显高于基线水平。TACE后3天和7天的LDH水平变化与sPD-L1水平变化之间呈正相关。在 TACE 术后 3 天和 7 天,AFP 升高组患者的 LDH 水平高于 AFP 正常组患者;在 TACE 术后 7 天,疾病稳定(SD)组患者的 LDH 水平高于完全反应(CR)组和部分反应(PR)组患者;在 TACE 术后 3 天和 7 天,肿瘤大于 5 厘米的患者的 LDH 水平高于肿瘤小于 5 厘米的患者(均 P < 0.有血管侵犯的患者在 TACE 后 3 天和 7 天的 sPD-L1 水平高于无血管侵犯的患者,SD 组在 TACE 后 3 天和 7 天的 sPD-L1 水平高于 CR 组和 PR 组,肿瘤 > 5 cm 的患者在 TACE 后 3 天和 7 天的 sPD-L1 水平高于肿瘤 < 5 cm 的患者(均 P < 0.05):结论:LDH表达与sPD-L1水平呈正相关,表明LDH是评估TACE后HCC患者免疫状态的潜在生物标志物。
{"title":"The Role of Lactate Dehydrogenase in Exploring the Immune Evasion in HCC Patients Who Underwent TACE: Implications for Clinical Application.","authors":"Yang Xie, Xiangyang Sun, Fubo Xie, Wencheng Jian, Qingliang Wang, Xiaochen Ma, Caixia Li, Kai Zhang","doi":"10.2147/JHC.S480090","DOIUrl":"10.2147/JHC.S480090","url":null,"abstract":"<p><strong>Purpose: </strong>To examine the relationship between lactate dehydrogenase (LDH) levels and soluble programmed cell death-ligand 1 (sPD-L1) levels in hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE).</p><p><strong>Methods: </strong>A total of 83 hCC patients participated in this study. Patients were categorized into subgroups based on their alpha-fetoprotein (AFP) levels, presence or absence of extrahepatic metastasis, vascular invasion, Barcelona Clinic Liver Cancer (BCLC) stage, tumor response, tumor size, and number LDH and sPD-L1 levels were compared before and after TACE (3, 7, and 30 days post-TACE).</p><p><strong>Results: </strong>LDH and sPD-L1 levels were significantly higher at 3 and 7 days post-TACE than at baseline. Positive correlations were observed between changes in LDH levels and sPD-L1 levels at 3 and 7 days post-TACE. LDH levels were higher in patients with elevated AFP compared to those in the normal AFP group at 3 and 7 days post-TACE, in the stable disease (SD) group compared to complete response (CR) and partial response (PR) groups at 7 days post-TACE, and in those with tumor > 5 cm compared with those with tumor ≤ 5 cm at 3 and 7 days after TACE (all <i>P</i> < 0.05). sPD-L1 levels were higher in patients with vascular invasion than those without vascular invasion at 3 and 7 days post-TACE, in the SD group compared to CR and PR groups at 3 and 7 days post-TACE, and in those with tumor > 5 cm compared to those with tumor < 5 cm at 3 and 7 days after TACE (all <i>P</i> < 0.05).</p><p><strong>Conclusion: </strong>A positive correlation was found between LDH expression and sPD-L1 levels, suggesting LDH as a potential biomarker for assessing immune status in HCC patients following TACE.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"1823-1833"},"PeriodicalIF":4.2,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Journal of Hepatocellular Carcinoma
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