ARTICLE | doi:10.20944/preprints202109.0502.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: Hepatocellular carcinoma; cirrhosis; neoangiogenesis factors
Online: 29 September 2021 (16:04:06 CEST)
Background: Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. The pathogenesis of chronic liver disease varies according to the underlying etiological factor, although in most cases it develops from a liver cirrhosis. The worsening progression of liver disease is accompanied by pathological angiogenesis, which is a prerequisite that favors the development of HCC. The aim of this study is to evaluate the clinical utility of circulating angiogenic markers VEGF, Ang-1, Ang-2, the Angiopoietin receptor (Tie1/2), HGF and PECAM-1 to screen early onset patients and to follow the evolution of HCC. Materials and Methods: We enrolled 62 patients; 33 out of 62 subjects were diagnosed for HCC and 29/62 for liver cirrhosis of different etiology without signs of neoplasia. Patients underwent venous blood sampling before and after treatments for VEGF, Ang-1, Ang-2, Tie1, Tie2, HGF and PECAM-1 measurement. Results: Ang-1 and Ang-2 are detectable not only in patients already suffering from HCC but also in cirrhotic patients without signs of cancer. Patients with HCC show higher HGF concentrations than patients with cirrhosis. A significant reduction in serum levels of Ang-2, Ang-2/Ang-1 and Ca 19-9 after DAAs therapy was observed. Moreover, VEGF levels were increased after treatment of HCC. Conclusion: The preliminary study here presented confirms that the mechanism of tumor angiogenesis is very complex and involves a very large number of factors. The integration of different methodologies and multi-marker algorithms is likely to emerge for the early diagnosis of HCC and the monitoring of the risk of relapse.
REVIEW | doi:10.20944/preprints201810.0450.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: hepatocellular carcinoma; natural killer cell
Online: 19 October 2018 (11:09:02 CEST)
Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.
ARTICLE | doi:10.20944/preprints201704.0181.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: microparticles, biomarkers, hepatocellular carcinoma
Online: 3 May 2017 (09:53:22 CEST)
Circulating microparticles (MPs) are novel potential biomarkers in cancer patients. Their role in hepatocellular carcinoma (HCC) is under intensive investigation. In this study we tested the hypothesis that MPs expressing the antigen HepPar1 are increased in the blood of subjects with HCC and may serve as markers of early recurrence after liver resection (LR). We studied fifteen patients affected by HCC undergoing LR and used flow cytometry to assess the number of circulating HepPar1+ MPs. Ten subjects without HCC (five with liver cirrhosis and 5 with healthy liver) were used as controls. After LR, HCC patients were followed-up for early recurrence, which occurred in seven cases. The number of circulating HepPar1+ MPs was significantly higher in subjects affected by HCC, compared to individuals without cancer (p<0.01). We also found that, among HCC patients, the number of circulating HepPar1+ MPs, measured before LR, was significantly higher in those who displayed early recurrence compared to those without recurrence (p=0.02). Of note, other types of circulating MPs, such as those derived from endothelial cells (CD144+) or those produced by the activated endothelium (CD144+/CD62+) were not associated with HCC, neither could predict HCC recurrence. HepPar1+ MPs deserve further investigation as novel biomarkers of disease and prognosis in HCC patients.
ARTICLE | doi:10.20944/preprints202102.0352.v1
Subject: Medicine & Pharmacology, Allergology Keywords: hepatocellular carcinoma; hepatitis B; growth factors; biomarkers; antibody array
Online: 17 February 2021 (09:36:17 CET)
Background: Hepatocellular carcinoma (HCC) is one of most common cancers with a high mortality rate. HBV/HCV infection is an important risk factor to trigger HCC. Therefore, developing serum biomarkers for early diagnosis is crucial to prolong survival in HCC patients. Methods: An antibody array technology was utilized to detect serum from 20 HBV-related HCC patients, 20 chronic hepatitis B patients and 20 normal population, whose results were further validated by ELISA. Results: Both antibody array and ELISA showed that ten growth factors (SCF R, GDF-15, HGF, FGF-4, IGFBP-1, PIGF, GH, GDNF, BDNF and IGF-1) were significantly differential in HCC patients when compared to the non-HCC population. Among these growth factors, the levels of SCF R, GDF-15, HGF, GH and IGF-1 showed significant correlation with hepatitis B and its severity, indicating that these growth factors may promote HCC progression by an HBV-specific mechanism. A therapy targeting these growth factors in hepatitis B patients may help to prevent the development of HCC. FGF4 and GH were found, for the first time, to be upregulated in HCC, suggesting that these two growth factors may serve as novel serum biomarkers for the early diagnosis of HCC. Conclusion: The combined detection of all the differential growth factors may improve the diagnostic accuracy of HCC.
REVIEW | doi:10.20944/preprints202105.0533.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: free radicals; oxidative stress; hepatocellular carcinoma; anti-oxidants; kaempferol
Online: 21 May 2021 (17:21:59 CEST)
Keywords: free radicals; oxidative stress; hepatocellular carcinoma; anti-oxidants; kaempferol
ARTICLE | doi:10.20944/preprints202101.0603.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Clock genes; Hepatocellular carcinoma; Ki67; Radiotherapy; Transgenic Per2::luc mice; γ-H2AX
Online: 29 January 2021 (08:15:35 CET)
This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on healthy liver (HL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were investigated in irradiated and non-irradiated organotypic slice culture (OSC) and ex vivo samples by detection of Ki67 and γ-H2AX. OSC proved useful to determine dose-dependent effects on proliferation and DNA damage but appeared unsuited to test the chronotherapeutic approach. Irradiation of ex vivo samples was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on HL were minimal at ZT20. Ex vivo samples revealed disruption in daily variation and down-regulation of all investigated clock genes except Per1 in non-irradiated HCC as compared with HL. Irradiation affected rhythmic clock gene expression in HL and HCC at all ZTs except at ZT20. Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.
REVIEW | doi:10.20944/preprints201909.0140.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: hepatocellular carcinoma; immune checkpoint inhibitors; HCC; pembrolizumab; nivolumab; immune microenvironment; targeted therapies
Online: 14 September 2019 (18:37:29 CEST)
Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib has been the standard of care for almost a decade until 2018 when FDA approved an alternative first-line agent namely lenvatinib. Whereas FOLFOX4 results an alternative first-line treatment for the chinese clinical oncology guidelines. In addition to cabozantinib, regorafenib, and ramucirumab, two therapeutics against the PD-L1/PD1 axis have been recently approved for subsequent-line therapy, as nivolumab and pembrolizumab. However, similar to other solid tumors, the response rate of single-agent targeting PD-L1/PD1 axis is low. Therefore a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors, the addition of immune checkpoint inhibitors after resection or during locoregional therapy, immune checkpoint inhibitors in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with an attent evaluation of new ICIs based combinatory approaches.
ARTICLE | doi:10.20944/preprints202204.0069.v2
Subject: Medicine & Pharmacology, Gastroenterology Keywords: hepatocellular carcinoma; conventional transarterial chemoembolization; emulsion; lipiodol; glass membrane emulsification device
Online: 6 June 2022 (05:53:21 CEST)
Background: Transarterial chemoembolization (TACE) is the standard treatment for BCLC-B hepatocellular carcinoma (HCC). A novel glass membrane emulsification device (GMD) produces a high percentage of water/oil emulsions with homogeneous and stable droplets. There are few reports on the efficacy of GMD-conventional-TACE (GMD-c-TACE)；therefore, we aimed to evaluate the effectiveness of GMD-c-TACE. Methods: Seventy-one patients with HCC with tumor diameter <5 cm who underwent c-TACE with and without GMD were included in this study to investigate local recurrence and hepatic functional reserve. Results: The local recurrence rates of TACE without GMD were 3.0% at 6 months, 16.7% at 12 months, and 35.0% at 18 months, around where it plateaued. Hence, the local recurrence rates in the GMD-c-TACE group were 7.7% at 14 months and 23.1% at 20 months, respectively. Thus, GMD-c-TACE had a significantly lower local recurrence. Multivariate analysis showed that GMD-c-TACE could suppress local recurrence and maintain hepatic reserve. Conclusions: GMD-c-TACE allows dense lipiodol accumulation in the tumor and attainment of good local control. Additionally, the inhibition of the release of anticancer drugs may maintain hepatic reserve. GMD-c-TACE is useful in preventing local recurrence and is expected to become the standard treatment form of c-TACE in the future.
ARTICLE | doi:10.20944/preprints202101.0244.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: DPP9; SNPs; Hepatocellular carcinoma; Survival; TCGA; DPP4 gene family
Online: 13 January 2021 (12:13:37 CET)
Dipeptidyl peptidase (DPP) 9, DPP8, DPP4 and fibroblast activation protein (FAP) are the four enzymatically active members of the S9b protease family. Associations of DPP9 with human liver cancer, exonic single nucleotide polymorphisms (SNPs) in DPP9 and loss of function (LoF) variants have not been explored. Human genomic databases including The Cancer Genome Atlas (TCGA) were interrogated to identify DPP9 LoF variants and associated cancers. Survival and gene signature analyses were performed on hepatocellular carcinoma (HCC) data. We found that DPP9 and DPP8 are intolerant to LoF variants. DPP9 LoF variants were most often associated with uterine carcinoma. Two DPP9 intronic SNPs that have been associated with lung fibrosis and COVID-19 were not associated with liver fibrosis or cancer. All four DPP4-like genes were overexpressed in liver tumours and their joint high expression was associated with poor survival in HCC. Increased DPP9 expression was associated with obesity in HCC patients.. High expression of genes that positively correlated with overexpression of DPP4, DPP8, and DPP9 were associated with very poor survival in HCC. Enriched pathways analysis of these positively correlated genes featured Toll-like receptor and SUMOylation pathways. This comprehensive data mining suggests that DPP9 is essential for human survival and the DPP4 protease family is important in cancer pathogenesis.
ARTICLE | doi:10.20944/preprints202007.0320.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: sarcopenia; hepatocellular carcinoma; grip strength; skeletal muscle index; lenvatinib; modified albumin-bilirubin grade
Online: 15 July 2020 (08:45:55 CEST)
Although sarcopenia is characterized by a loss of muscle strength and skeletal muscle mass, few studies have evaluated the effect of muscle strength on hepatocellular carcinoma (HCC) patients. We separately evaluated the impact of sarcopenia-related factors (grip strength [GS] and the skeletal muscle index [SMI]) on the survival among lenvatinib-treated unresectable HCC (u-HCC) patients. This single-center cohort study was conducted at a university hospital. The study population included 63 lenvatinib-treated u-HCC patients managed between April 2018 and April 2020. A decreased GS and decreased SMI were found in 21 (33.3%) and 22 (34.9%) patients, respectively. The overall survival (OS) of the normal GS group was significantly higher than that of the decreased GS group, while that of the normal and decreased SMI groups did not differ markedly. There were no significant differences in the progression-free survival between the normal GS and decreased GS groups or the normal SMI and decreased SMI groups. A multivariate Cox proportional hazards model showed that ALBI2b (hazard ratio [HR] 4.39) and a decreased GS (HR 3.55) were independently associated with an increased risk of poor prognosis. In addition to the hepatic functional reserve, a decreased GS was a poor prognostic factor in lenvatinib-treated u-HCC patients.
ARTICLE | doi:10.20944/preprints202107.0559.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Hepatocellular carcinoma; Lenvatinib; Hepatic arterial infusion chemotherapy; Propensity score matching
Online: 26 July 2021 (09:59:34 CEST)
The comparative efficacy and safety between lenvatinib and hepatic artery infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC) are still unclear. This multicenter historical cohort study enrolled 244 patients who were treated with HAIC (n = 173) or lenvatinib (n = 71) between 2012 and 2020. Propensity score matching (PSM) was performed, and 52 patients were selected per group. Clinical outcomes and safety were compared. Objective response rate (ORR) was not different between the two groups (26.0% vs. 23.1%, P = 0.736). Before PSM, HAIC group had a higher proportion of Child-Pugh B and portal vein tumor, whereas lenvatinib group had more patients with extrahepatic metastases, which was adjusted after PSM. There were no differences in progression-free survival (PFS) and overall survival (OS) after PSM (HAIC vs. lenvatinib, median PFS, 3.6 vs. 4.0 months, P = 0.706; median OS 10.8 vs. 7.9 months, P = 0.106). Multivariate Cox-regression showed that alpha-fetoprotein ≤ 1000 ng/mL was only associated factor for OS after PSM in all patients (hazard ratio = 0.421, P = 0.011). Subgroup analysis for patients with high tumor burden beyond the REFLECT eligibility criteria revealed that HAIC group (n = 29) had a significantly longer OS than did lenvatinib group (n = 30) (10.0 vs. 5.4 months, P=0.004). More patients in HAIC group achieved better liver function than those in lenvatinib group at the time of best responses. There was no difference in the incidence of grade 3 and 4 adverse events between the two groups. Therefore, lenvatinib is comparable to HAIC in terms of ORR and OS in unresectable HCC meeting REFLECT eligibility criteria.
ARTICLE | doi:10.20944/preprints201907.0075.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: hepatocellular carcinoma; objective response; modified RECIST; sorafenib; hepatic arterial infusion chemotherapy
Online: 4 July 2019 (10:56:53 CEST)
Background In SILIUS (NCT01214343), combination of sorafenib and hepatic arterial infusion chemotherapy did not significantly improve overall survival in patients with advanced hepatocellular carcinoma (HCC) compared with sorafenib alone. In this study, we explored the relationship between objective response by mRECIST and overall survival (OS) in the sorafenib group, in the combination group and in all patients in the SILIUS trial. Methods Association between objective response and OS in patients treated with sorafenib (n=103), combination (n=102) and all patients (n=205) were analyzed. The median OS of responders was compared with that of non-responders. Landmark analyses were performed according to objective response at several fixed time points, as sensitivity analyses, and the effect on OS was evaluated by Cox regression analysis with objective response as a time-dependent covariate, with other prognostic factors was performed. Results In the sorafenib group, OS of responders (n = 18) was significantly better than that of non-responders (n = 78) (p < 0.0001), where median OS was 27.2 (95% CI, 16.0–not reached) months for responders and 8.9 (95% CI, 6.5–12.6) months for non-responders. HRs from landmark analyses at 4, 6, and 8 months were 0.45 (p=0.0330), 0.37 (p=0.0053), and 0.36 (p=0.0083), respectively. Objective response was an independent predictor of OS based on unstratified Cox regression analyses. In the all patients and the combination group, similar results were obtained. Conclusion In the SILIUS trial, objective response was an independent prognostic factor for OS in patients with HCC.
ARTICLE | doi:10.20944/preprints201609.0074.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: hepatocellular carcinoma; hepatitis B virus X protein; Notch1 pathway; ERK; AKT
Online: 21 September 2016 (09:49:13 CEST)
Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.
ARTICLE | doi:10.20944/preprints202110.0038.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: hepatocellular carcinoma; percutaneous radiofrequency ablation; chemolipiodolization; risk factors; propensity score-matched analysis
Online: 4 October 2021 (10:19:37 CEST)
We aimed to compare prognostic factors for overall survival (OS) following percutaneous radiofrequency ablation (PRFA) with or without chemolipiodolization (CL) for early-stage hepatocellular carcinoma (HCC) using propensity score-matched analysis. We enrolled 221 patients with early-stage HCC who received PRFA with (n = 76) or without (n = 145) CL in Saga Central Hospital between April 2004 and December 2020. No significant difference was observed in OS between PRFA with and without CL cohorts (median survival time [MST]: 5.4 vs. 4.5 years; p = 0.0806). To reduce confounding effects, 108 patients were selected using propensity score-matched analysis (n = 54 for each treatment). No significant difference was observed in OS between the cohorts (MST: 3.6 vs. 4.0 years; p = 0.5474). After stratification according to tumor size, no significant difference was observed in OS for patients with tumor size ≥20 mm between PRFA with and without CL cohorts (MST: 3.4 vs. 3.5 years; p = 0.8236). PRFA with CL was not a significant prognostic factor in both univariate and multivariate analyses (p = 0.5477 and 0.9600, respectively). Our findings suggest that PRFA with CL does not demonstrate longer prognostic effects than PRFA without CL in early-stage HCC, regardless of tumor size.
ARTICLE | doi:10.20944/preprints202011.0691.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Huanglian Decoction (Coptidis Rhizoma, Zingiberis Rhizoma, Folium Artemisiae Argyi, Mume Fructus); Hepatocellular carcinoma; TCGA; GEO
Online: 27 November 2020 (13:14:24 CET)
Background: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in human populations worldwide. Conversely, Huanglian Decoction is one of the most important Chinese medicine formulas, with the potential to treat cancer. Methods: To identify differentially expressed genes (DEG), we herein downloaded gene expression profile data from the TCGA (TCGA-LIHC) and GEO (GSE45436) databases. We obtained phytochemicals of the four constituent herbs of Huanglian Decoction from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). We also established a regulatory network of DEG and their drug target genes and subsequently analyzed key genes using bioinformatic approaches. Furthermore, we explored the effect of Huanglian Decoction by conducting in vitro experiments so as to verify the prediction. In particular, the CCNB1 gene was knockdown to verify the primary target of this Decoction. Results: Based on the results of network pharmacological analysis, we revealed that there are 5 bioactive compounds in Huanglian Decoction acting on HCC. In addition, our findings confirmed that CCNB1 was the primary key gene, which can be highly expressed in tumors and was significantly associated with a worse prognosis (P = 0.002) according to PPI network analysis of the target genes of these five compounds, as well as expression and prognosis analyses in tumors. We also noted that CCNB1 can be used as an independent prognostic indicator of HCC (P < 0.01). Moreover, in vitro experimental results demonstrate that Huanglian Decoction can significantly inhibit the growth, migration, and invasion of HCC cells. Finally, further analysis showed that this Decoction may inhibit the growth of HCC cells by down-regulating the expression level of CCNB1.
ARTICLE | doi:10.20944/preprints202008.0218.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: hepatocellular carcinoma; diffusion-weighted imaging; magnetic resonance; hepatic arterial infusion chemotherapy
Online: 9 August 2020 (15:34:00 CEST)
This study aimed to identify the utility of diffusion-weighted magnetic resonance (MR) imaging with an apparent diffusion coefficient (ADC) map as a predictor of the intrahepatic response of hepatocellular carcinoma (HCC) to cisplatin-based hepatic arterial infusion chemotherapy (HAIC). We retrospectively evaluated 113 consecutive patients with HCC who underwent gadoxetic acid-enhanced and diffusion-weighted MR imaging. The appropriate cutoff for the tumor-to-liver ADC ratio was determined to be 0.741. Of the 113 patients, 51 (45%) presented with a tumor-to-liver ADC ratio < 0.741. Evaluation of the intrahepatic treatment response after 2-3 cycles of HAIC in these 51 patients revealed that 20 patients (39%) experienced an objective response to HAIC. On the other hand, only 10 of the 62 patients with a tumor-to-liver ADC ratio ≥ 0.741 (16%) experienced an objective response. Thus, the objective response rate was significantly higher in patients with a tumor-to-liver ADC ratio < 0.741 than in those with a tumor-to-liver ADC ratio ≥ 0.741 (P = 0.006). Multivariate logistic regression analysis using parameters including perfusion alteration, percentage of a non-enhancing portion, and tumor-to-liver ADC ratio revealed that a tumor-to-liver ADC ratio < 0.741 (odds ratio 3.03; P = 0.015) is the sole predictor of an objective response to HAIC. Overall survival rates were significantly higher in patients with objective responses to HAIC than in those without objective responses (P = 0.001 by log-rank test). In conclusion, patients with unresectable HCC with a tumor-to-liver ADC ratio < 0.741 showed a favorable intrahepatic response to HAIC. Therefore, diffusion-weighted MR imaging can play a critical role as a predictor of response to cisplatin-based HAIC in unresectable HCC.
ARTICLE | doi:10.20944/preprints202012.0406.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Hepatocellular carcinoma; transcatheter arterial chemoembolization; circulating tumor cells; tumor progression; predictive marker
Online: 16 December 2020 (11:26:42 CET)
Circulating tumor cells (CTCs) enumeration is a promising technique to predict cancer prognosis and treatment response. CTCs were evaluated in healthy subjects, cirrhotic controls and hepatocarcinoma (HCC) patients. CTCs were isolated using microfluidic system based on the expression of EpCAM, EGFR and three epithelial to mesenchymal transition (EMT) markers. Patients were stratified according to disease progression and exitus. Although counts of individual CTCs, clustered CTCs and α-fetoprotein (AFP) at basal level in patients with HCC were significantly increased compared with the values obtained in cirrhotic patients and control subjects, only individual CTCs (p=0.027), but not clustered CTCs (p=0.063) and AFP (p=0.072), were independent predictors of HCC development. The univariate regression model showed that basal levels of CTCs46 were related to high risk of HCC (Odds Ratio 3.467, p=0.011). The stratification of our cohort according to disease progression and death showed that basal individual CTCs 76 (Hazard Ratio 5.131, p=0.004) were related to disease progression, as well as the difference of clustered CTCs between 1-month and baseline levels 1.5 were related to death (Hazard Ratio 10.204, p=0.036). In conclusion, the preoperative and 1-month measurements of CTCs in blood constitute useful markers to predict the outcome of patients under TACE treatment.
ARTICLE | doi:10.20944/preprints202207.0018.v1
Subject: Life Sciences, Virology Keywords: hepatocellular carcinoma (HCC); hepatitis B virus (HBV); mutations; HBV/HIV co-infection; Botswana; Africa
Online: 1 July 2022 (16:31:00 CEST)
Mutations within the hepatitis B virus (HBV) genome have been associated with rapid progres-sion to hepatocellular carcinoma (HCC); however, there is limited information regarding the prevalence and impact of these mutations in most of sub-Saharan Africa, including Botswana. We aimed to determine the prevalence of HBV mutations known to be associated with progression to HCC using a retrospective, cross-sectional analysis of 48 previously generated HBV sequences from adults with concomitant HBV/HIV initiating HIV antiretroviral therapy in Botswana. The sequences were aligned with reference sequences, and HCC-associated mutations were manually identified using BioEdit. Sixteen (33.3 %) of 48 participant samples had 20 HCC-associated mu-tations. Seven HCC mutations were present in the core region, 4 in the preCore region, 7 in the X region, and one mutation in the surface region, as well as deletions within the preSurface 1 region. Seven of the 16 participants (43.8%) had multiple HCC-associated mutations. There were also previously uncharacterized mutations at positions with known HCC-associated mutations. HCC-associated mutations were common in this cohort; hence, some participants may require close clinical monitoring as they might be more prone to rapid disease progression. Other functionally uncharacterized polymorphisms were also detected and require characterization in future studies.
ARTICLE | doi:10.20944/preprints202109.0429.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: hepatocellular carcinoma; hepatic arterial infusion chemotherapy; cisplatin; sorafenib; multikinase inhibitors; risk factors; propensity score-matched analysis
Online: 24 September 2021 (12:38:25 CEST)
Given that the outcome of hepatic arterial infusion chemotherapy (HAIC) with cisplatin for intrahepatic advanced hepatocellular carcinoma (HCC) is unclear, we aimed to compare prognostic factors for overall survival (OS) following HAIC with cisplatin versus sorafenib for intrahepatic advanced HCC using propensity score-matched analysis. We enrolled 348 patients with intrahepatic advanced HCC who received HAIC with cisplatin (n = 97) or sorafenib (n = 251) between June 2006 and March 2020. No significant difference was observed in OS between HAIC with cisplatin and sorafenib cohorts (median survival time [MST]: 13.9 vs. 12.7 months; p = 0.0989). To reduce confounding effects, 176 patients were selected using propensity score-matched analysis (n = 88 for each treatment). HAIC with cisplatin significantly prolonged OS compared with sorafenib (MST: 16.2 vs. 12.2 months; p = 0.0060). Following stratification according to the Child–Pugh classification, for both patients with class A (MST: 24.0 vs. 15.6 months; p = 0.0097) and class B (MST: 8.5 vs. 6.9 months; p = 0.0391), HAIC with cisplatin rather than sorafenib significantly prolonged OS. Our findings suggest that HAIC with cisplatin demonstrates longer prognostic effects than sorafenib in intrahepatic advanced HCC, regardless of the hepatic reserve.
ARTICLE | doi:10.20944/preprints201906.0285.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: hepatocellular carcinoma; lenvatinib; transcatheter arterial chemoembolisation; intermediate stage; up-to-seven criteria
Online: 27 June 2019 (08:13:58 CEST)
Background: Although transcatheter arterial chemoembolisation (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be more favourable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. Methods: This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria [unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function] were selected for the study. Propensity score matching was used to adjust for patient demographics. Results: After propensity-score matching, outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, 1 in early access program and 15 in real world setting) and 60 patients treated with cTACE as the initial treatment was compared. The change of ALBI score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in lenvatinib group (p = 0.254) and -2.66 to -2.09 in cTACE group (p < 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%; p < 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). Conclusion: In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides more favorable outcome than TACE.
ARTICLE | doi:10.20944/preprints202202.0222.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: hepatocellular carcinoma; lenvatinib; molecular targeted agents; complete response; CT value
Online: 18 February 2022 (04:05:18 CET)
Purpose: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. Method: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e. the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. Results: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (>30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (<30.6%) N30-CTav group (P<0.001, 61.5% at 1 year). Conclusion: The cut-off value of 30.2 HU for CTav (N30-CTav) might be appropriate for identifying post-lenvatinib necrosis in HCC, and an N30-CTav occupancy rate of >30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.
ARTICLE | doi:10.20944/preprints202208.0324.v1
Subject: Life Sciences, Immunology Keywords: T cytotoxic cells; Leukocyte-associated Immunoglobulin-like Receptor-1; LAIR-1; Hepatitis C virus genotype 4; HCV G4; hepatocellular carcinoma; cirrhosis; immune inhibitory checkpoints; inflammation; prognosis; insulin resistance
Online: 17 August 2022 (11:38:10 CEST)
Background and Aim. Since virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, post-hepatitis C virus (HCV) infection would be a cause for liver cirrhosis that would progress to HCC. Cytotoxic T cells (Tc) are known to be involved in post-HCV complications and HCC pathogenesis. The inhibitory checkpoint Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is expressed on Tc. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression post-HCV and moreover, to evaluate LAIR-1 expression as a non-invasive biomarker for HCC progression in the context of liver cirrhosis post-HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. We studied LAIR-1 expression on Tc related to the progression of liver cirrhosis in a case-controlled study enrolled 64 patients with post-HCV G4-HCC and 37 patients with post-HCV G4-liver cirrhosis. Methods: LAIR-1 expression was analyzed by flow cytometry. Results: LAIR-1 expression on Tc and the percentage of Tc positive for LAIR-1 (LAIR-1+Tc %) were significantly higher in the post-HCV G4-HCC group compared to the post-HCV G4-liver cirrhosis
REVIEW | doi:10.20944/preprints201909.0071.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Sorafenib; hepatocellular carcinoma; prognostic factors; predicitve factors
Online: 6 September 2019 (10:32:29 CEST)
Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, currently predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.
ARTICLE | doi:10.20944/preprints202102.0335.v1
Subject: Biology, Anatomy & Morphology Keywords: IQGAP1; MST2; LATS1, YAP1, Hippo, Bile acid, hepatocellular carcinoma.
Online: 16 February 2021 (14:08:12 CET)
The Hippo pathway regulates a complex signalling network which mediates several biological functions including cell proliferation, organ size and apoptosis. Several scaffold proteins regulate the crosstalk of the members of the pathway with other signalling pathways and play an important role in the diverse output controlled by this pathway. In this study we have identified the scaffold protein IQGAP1 as a novel interactor of the core kinases of the Hippo pathway, MST2 and LATS1. Our results indicate that IQGAP1 scaffolds MST2 and LATS1, supresses their kinase activity, and YAP1-dependent transcription. Additionally, we show that IQGAP1 is a negative regulator of the non-canonical pro-apoptotic pathway and may enable the crosstalk between this pathway and the ERK and AKT signalling modules. Our data also show that bile acids regulate the IQGAP1-MST2-LATS1 signalling module in hepatocellular carcinoma cells which could be necessary for the inhibition of MST2-dependent apoptosis and hepatocyte transformation.
REVIEW | doi:10.20944/preprints201903.0267.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: hepatocellular carcinoma, gut microbiota, gut-liver axis, intestinal dysbiosis
Online: 28 March 2019 (13:43:07 CET)
Hepatocellular carcinoma (HCC), one of the leading causes of death worldwide, has a causal nexus with liver injury, inflammation, and regeneration that accumulate over decades. Observations from recent studies have accounted for the involvement of the gut-liver axis in the pathophysiological mechanism responsible for HCC. The human intestine nurtures a diversified colony of microorganisms residing in the host ecosystem. The intestinal barrier is critical for conserving the normal physiology of the gut microbiome. Therefore, a rupture of this barrier or dysbiosis cause the intestinal microbiome to serve as the main source of portal-vein endotoxins such as lipopolysaccharide, in the progression of hepatic diseases. Indeed, increased bacterial translocation is a key sign of HCC. Considering the limited number of clinical studies on HCC with respect to the microbiome, we focus on the clinical as well as animal studies involving the gut microbiota with the current understandings of the mechanism by which the intestinal dysbiosis promotes hepatocarcinogenesis. Future research might offer mechanistic insights into the specific phyla targeting the leaky gut, as well as microbial dysbiosis, and their metabolites, as key pathways that drive HCC-promoting microbiome-mediated liver inflammation and fibrosis, thereby restoring the gut barrier function.
ARTICLE | doi:10.20944/preprints201612.0142.v1
Subject: Life Sciences, Microbiology Keywords: aflatoxin B1; transaminases; hepatocellular carcinoma; Saudi patients; liver dysfunction
Online: 29 December 2016 (10:59:51 CET)
Background: Exposure to chronic low levels of aflatoxin B1 (AFB1) contamination can lead to immune suppression and nutritional consequences that might greatly contributed in the increase of hepatocellular carcinoma (HCC). The toxicity of AFB1 is greatly vary between different population, affected by age, gender, and environmental factors. Material and subjects: Aflatoxin B1 (AFB1) was measured in 50 blood samples collected from non B, C hepatitis viruses and non CMV-Ab liver disease patients from different general hospitals and polyclinic in KSA during period 01-2013 to 06-2014. All Patients demonstrate elevation of ALT and AST with unknown etiology. Serum samples were obtained and kept at −20 °C for AFB1detection. Results: Out of the 50 blood samples, 38 demonstrate a detectable serum level of AFB1 while the remaining 12 patients were AFB1 negative and used as control participants. While AST was non-significantly different in AFB1 exposed patients, ALT was significantly higher in AFB1 positive samples compared to control AFB1-negative. AFB1 was positively correlated with AST and ALT as liver function enzymes and with age as a risk factor of long duration of AFB1 chronic exposure. Multiple linear regression analysis ascertained the association between AFB1 chronic exposure and ALT increase in liver dysfunction Saudi patients. Conclusion: Measurement of elevated ALT as marker of liver injury in AFB1 chronically exposed Saudi patients can help to avoid the future development of HCC. Moreover, early detection of AFB1 exposure, together with early vaccination against HBV and HCV can remove the synergistic effects of these two etiological factors and thus decrease the risk of developing liver cancer.
Subject: Medicine & Pharmacology, Allergology Keywords: contrast-enhanced ultrasound (CEUS); Liver Imaging Reporting and Data System (LI-RADS); differential diagnosis; hepatocellular carcinoma (HCC); tuberculosis
Online: 8 December 2020 (14:59:44 CET)
Background: The liver is involved in disseminated tuberculosis in more than 80% of the cases while primary liver involvement is rare, representing < 1% of all cases. Hepatic tuberculosis (TB) can be treated by conventional anti-TB therapy, however, diagnosing this disease still remains a challenge. The diagnosis might be particularly difficult in patients with a single liver lesion that could be misdiagnosed as a tumor or other focal liver lesions. While computed tomography and magnetic resonance imaging findings have been described, there is a paucity of literature on contrast-enhanced ultrasound (CEUS) features of hepatic TB. Case Summary: herein, we describe a case of a patient with tuberculous lymphadenopathy and chronic HCV-related liver disease who developed a single macronodular hepatic TB lesion. Due to the finding of a hepatocellular carcinoma (HCC) highly suggestive CEUS pattern, specifically a LR5 category according to the Liver Imaging Reporting and Data System (LI-RADS), and a good response to antitubercular therapy, a non-invasive diagnosis of HCC was made, and the patient underwent liver resection. We also review the published literature on imaging features of hepatic TB and discuss the diagnostic challenge represented by hepatic TB when occurs as a single focal liver lesion. Conclusions: this report shows for the first time that CEUS pattern of hepatic TB might be misinterpreted as HCC and specific imaging features are lacking. Personal history and epidemiological data are mandatory in interpreting CEUS findings of a focal liver lesion even when the imaging pattern is highly suggestive of HCC.
ARTICLE | doi:10.20944/preprints202104.0020.v1
Subject: Life Sciences, Biochemistry Keywords: hepatitis C virus; hepatocellular carcinoma; immunotherapy; multi-component DNA vaccine; nucleocapsid (core) protein; telomerase reverse transcriptase; eukaryotic expression; CD4+ and CD8+ T cell response; immune suppression; assays of reporter expression; induction of type I interferons
Online: 1 April 2021 (13:18:59 CEST)
Chronic HCV infection and associated liver cancer impose a heavy burden on the healthcare system. Direct acting antivirals eliminate HCV, unless it is drug resistant, and partially reverse liver disease, but they cannot cure HCV-related cancer. Possible remedy could be a multi-component immunotherapeutic vaccine targeting both HCV-infected and malignant cells, also those not infected with HCV. To meet this need we developed a two-component DNA vaccine based on the highly conserved core protein of HCV to target HCV-infected cells, and a renowned tumor associated antigen telomerase reverse transcriptase (TERT) based on the rat TERT, to target malignant cells. Their synthetic genes were expression-optimized, and HCV core was truncated after aa 152 (Core152opt) to delete the domain interfering with immunogenicity. Core152opt and TERT DNA were highly immunogenic in BALB/c mice, inducing IFN-γ/IL-2/TNF-α response of CD4+ and CD8+ T cells. Also, DNA-immunization with TERT enhanced cellular immune response against luciferase encoded by a co-delivered plasmid (Luc DNA). However, DNA-immunization with Core152opt and TERT mix resulted in abrogation of immune response against both components. A loss of bioluminescent signal after co-delivery of TERT and Luc DNA into mice indicated that TERT affects the in vivo expression of luciferase directed by the immediate early cytomegalovirus and interferon-β promoters. Panel of mutant TERT variants was created and tested for their expression effects. TERT with deleted N-terminal nucleoli localization signal and mutations abrogating telomerase activity still suppressed the IFN-β driven Luc expression, while the inactivated reverse transcriptase domain of TERT and its analogue, enzymatically active HIV-1 reverse transcriptase, exerted only weak suppressive effects, implying that suppression relied on the presence of the full-length/nearly full-length TERT, but not its enzymatic activity. The effect(s) could be due to interference of the ectopically expressed xenogeneic rat TERT with biogenesis of mRNA, ribosomes and protein translation in murine cells, affecting the expression of immunogens. HCV core can aggravate this effect, leading to early apoptosis of co-expressing cells, preventing the induction of immune response.
ARTICLE | doi:10.20944/preprints201810.0073.v1
Subject: Engineering, Biomedical & Chemical Engineering Keywords: Classification; F-score; Gray-Level Co-occurrence Matrix (GLCM); Gray-Level Run-Length Matrix (GLRLM); Hepatocellular Carcinoma (HCC); Liver Cancer; Liver Abscess; Image Texture, Sequential Backward Selection (SBS); Sequential Forward Selection (SFS); Support Vector Machine (SVM); Ultrasound Image.
Online: 4 October 2018 (14:01:42 CEST)
This paper discusses the computer-aided (CAD) classification between Hepatocellular Carcinoma (HCC), i.e., the most common type of liver cancer, and Liver Abscess, based on ultrasound image texture features and Support Vector Machine (SVM) classifier. Among 79 cases of liver diseases, with 44 cases of HCC and 35 cases of liver abscess, this research extracts 96 features of Gray-Level Co-occurrence Matrix (GLCM) and Gray-Level Run-Length Matrix (GLRLM) from the region of interests (ROIs) in ultrasound images. Three feature selection models, i) Sequential Forward Selection, ii) Sequential Backward Selection, and iii) F-score, are adopted to determine the identification of these liver diseases. Finally, the developed system can classify HCC and liver abscess by SVM with the accuracy of 88.875%. The proposed methods can provide diagnostic assistance while distinguishing two kinds of liver diseases by using a CAD system.