A Web-Based Prediction Model for Cancer-Specific Survival of Elderly Patients With Early Hepatocellular Carcinoma: A Study Based on SEER Database

Background: Primary liver cancer is a common malignant tumor primarily represented by hepatocellular carcinoma (HCC). The number of elderly patients with early HCC is increasing, and older age is related to a worse prognosis. However, an accurate predictive model for the prognosis of these patients is still lacking.Methods: Data of eligible elderly patients with early HCC in Surveillance, Epidemiology, and End Results database from 2010 to 2016 were downloaded. Patients from 2010 to 2015 were randomly assigned to the training cohort (n = 1093) and validation cohort (n = 461). Patients' data in 2016 (n = 431) was used for external validation. Independent prognostic factors were obtained using univariate and multivariate analyses. Based on these factors, a cancer-specific survival (CSS) nomogram was constructed. The predictive performance and clinical practicability of our nomogram were validated. According to the risk scores of our nomogram, patients were divided into low-, intermediate-, and high-risk groups. A survival analysis was performed using Kaplan–Meier curves and log-rank tests.Results: Age, race, T stage, histological grade, surgery, radiotherapy, and chemotherapy were independent predictors for CSS and thus were included in our nomogram. In the training cohort and validation cohort, the concordance indices (C-indices) of our nomogram were 0.739 (95% CI: 0.714–0.764) and 0.756 (95% CI: 0.719–0.793), respectively. The 1-, 3-, and 5-year areas under receiver operating characteristic curves (AUCs) showed similar results. Calibration curves revealed high consistency between observations and predictions. In external validation cohort, C-index (0.802, 95%CI: 0.778–0.826) and calibration curves also revealed high consistency between observations and predictions. Compared with the TNM stage, nomogram-related decision curve analysis (DCA) curves indicated better clinical practicability. Kaplan–Meier curves revealed that CSS significantly differed among the three different risk groups. In addition, an online prediction tool for CSS was developed.Conclusions: A web-based prediction model for CSS of elderly patients with early HCC was constructed and validated, and it may be helpful for the prognostic evaluation, therapeutic strategy selection, and follow-up management of these patients.

Preferred Treatment with Curative Intent for Left Lateral Segment Early Hepatocellular Carcinoma under the Era of Minimal Invasive Surgery

Background: Hepatocellular carcinoma (HCC) occurring at the left lateral segment (LLS) is relatively susceptible to treatment with curative intent in terms of tumor location. However, outcomes might vary depending on the selection of treatment modalities. This study aimed to analyze patients who had undergone curative treatment for early HCC at LLS. Methods: A retrospective analysis of 179 patients who underwent curative treatment for early HCC at LLS was performed. Patients were grouped based on treatment modalities, including radiofrequency ablation (RFA) and liver resection (LR). The long-term outcomes of the two groups were compared. Additionally, the impact of the LR approach on patient outcomes was analyzed. Results: Among these patients, 60 received RFA and 119 underwent LR as primary treatment with curative intent. During follow-up, a significantly higher incidence of HCC recurrence was observed in the RFA group (37/60, 61.7%) than in the LR group (45/119, 37.8%) (p = 0.0025). The median time of HCC recurrence was 10.8 (range: 1.1–60.9 months) and 17.6 (range: 2.4–94.8 months) months in the RFA and LR groups, respectively. In addition, multivariate analysis showed that liver cirrhosis, multiple tumors, and RFA treatment were significant risk factors for HCC recurrence. The 1-, 2-, and 5-year overall survival rates in the RFA and LR groups were 96.4%, 92.2%, and 71.5% versus 97.3%, 93.6%, and 87.7%, respectively. (p = 0.047). Moreover, outcomes related to LR were comparable between laparoscopic and conventional open methods. The 1-, 2-, and 5-year recurrence free survival rates in the laparoscopic (n = 37) and conventional open (n = 82) LR groups were 94.1%, 82.0%, and 66.9% versus 86.1%, 74.6%, and 53.1%, respectively. (p = 0.506) Conclusion: Early HCC at LLS had satisfactory outcomes after curative treatment, in which LR seems to have a superior outcome, as compared to RFA treatment. Moreover, laparoscopic LR could be considered a preferential option in the era of minimally invasive surgery.

Autoantibody to GNAS in Early Detection of Hepatocellular Carcinoma: A Large-Scale Sample Study Combined with Verification in Serial Sera from HCC Patients

The aim of this study was to explore the value of autoantibody to GNAS in the early detection of hepatocellular carcinoma (HCC). In a large-scale sample set of 912 participants (228 cases in each of HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NCs) groups), autoantibody to GNAS was detected with a positive result in 47.8% of HCC patients, which was significantly higher than that in patients with LC (35.1%), CHB (19.7%), and NCs (19.7%). Further analysis showed that the frequency of autoantibody to GNAS started increasing in compensated cirrhosis patients (37.0%) with a jump in decompensated cirrhosis patients (53.2%) and reached a peak in early HCC patients (62.4%). The increasing autoantibody response to GNAS in patients at different stages was closely associated with the progression of chronic liver lesions. The result from 44 human serial sera demonstrated that 5 of 11 (45.5%) HCC patients had elevated autoantibody to GNAS before and/or at diagnosis of HCC. Moreover, 46.1% and 62.4% of high positive rates in alpha-fetoprotein (AFP) negative and early-stage HCC patients can supplement AFP in early detection of HCC. These findings suggest that autoantibody to GNAS could be used as a potential biomarker for the early detection of HCC.

The role of BCL9 genetic variation as a biomarker for hepatitis C-related hepatocellular carcinoma in Egyptian patients

Background Hepatocellular carcinoma (HCC) is considered one of the most common cancers related to mortality around the world, and susceptibility is related with genetic, lifestyle, and environmental factors. Copy number variation of the Bcell CLL/lymphoma 9 (BCL9) gene is a type of structural variation which can influence gene expression and can be related with specific phenotypes and diseases and has a role in hepatocarcinogenesis. Our aims were to assess the copy number variation (CNV) in the BCL9 gene and explore its role in HCV-related HCC Egyptian patients. A total of 50 HCV-related HCC patients were enrolled in the study (including 25 early HCC and 25 late HCC cases); the copy number of the BCL9 gene was detected using quantitative polymerase reaction. Results There was a highly statistically significant difference between the two groups (early and late HCC patients) in gender, bilharziasis, performance status, child score class, child grade, focal lesion size, portal vein, and ascites. CNV was detected and represented by the gain in the BCL9 gene in 14% of patients, and all of them were males. Also, it was noticed that the ratio of gain in BCL9 copy number in late individuals was about 1.5 times than that in early HCC individuals. Moreover, our results showed that the distribution of performance status > 1, average and enlarged liver, focal lesion size, thrombosed portal vein, and AFP was higher in patients with BCL9 copy number gain. Conclusion We detected about 14% gain in BCL9 copy number in Egyptian HCC patients. But the variation in copy number of the BCL9 gene did not affect HCC development in our patients’ cohort.

Molecular Alterations of Circulating Cell-Free DNA in the Pathological Progression of Hepatocellular Carcinoma

Background. Hepatocellular carcinoma (HCC) is one of the most malignant cancers. Early diagnosis of HCC is important to reduce the mortality rate. The aim of this study is to explore the plasma cell-free DNA (cfDNA) mutation profile in the pathological progression of HCC and to investigate the significance of plasma cfDNA mutations in the early diagnosis of HCC. Methods. Thirty-seven patients with chronic hepatitis B (CHB), eight with liver cirrhosis (LC), and eleven with HCC were enrolled in this cohort. Plasma cfDNA and white blood cell DNA were isolated, and plasma cfDNA mutation profiles were detected using a targeted gene panel. Results. The sequencing results of plasma cfDNA showed that HCC-related gene mutations were present in patients with CHB and LC. The mutation burden of HCC-related genes increased from CHB and LC to HCC. In patients with HCC, the average mutation burden of NRAS (10.1%), TP53 (7.4%), PTEN (4.2%), and APOB (2.6%) was the highest. The average mutation burden of PTEN, APOB, FRAS1, KDM6A, DDR2, TTK, NRAS, TP53, PTPRB, MPL, FCRL1, HN1, and SFN gradually increased from CHB and LC to HCC. The mutation burden of 18 HCC-related genes had an area under the receiver operating characteristics of 0.92 for the diagnosis of HCC. Conclusions. The mutation burden of HCC-related genes increased from CHB and LC to HCC. An optimal combination of cfDNA mutations in the gene panel for diagnosing HCC in patients with CHB and LC was selected. Our study indicates that somatic mutations in plasma cfDNA may serve as potential biomarkers for early HCC diagnosis.

Comparison of the efficacy of radiofrequency ablation vs. liver resection in the treatment of hepatocellular carcinoma within Milan criteria with severe fibrosis

BackgroundThe efficacy of RFA in the treatment of HCC with severe fibrosis is still unclear. The objective of this study is to compare the efficacy of RFA with liver resection in the treatment of HCC within Milan criteria.MethodsThe data used in the study were from the SEER database. Patients with HCC within Milan criteria were included in the study. A total of 1432 patients were included in the study; among them, 1038 patients received RFA, and 394 patients received liver resection. Propensity score matching (PSM) was used to reduce selection bias.ResultsBefore PSM, the median overall survival (mOS) and median cancer-specific survival (mCSS) in the resection group were longer than the mOS and mCSS in the RFA group. However, the8re were no statistically significant differences in mOS or mCSS between the two groups (both P>0.05). After PSM, similar results were presented, and the mOS and mCSS in the resection group were similar to those in the RFA group (both P>0.05). The multivariable Cox regression analysis showed that RFA did not increase the all-cause mortality risk and cancer-specific mortality risk compared with resection before PSM. In the competing risk analysis, after excluding the potential factors that might influence the outcomes, RFA still did not increase the mortality risk compared with resection before PSM and after PSM. In the subgroup analysis. The efficacy of RFA is comparable to that of resection in patients with tumor sizes no more than 3 cm before PSM and after PSM.ConclusionThe efficacy of RFA is similar to that of resection in the treatment of early HCC patients with severe fibrosis, especially in patients with tumor sizes no more than 3 cm.

Five-Lipoxygenase-Activating Protein Mediated CYLD Attenuation is a Candidate Driver in Hepatic Malignant Lesion

Background: Hepatocellular carcinoma (HCC) is an inflammation-associated cancer. However, the lipid pro-inflammatory mediators have only been seldom investigated in HCC pathogenesis. Activation of NF-κB and expression of c-Myc are negatively regulated by cylindromatosis (CYLD) in hepatocarcinogenesis. But it remains largely unknown whether lipid pro-inflammatory mediators are involved in CYLD suppression. Here, we aimed to evaluate the significance of hepatic lipid pro-inflammatory metabolites of arachidonate affected CYLD expression via 5-lipoxygenase (5-LO)-pathway.Methods: Resection liver tissues from HCC patients or donors were evaluated for the correlation of 5-LO/cysteinyl leukotrienes (CysLTs)-signaling to expression of CYLD. The impact of functional components in 5-LO/CysLTs cascade on survival of HCC patients was subsequently assessed. Both livers from canines, a routine animal for drug safety evaluation, and genetic-modified human HCC cells treated with hepatocarcinogen aristolochic acid I (AAI) were further used to reveal the possible relevance between 5-LO pathway activation and CYLD depression. Results: 5-LO-activating protein (FLAP), an essential partner of 5-LO, significantly overexpressed and was parallel to CYLD depression, CD34 neovascular localization, and high Ki-67 expression in the resection tissues from HCC patients. Importantly, high hepatic FLAP transcription markedly shortened the median survival time of HCC patients after surgical resection. In the livers of AAI-treated canines, FLAP overexpression was parallel to enhanced CysLTs contents, simultaneous attenuated CYLD expression. Moreover, knock-in FLAP significantly diminished the expression of CYLD in AAI-treated human HCC cells.Conclusions: Hepatic FLAP/CysLTs axis is a crucial suppressor of CYLD in HCC pathogenesis, which highlights a novel mechanism in hepatocarcinogenesis and development. FLAP therefore can be explored for the early HCC detection and a target of anti-HCC therapy.

The Prognostic Value of the Albumin to Gamma-Glutamyltransferase Ratio in Patients with Hepatocellular Carcinoma Undergoing Radiofrequency Ablation

Albumin to gamma-glutamyltransferase ratio (AGR) is a newly developed biomarker for the prediction of patients’ prognosis in solid tumors. The purpose of the study was to establish a novel AGR-based nomogram to predict tumor prognosis in patients with early-stage HCC undergoing radiofrequency ablation (RFA). 394 hepatocellular carcinoma (HCC) patients who had received RFA as initial treatment were classified into the training cohort and validation cohort. Independent prognostic factors were identified by univariate and multivariate analyses. The value of AGR was evaluated by the concordance index ( C -index), receiver operating characteristic (ROC) curves, and likelihood ratio tests (LAT). Logistic regression and nomogram were performed to establish the pretreatment scoring model based on the clinical variables. As a result, AGR = 0.63 was identified as the best cutoff value to predict overall survival (OS) in the training cohort. According to the results of multivariate analysis, AGR was an independent indicator for OS and recurrence-free survival (RFS). In both training cohort and validation cohort, the high-AGR group showed better RFS and OS than the low-AGR group. What is more, the C -index, area under the ROC curves, and LAT χ 2 values suggested that AGR outperformed the Child-Pugh (CP) grade and albumin-bilirubin (ALBI) grade in terms of predicting OS. The AGR, AKP, and tumor size were used to establish the OS nomogram. Besides, the results of Hosmer-Lemeshow test and calibration curve analysis displayed that both nomograms in the training and validation cohorts performed well in terms of calibration. Therefore, the AGR-based nomogram can predict the postoperative prognosis of early HCC patients undergoing RFA.

Serum Anti-14-3-3 Zeta Autoantibody as a Biomarker for Predicting Hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Alpha-fetoprotein (AFP) is still the only serum biomarker widely used in clinical settings. However, approximately 40% of HCC patients exhibit normal AFP levels, including very early HCC and AFP-negative HCC; for these patients, serum AFP is not applicable as a biomarker of early detection. Thus, there is an urgent need to identify novel biomarkers for patients for whom disease cannot be diagnosed early. In this study, we screened and identified novel proteins in AFP-negative HCC and evaluated the feasibility of using autoantibodies to those protein to predict hepatocarcinogenesis. First, we screened and identified differentially expressed proteins between AFP-negative HCC tissue and adjacent non-tumor liver tissue using SWATH-MS proteome technology. In total, 2,506 proteins were identified with a global false discovery rate of 1%, of which 592 proteins were expressed differentially with 175 upregulated and 417 downregulated (adjusted p-value <0.05, fold-change FC ≥1.5 or ≤0.67) between the tumor and matched benign samples, including 14-3-3 zeta protein. For further serological verification, autoantibodies against 14-3-3 zeta in serum were evaluated using enzyme-linked immunosorbent, Western blotting, and indirect immunofluorescence assays. Five serial serum samples from one patient with AFP-negative HCC showed anti-14-3-3 zeta autoantibody in sera 9 months before the diagnosis of HCC, which gradually increased with an increase in the size of the nodule. Based on these findings, we detected the prevalence of serum anti-14-3-3 zeta autoantibody in liver cirrhosis (LC) patients, which is commonly considered a premalignant liver disease of HCC. We found that the prevalence of autoantibodies against 14-3-3 zeta protein was 16.1% (15/93) in LC patient sera, which was significantly higher than that in patients with chronic hepatitis (0/75, p = 0.000) and normal human sera (1/60, 1.7%, p = 0.01). Therefore, we suggest that anti-14-3-3 zeta autoantibody might be a biomarker for predicting hepatocarcinogenesis. Further follow-up and research of patients with positive autoantibodies will be continued to confirm the relationship between anti-14-3-3 zeta autoantibody and hepatocarcinogenesis.

Evaluating the diagnostic value of serum Des-γ carboxy prothrombin in the detection of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is amongst the most common cancers in the world and Vietnam. Most HCC patients are diagnosed late, so the effect of treatment is limited. Hence, early diagnosis for high-risk populations using medical imaging and serum markers is very important to control HCC. Recently, α-fetoprotein (AFP) has been popularly used as a serum marker for screening of HCC. Unfortunately, AFP is not trustworthy enough for HCC diagnosis, especially early HCC. Therefore, this study was deployed to estimate the ability of serum Des-γ carboxy prothrombin (DCP) applied in the diagnosis of HCC. DCP and AFP concentration in serum of 50 early HCC patients (stage A), 50 late HCC patients (stage B and C), 50 HBV/HCV-infected patients, and 50 healthy persons were identified. ROC curve analysis manifested that with the cut-off value at 11.93 ng/ml, DCP allowed identifying HCC cases with the sensitivity and specificity of 50 and 94%, respectively. With early HCC, the sensitivity of DCP decreased to 34%, while the specificity was unchanged. In the case of AFP, results showed that the sensitivity and specificity of this marker for HCC were 39 and 95%, with the cut-off value at 952.1 ng/ml. For early HCC, it was impossible to use AFP for diagnosis. The combination of DCP and AFP serum markers in the detection of HCC did not improve the sensitivity of the diagnosis compared to that of DCP alone. The study demonstrated that serum biomarker DCP can be used instead of AFP in the diagnosis of HCC, which improves the diagnostic sensitivity