Search results for: Hepatocellular carcinoma

Authors: Hatem A. El-Mezayen, Hossam Darwesh

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Background/Aim: Hepatocellular carcinoma (HCC) is often diagnosed at advanced stage where effective therapies are lacking. Identification of new scoring system is needed to discriminate HCC patients from those with chronic liver disease. Based on the link between vascular endothelial growth factor (VEGF) and HCC progression, we aimed to develop a novel score based on combination of VEGF and routine laboratory tests for early prediction of HCC. Methods: VEGF was assayed for HCC group (123), liver cirrhosis group (210) and control group (50) by Enzyme Linked Immunosorbent Assay (ELISA). Data from all groups were retrospectively analyzed including α feto protein (AFP), international normalized ratio (INR), albumin and platelet count, transaminases, and age. Areas under ROC curve were used to develop the score. Results: A novel index named hepatocellular carcinoma-vascular endothelial growth factor score (HCC-VEGF score)=1.26 (numerical constant) + 0.05 ×AFP (U L-1)+0.038 × VEGF(ng ml-1)+0.004× INR –1.02 × Albumin (g l-1)–0.002 × Platelet count × 109 l-1 was developed. HCC-VEGF score produce area under ROC curve of 0.98 for discriminating HCC patients from liver cirrhosis with sensitivity of 91% and specificity of 82% at cut-off 4.4 (ie less than 4.4 considered cirrhosis and greater than 4.4 considered HCC). Conclusion: Hepatocellular carcinoma-VEGF score could replace AFP in HCC screening and follow up of cirrhotic patients.

Keywords: Hepatocellular carcinoma, cirrhosis, HCV, diagnosis, tumor markers

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Authors: Aml M. El-Sharkawy, Hossam M. Darwesh

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Abstract— Background/Aim: Hepatocellular carcinoma (HCC) is often diagnosed at advanced stage where effective therapies are lacking. Identification of new scoring system is needed to discriminate HCC patients from those with chronic liver disease. Based on the link between tumor associated trypsin inhibitor (TATI) and HCC progression, we aimed to develop a novel score based on combination of TATI and routine laboratory tests for early prediction of HCC. Methods: TATI was assayed for HCC group (123), liver cirrhosis group (210) and control group (50) by Enzyme Linked Immunosorbent Assay (ELISA). Data from all groups were retrospectively analyzed including α feto protein (AFP), international normalized ratio (INR), albumin and platelet count, transaminases, and age. Areas under ROC curve were used to develop the score. Results: A novel index named hepatocellular carcinoma-vascular endothelial growth factor score (HCC-TATI score) = 3.1 (numerical constant) + 0.09 ×AFP (U L-1) + 0.067 × TATI (ng ml-1) + 0.16 × INR – 1.17 × Albumin (g l-1) – 0.032 × Platelet count × 109 l-1 was developed. HCC-TATI score produce area under ROC curve of 0.98 for discriminating HCC patients from liver cirrhosis with sensitivity of 91% and specificity of 82% at cut-off 6.5 (ie less than 6.5 considered cirrhosis and greater than 4.4 considered HCC). Conclusion: Hepatocellular carcinoma-TATI score could replace AFP in HCC screening and follow up of cirrhotic patients.

Keywords: Hepatocellular carcinoma, cirrhosis, HCV, diagnosis, TATI

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Authors: Ilirian Laçi, Alketa Spahiu

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Modality of treatment in hepatocellular carcinoma (HCC) patients depends on the stage of the disease. The Barcelona Clinic Liver Cancer Classification (BCLC) is the preferred staging system. There are many patients initially present with intermediate-stage disease. For these patients, transarterial chemoembolization (TACE) is the treatment of choice. The differences in individual factors that are not captured by the BCLC framework, such as the tumor growth pattern, degree of hypervascularity, and vascular supply, complicate further evaluation of these patients. Because of these differences, not all patients benefit equally from TACE. Several tools have been devised to aid the decision-making process, which have shown promising initial results but have failed external evaluation and have not been translated to the clinic aspects. Criteria for treatment decisions in daily clinical practice are needed in all stages of the disease.

Keywords: hepatocellular carcinoma, transarterial chemoembolization, TACE, liver

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Authors: Yu-Chih Wang, Chia-Yu Lai, Hsiao-Tien Liu, Yi-Ju Chen, Shao-Bin Cheng

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Liver transplant has been one of the curative treatment options for hepatocellular carcinomaunder certain oncological conditions. Two of the most validated criteria are from Milan in1996 and USCF in 2001, suggesting number and size limits of tumor without vascularinvasion or distant metastasis. We performed a retrospective cohort study of hepatocellular carcinoma patients undergoing livertransplant between August 2003 and December 2020 in our institute. Clinical andpathological characteristic, survival outcome, and recurrent pattern were analysed.UCSF criteria was applied for living donor transplantation, and Milan criteria was applied for deceased donor transplantation. Of 180 total patients, 52 cases(28.8%) with diagnosis of hepatocellular carcinoma, including26 living donor(LD) and 26 deceased donor(DD) liver transplant. Complete pathologicalremission was significantly more in the DD group(p=0.009). Pathological reports showed that30.8% of DD group exceeded Milan criteria, and 19.2% of LD group exceeded UCSFcriteria.After a median follow-up of 52.2 months, the 1-year, 3-year and 5-year overall survival was 87.6%, 74.1%, and 71.8%, respectively.Meanwhile, progression-free survival was 93.1%, 85.7%, and 81.6% for 1, 3, and 5-year, respectively, similar to that in Mazzaferro et al, 1996. We concluded that Liver transplant could be applied cautiously in expanded criteria for patent withhepatocellular carcinoma.

Keywords: liver transplant, milan criteria, UCSF criteria, living donor transplantation, deceased donor transplantation

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Authors: Jer-Yuh Liu, Je-Chiuan Ye, Jin-Ming Hwang

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Protein kinase C alpha (PKCα) is a key signaling molecule in human cancer development. As a therapeutic strategy, targeting PKCα is difficult because the molecule is ubiquitously expressed in non-malignant cells. PKCα is regulated by the cooperative interaction of the transcription factors myeloid zinc finger 1 (MZF-1) and Ets-like protein-1 (Elk-1) in human cancer cells. By conducting tissue array analysis, herein, we determined the protein expression of MZF-1/Elk-1/PKCα in various cancers. The data show that the expression of MZF-1/Elk-1 is correlated with that of PKCα in hepatocellular carcinoma (HCC), but not in bladder and lung cancers. In addition, the PKCα down-regulation by shRNA Elk-1 was only observed in the HCC SK-Hep-1 cells. Blocking the interaction between MZF-1 and Elk-1 through the transfection of their binding domain MZF-160–72 decreased PKCα expression. This step ultimately depressed the epithelial-mesenchymal transition potential of the HCC cells. These findings could be used to develop an alternative therapeutic strategy for patients with the PKCα-derived HCC.

Keywords: protein kinase C alpha, myeloid zinc finger 1, ets-like protein-1, hepatocellular carcinoma

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Authors: Nabila N. El-Maraghy, Amany Essa, Yousra Abdel–Mottaleb, Nada Ismail

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The use of combination of chemotherapy and natural products to influence the cell death with low doses of chemotherapeutic agents and few side effects has recently emerged as a new method of cancer therapy. Aim: Evaluation the modulatory effect of Thymoquinone on HepG2 cells treated with Sorafenib. Methods: Hepatocellular Carcinoma HepG2 cell line was treated with Sorafenib and TQ individually and in combination. The effect of these treatments on cell viability (MTT assay), apoptosis (Expression of Caspase-3) and oxidative markers (GSH content and extent of lipid peroxidation) was determined. Results: When compared the effect of both agents alone and the combination of the IC50 of Sorafenib and the IC50 TQ, the combination resulted in reduction of cell inhibition and apoptosis and antagonize their actions on GSH content and extent of lipid peroxidation which are increased. This study showed potent anti-tumor activity of both TQ and Sorafenib separately on HepG2 but upon combination surprisingly they interacted and give antagonistic effect. Conclusion: Co-treatment resulted in antagonistic interaction between Sorafenib and Thymoquinone.

Keywords: antagonism, hepatocellular carcinoma, sorafenib, thymoquinone

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Authors: Mohamed Abdel-Hamid, Olfat Gamil Shaker, Doha El-Sayed Ellakwa, Eman Fathy Abdel-Maksoud

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Introduction: Despite advances in the knowledge of the molecular virology of hepatitis C virus (HCV), the mechanisms of hepatocellular injury in HCV infection are not completely understood. Hepatitis C viral infection (HCV) influences the susceptibility to apoptosis. This could lead to insufficient antiviral immune response and persistent viral infection. Aim of this study: was to examine whether BCL-2 gene polymorphism at codon 43 (+127G/A or Ala43Thr) has an impact on development of hepatocellular carcinoma caused by chronic hepatitis C Egyptian patients. Subjects and Methods: The study included three groups; group 1: composing of 30 patients with hepatocellular carcinoma (HCC), group 2 composing of 30 patients with HCV, group 3 composing of 30 healthy subjects matching the same age and socioeconomic status were taken as a control group. Gene polymorphism of BCL2 (Ala43Thr) were evaluated by PCR-RFLP technique and measured for all patients and controls. Results: The summed 43Thr genotype was more frequent and statistically significant in HCC patients as compared to control group. This genotype of BCL2 gene may inhibit the programmed cell death which leads to disturbance in tissue and cells homeostasis and reduction in immune regulation. This result leads to viral replication and HCV persistence. Moreover, virus produces variety of mechanisms to block genes participated in apoptosis. This mechanism proves that HCV patients who have 43Thr genotype are more susceptible to HCC. Conclusion: The data suggest for the first time that the BCL2 polymorphism is associated with the susceptibility to HCC in Egyptian populations and might be used as molecular markers for evaluating HCC risk. This study clearly demonstrated that Chronic HCV exhibit a deregulation of apoptosis with the disease progression. This provides an insight into the pathogenesis of chronic HCV infection, and may contribute to the therapy.

Keywords: BCL2 gene, Hepatitis C Virus, Hepatocellular carcinoma, sensitivity, specificity, apoptosis

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Authors: Hongmeng Su, Luyu Zhao, Yanyan Qian, Hong Fan

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Aim: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors that endanger human health seriously. RNA methylation, especially N6-methyladenosine (m⁶A) and 5-methylcytosine (m⁵C), a crucial epigenetic transcriptional regulatory mechanism, plays an important role in tumorigenesis, progression and prognosis. This research aims to systematically evaluate the prognostic value of m⁶A and m⁵C modulators in HCC patients. Methods: Twenty-four modulators of m⁶A and m⁵C were candidates to analyze their expression level and their contribution to predict the prognosis of HCC. Consensus clustering analysis was applied to classify HCC patients. Cox and LASSO regression were used to construct the risk model. According to the risk score, HCC patients were divided into high-risk and low/medium-risk groups. The clinical pathology factors of HCC patients were analyzed by univariate and multivariate Cox regression analysis. Results: The HCC patients were classified into 2 clusters with significant differences in overall survival and clinical characteristics. Nine-gene risk model was constructed including METTL3, VIRMA, YTHDF1, YTHDF2, NOP2, NSUN4, NSUN5, DNMT3A and ALYREF. It was indicated that the risk score could serve as an independent prognostic factor for patients with HCC. Conclusion: This study constructed a Nine-gene risk model by modulators of m⁶A and m⁵C and investigated its effect on the clinical prognosis of HCC. This model may provide important consideration for the therapeutic strategy and prognosis evaluation analysis of patients with HCC.

Keywords: hepatocellular carcinoma, m⁶A, m⁵C, prognosis, RNA methylation

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Authors: Xiaoyuan Chen

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Background: This study aimed to characterize the epidemiological and clinical features of five rare subtypes of hepatocellular carcinoma (HCC) and to create a competing risk nomogram for predicting cancer-specific survival. Methods: This study used the Surveillance, Epidemiology, and End Results database to analyze the clinicopathological data of 50,218 patients with classic HCC and five rare subtypes (ICD-O-3 Histology Code=8170/3-8175/3) between 2004 and 2018. The annual percent change (APC) was calculated using Joinpoint regression, and a nomogram was developed based on multivariable competing risk survival analyses. The prognostic performance of the nomogram was evaluated using the Akaike information criterion, Bayesian information criterion, C-index, calibration curve, and area under the receiver operating characteristic curve. Decision curve analysis was used to assess the clinical value of the models. Results: The incidence of scirrhous carcinoma showed a decreasing trend (APC=-6.8%, P=0.025), while the morbidity of other rare subtypes remained stable from 2004 to 2018. The incidence-based mortality plateau in all subtypes during the period. Clear cell carcinoma was the most common subtype (n=551, 1.1%), followed by fibrolamellar (n=241, 0.5%), scirrhous (n=82, 0.2%), spindle cell (n=61, 0.1%), and pleomorphic (n=17, ~0%) carcinomas. Patients with fibrolamellar carcinoma were younger and more likely to have non-cirrhotic liver and better prognoses. Scirrhous carcinoma shared almost the same macro clinical characteristics and outcomes as classic HCC. Clear cell carcinoma tended to occur in the Asia-Pacific elderly male population, and more than half of them were large HCC (Size>5cm). Sarcomatoid (including spindle cell and pleomorphic) carcinoma was associated with larger tumor size, poorer differentiation, and more dismal prognoses. The pathological subtype, T stage, M stage, surgery, alpha-fetoprotein, and cancer history were identified as independent predictors in patients with rare subtypes. The nomogram showed good calibration, discrimination, and net benefits in clinical practice. Conclusion: The rare subtypes of HCC had distinct clinicopathological features and biological behaviors compared with classic HCC. Our findings could provide a valuable reference for clinicians. The constructed nomogram could accurately predict prognoses, which is beneficial for individualized management.

Keywords: hepatocellular carcinoma, pathological subtype, fibrolamellar carcinoma, scirrhous carcinoma, clear cell carcinoma, spindle cell carcinoma, pleomorphic carcinoma

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Authors: Imeobong Joseph Inyang, Aniekan-Augusta Okon Eyo, Abel William Essien

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Hepatitis B virus (HBV) is one of the known human carcinogens. The presence of HBsAg in liver tissues indicates active viral replication. More than 85% of Hepatocellular Carcinoma (HCC) cases occur in countries with increased rates of chronic HBV infection. An evaluation study to determine the relationship between positivity for HBsAg and development of HCC and its distribution between age and gender of subjects was done. Shikata Orcein and Haematoxylin and Eosin (H&E) staining techniques were performed on liver sections. A total of 50 liver tissue specimens comprising 38 biopsy and 12 post-mortem specimens were processed. Thirty-five of the 50 specimens were positive for HBsAg with Orcein stain whereas only 16 were positive with H&E stain, and these were also positive with Orcein stain, giving an HBsAg prevalence of 70.0% (35/50). The prevalence of HCC in the study was 56.0% (28/50), of which 21 (75.0%) cases were positive for HBsAg, 18 (64.3%) were males while 10 (35.7%) were females distributed within the age range of 20-70 years. The highest number of HBsAg positive HCC cases, 7/21 (33.3%) occurred in the age group 40-49 years. There was no relationship in the pattern of distribution of HCC between age and gender using the Pearson correlation coefficient (r = 0.0474; P < 0.05). HBV infection predisposed to HCC. Orcein technique was more specific and is therefore recommended for screening of liver tissues where facilities for immunohistochemistry are inaccessible.

Keywords: Hepatitis B. surface antigen, hepatocellular carcinoma, orcein, pathology

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Authors: Panadda Rojpibulstit, Suthathip Kittisenachai, Songchan Puthong, Sirikul Manochantr, Pornpen Gamnarai, Sasichai Kangsadalampai, Sittiruk Roytrakul

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Hepatocellular carcinoma (HCC) is the most primary hepatic cancer worldwide. Nowadays a targeted therapy via monoclonal antibodies (mAbs) specific to tumor-associated antigen is continually developed in HCC treatment. In this regard, after establishing and consequently exploring Hep88 mAb’s tumoricidal effect on hepatocellular carcinoma cell line (HepG2 cell line), the Hep88 mAb’s specific Ag from both membrane and cytoplasmic fractions of HepG2 cell line was identified by 2-D gel electrophoresis and western blot analysis. After in-gel digestion and subsequent analysis by liquid chromatography-mass spectrometry (LC-MS), mortalin (HSPA9) and alpha-enolase were identified. The recombinant proteins specific to Hep88 mAb were cloned and expressed in E.coli BL21 (DE3). Moreover, alteration of HepG2 and Chang liver cell line after being induced by Hep88 mAb for 1-3 days was investigated using a transmission electron microscope. The result demonstrated that Hep88 mAb can bind to the recombinant mortalin (HSPA9) andalpha-enolase. In addition, gradual appearance of mitochondria vacuolization and endoplasmic reticulum dilatation were observed. Taken together, paraptosis-like programmed cell death (PCD) of HepG2 is induced by binding of mortalin (HSPA9) and alpha-enolase to Hep88 mAb. Mortalin depletion by formation of Hep88 mAb-mortalin (HSPA9) complex might initiate transcription-independent of p53-mediated apoptosis. Additionally, Hep88 mAb-alpha-enolase complex might initiate HepG2 cells energy exhaustion by glycolysis pathway obstruction. These results imply that Hep88 mAb might be a promising tool for development of an effective treatment of HCC in the next decade.

Keywords: Hepatocellular carcinoma, Monoclonal antibody, Paraptosis-like program cell death, Transmission electron microscopy, mortalin (HSPA9), alpha-enolase

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Authors: Sagri Sharma

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Analysis of diseases integrating multi-factors increases the complexity of the problem and therefore, development of frameworks for the analysis of diseases is an issue that is currently a topic of intense research. Due to the inter-dependence of the various parameters, the use of traditional methodologies has not been very effective. Consequently, newer methodologies are being sought to deal with the problem. Supervised Learning Algorithms are commonly used for performing the prediction on previously unseen data. These algorithms are commonly used for applications in fields ranging from image analysis to protein structure and function prediction and they get trained using a known dataset to come up with a predictor model that generates reasonable predictions for the response to new data. Gene expression profiles generated by DNA analysis experiments can be quite complex since these experiments can involve hypotheses involving entire genomes. The application of well-known machine learning algorithm - Support Vector Machine - to analyze the expression levels of thousands of genes simultaneously in a timely, automated and cost effective way is thus used. The objectives to undertake the presented work are development of a methodology to identify genes relevant to Hepatocellular Carcinoma (HCC) from gene expression dataset utilizing supervised learning algorithms and statistical evaluations along with development of a predictive framework that can perform classification tasks on new, unseen data.

Keywords: artificial intelligence, biomarker, gene expression datasets, hepatocellular carcinoma, machine learning, supervised learning algorithms, support vector machine

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Authors: Peri Harish Kumar, Sai Sharan Dwarka, Tajbinder Singh Bains, Suneet John Joseph, Chaitanya Kiran, Sambhu Dutta, Sarah Makram, Mohamed Sayed Zaazouee, Alaa Ahmed Elshanbary

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Objective: To identify cancer and non-cancer causes of death in hepatocellular carcinoma (HCC) patients over different time periods after diagnosis and to compare the mortality risk of each cause in HCC patients with the general population. Methods: In this retrospective cohort study, data of 67,637 HCC patients from 1975 to 2016 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. We investigated the association between different causes of death and the following variables: age, race, tumor stage at diagnosis, and treatment (surgery, chemotherapy, and radiotherapy); each according to the periods of <1 year, 1-5 years, 5-10 years, and >10 years following the diagnosis. Standardized mortality ratios (SMRs) and their 95% confidence intervals (CIs) were calculated for cancer and non-cancer deaths in each of the mentioned periods following diagnosis. Results: Data of 67,637 patients, of whom 50,571 patients died during the follow-up period, were analyzed. Most deaths were due to HCC itself (35,535, 70.3%), followed by other cancers (3,983, 7.9%). Common causes of non-cancer mortality included infectious and parasitic diseases including HIV (2,823 patients, SMR=105.68, 95% CI: 101.82-109.65), chronic liver disease (2,719 patients, SMR=76.56, 95% CI: 73.71,79.5), and heart diseases (1,265 patients, SMR=2.26, 95% CI: 2.14-2.39), with higher mortality risk in HCC patients than in the general population. Conclusion: Cancers stand for most deaths in patients with HCC. Besides, infectious, and parasitic diseases including HIV represent the commonest non-cancer cause of mortality.

Keywords: hepatocellular carcinoma, seer, causes of death, mortality

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Authors: Doaa Hashad, Amany Elyamany, Perihan Salem

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Introduction: Hepatitis C virus infection (HCV) constitutes a serious dilemma that has an impact on the health of millions of Egyptians. Hepatitis C virus related hepatocellular carcinoma (HCV-HCC) is a crucial consequence of HCV that represents the third cause of cancer-related deaths worldwide. Aim of the study: assess the use of mitochondrial DNA (mtDNA) content as a non-invasive molecular biomarker in hepatitis c virus related hepatocellular carcinoma (HCV-HCC). Methods: A total of 135 participants were enrolled in the study. Volunteers were assigned to one of three groups equally; a group of HCV related cirrhosis (HCV-cirrhosis), a group of HCV-HCC and a control group of age- and sex- matched healthy volunteers with no evidence of liver disease. mtDNA was determined using a quantitative real-time PCR technique. Results: mtDNA content was lowest in HCV-HCC cases. No statistically significant difference was observed between the group of HCV-cirrhosis and the control group as regards mtDNA level. HCC patients with multi-centric hepatic lesions had significantly lower mtDNA content. On using receiver operating characteristic curve analysis, a cutoff of 34 was assigned for mtDNA content to distinguish between HCV-HCC and HCV-cirrhosis patients who are not yet complicated by malignancy. Lower mtDNA was associated with greater HCC risk on using healthy controls, HCV-cirrhosis, or combining both groups as a reference group. Conclusions: mtDNA content might constitute a non-invasive molecular biomarker that reflects tumor burden in HCV-HCC cases and could be used as a predictor of HCC risk in patients of HCV-cirrhosis. In addition, the non significant difference of mtDNA level between HCV-cirrhosis patients and healthy controls could eliminate the grey zone created by the use of AFP in some cirrhotic patients.

Keywords: DNA copy number, HCC, HCV, mitochondrial

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Authors: Shan-Ying Wu, Sheng-Hui Lan, Xi-Zhang Lin, Ih-Jen Su, Ting-Fen Tsai, Chia-Jui Yen, Tsung-Hsueh Lu, Fu-Wen Liang, Huey-Jen Su, Chun-Li Su, Hsiao-Sheng Liu

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In hepatocelluar carcinoma (HCC), dysregulated expression of cyclin D1 and impaired autophagy has been reported separately. However, the relationship between them has not been explored. In this study, we demonstrated that autophagy was inversely correlated with cyclin D1 expression in 147 paired HCC patient specimens. HCC specimen with highly expression of cyclin D1 shows correlation with poor overall survival rate. Furthermore, induction of autophagy by amiodarone (antiarrhythmic drug) in Hep 3B cells, cyclin D1 was recruited into autophagosomes demonstrated by immune-gold labeling of cyclin D1 after extraction of autophagosomes. We further demonstrated that autophagy suppresses Hep 3B cell proliferation, and further analysis revealed that cell cycle was arrested at G1 phase. The interaction between LC3 (maker of autophagy) and cyclin D1 was increased after autophagy induction. In addition, ubiquitinated-cyclin D1 was also increased after autophagy induction, which is selectively degraded by autophagosome through binding with SQSTM1/p62 (an adaptor protein). In vivo study showed that amiodarone induced autophagy suppresses liver tumor formation in xenograft mouse and orthotopic rat model through decreasing cyclin D1 expression and inhibition of cell proliferation. Altogether, we reveal a novel mechanism that ubiquitinated cyclin D1 degraded by autophagic pathway by p62 and amiodarone is a promising drug for targeting cyclin D1 in liver cancer therapy.

Keywords: autophagy, cyclin D1, hepatocellular carcinoma, amiodarone

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Authors: Ali Kassem, Aly Taha, Abeer Hassan, Kazuhide Higuchi

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Introduction: Trans arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) is usually followed by hepatic dysfunction that limits its efficacy. L-carnitine is recently studied as hepatoprotective agent. Our aim is to evaluate the L-carnitine effects against the deterioration of liver functions after TACE. Method: 53 patients with intermediate stage HCC were assigned into two groups; L-carnitine group (26 patients) who received L-carnitine 300 mg tablet twice daily from 2 weeks before to 12 weeks after TACE and control group (27 patients) without L-carnitine therapy. 28 of studied patients received branched chain amino acids granules. Results: There were significant differences between L-carnitine Vs. control group in mean serum albumin change from baseline to 1 week and 4 weeks after TACE (p < 0.05). L-Carnitine maintained Child-Pugh score at 1 week after TACE and exhibited improvement at 4 weeks after TACE (p < 0.01 Vs 1 week after TACE). Control group has significant Child-Pugh score deterioration from baseline to 1 week after TACE (p < 0.05) and 12 weeks after TACE (p < 0.05). There were significant differences between L-carnitine and control groups in mean Child-Pugh score change from baseline to 4 weeks (p < 0.05) and 12 weeks after TACE (p < 0.05). L-carnitine displayed improvement in (PT) from baseline to 1 week, 4 w (p < 0.05) and 12 weeks after TACE. PT in control group declined less than baseline along all follow up intervals. Total bilirubin in L-carnitine group decreased at 1 week post TACE while in control group, it significantly increased at 1 week (p = 0.01). ALT and C-reactive protein elevation were suppressed at 1 week after TACE in Lcarnitine group. The hepatoprotective effects of L-carnitine were enhanced by concomitant use of branched chain amino acids. Conclusion: L-carnitine and BCAA combination therapy offer a novel supportive strategy after TACE in HCC patients.

Keywords: hepatocellular carcinoma, L-carnitine, liver functions , trans-arterial embolization

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Authors: Fangtian Fan, Zhaoguo Liu, Yin Lu

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Early recurrence (ER) (< 1 year) after liver resection is one of the most important factors that impacts the prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms and predictive indexes of ER after curative resection remain largely unknown. The present study aimed to exploit the role of EGFR signaling in EMT and early recurrence of HCC after curative resection and elucidate the molecular mechanisms. Our results showed that nuclear beta-catenin / PKM2 was a independent predictor of early recurrence after curative resection in EGFR-overexpressed HCC. Mechanistic investigation indicated that nuclear accumulation of beta-catenin and PKM2 induced by EGFR signal promoted HCC cell invasion and proliferation, which were required for early recurrence of HCC. These effects were mediated by PI3K/AKT and ERK pathways rather than the canonical Wnt signaling. In conclusions, EGFR signal induced-nuclear translocation of beta-catenin and PKM2 promotes HCC malignancy and indicates early recurrence after curative resection.

Keywords: beta-catenin, early recurrence, hepatocellular carcinoma, malignancy, PKM2

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Authors: Bui Phuong Linh, Yuki Sakakibara, Ryuto Tanaka, Elizabeth H. Pigney, Taishi Hashiguchi

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Non-alcoholic steatohepatitis (NASH) is a chronic liver disease, often associated with type II diabetes, which sometimes progresses to more serious conditions such as liver fibrosis and hepatocellular carcinoma (HCC). NASH has become an important health problem worldwide, buttherapeutic agents for NASH have not yet been approved, and animal models with high clinical correlation are required. TheSTAM™ mouse shows the same pathological progression as human NASH patients and has been widely used for both drug efficacy and basic research, such as lipid profiling and gut microbiota research. In this study, we analyzed the RNA-seq data of STAM™mice at each pathological stage (steatosis, steatohepatitis, liver fibrosis, and HCC) and examined the clinical correlation at the genetic level. NASH was induced in male mice by a single subcutaneous injection of 200 µg streptozotocin solution 2 days after birth and feeding with high fat dietafter 4 weeks of age. The mice were sacrificed and livers collected at 6, 8, 10, 12, 16, and 20 weeks of age. For liver samples, the left lateral lobe was snap frozen in liquid nitrogen and stored at -80˚C for RNA-seq analysis. Total RNA of the cells was isolated using RNeasy mini kit. The gene expression of the canonical pathways in NASH progression from steatosis to hepatocellular carcinoma were analyzed, such as immune system process, oxidation-reduction process, lipid metabolic process. Moreover, since it has been reported that genetic traits are involved in the development of NASH-HCC, we next analyzed the genetic mutations in the STAM™mice. The number of individuals showing mutations in Mtorinvolved in Insulin signaling increases as the disease progresses, especially in the liver cancer phase. These results indicated a clinical correlation of gene profiles in the STAM™mouse.

Keywords: steatosis, non-alcoholic steatohepatitis, fibrosis, hepatocellular carcinoma, RNA-seq

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Authors: Shu-Jun Li, Cheng-Cao Sun, De-Jia Li

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Recently, long noncoding RNAs (lncRNAs) have been emerged as crucial regulators of human diseases and prognostic markers in numerous of cancers, including colorectal carcinoma (CRC). Here, we identified an oncogenetic lncRNA HULC, which may promote colorectal tumorigenesis. HULC has been found to be up-regulated and acts as oncogene in gastric cancer and hepatocellular carcinoma, but its expression pattern, biological function and underlying mechanism in CRC is still undetermined. Here, we reported that HULC expression is also over-expressed in CRC, and its increased level is associated with poor prognosis and shorter survival. Knockdown of HULC impaired CRC cells proliferation, migration and invasion, facilitated cell apoptosis in vitro, and inhibited tumorigenicity of CRC cells in vivo. Mechanistically, RNA immunoprecipitation (RIP) and RNA pull-down experiment demonstrated that HULC could simultaneously interact with EZH2 to repress underlying targets NKD2 transcription. In addition, rescue experiments determined that HULC oncogenic function is partly dependent on repressing NKD2. Taken together, our findings expound how HULC over-expression endows an oncogenic function in CRC.

Keywords: long noncoding RNA, HULC, NKD2, colorectal carcinoma, proliferation, apoptosis

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Authors: Bhushan Bhalgat, Suresh Singh, Phanindra Swain, Kamal Kishore Lakhera

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Carcinoma of cervix and carcinoma of vulva have been associated with common predisposing factors like human papillomavirus and smoking. Skip metastases and metachronous appearance of both these tumours have been reported. There is no case report showing synchronous appearance of these tumours in English literature. We herewith report a case report of a middle aged female patient who presented with per vaginal bleeding, and on examination, a cervical mass was palpable. Also, a proliferative growth was seen over her left vulva. Biopsy of both lesions came out to be squamous cell carcinoma and carcinoma in situ, respectively. A radical hysterectomy and bilateral pelvic and paraaortic lymph nodal dissection was performed along with left simple vulvectomy. This thereby underscores that any lesion over vulva appearing during or after treatment of cervical carcinoma should be biopsied to rule out vulvar carcinoma.

Keywords: carcinoma of cervix, carcinoma of vulva, synchronous tumours, gynecological oncology

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Authors: Maha Soltan, Amal Z. Hassan, Howaida I. Abd-Alla, Atef G. Hanna

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Two naturally known cardenolides; acovenoside A and acobioside A were isolated from the Egyptian cultivar; Acokanthera spectabilis leaves. It is an ornamental and poisonous plant that has been traditionally claimed for their medicinal properties against infectious microbes, killing worms and curing some inflammations at little amounts. We examined the growth inhibition effects of both cardenolides against four types of human cancer cell lines using Sulphorhodamine B assay. In addition, the clonogenic assay was also performed for testing the growth inhibiting power of the isolated compounds. An in vitro mechanistic investigation was further accomplished against hepatocellular carcinoma HepG2 cell line. Microscopic examination, colorimetric ELISA and flow cytometry techniques were our tools of proving at least part of the anticancer pathway of the tested compounds. Both compounds were able to inhibit the growth of 4 human cancer cell lines at less than 100 nM. In addition, they were able to activate the executioner Caspase-3 and apoptosis was then induced as a consequence of cell growth arrest at G2/M. An attention must be payed to those bioactive agents particularly when giving their activity against cancer cells at considerable small values while presenting safe therapeutic margins as indicated by literature.

Keywords: anticancer, cardenolides, Caspase-3, apoptosis

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Authors: Pelin Balcik Ercin

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Introduction: ZEB transcription factor family member ZEB2, has a role in epithelial to mesenchymal transition during development and metastasis. The altered circulating extracellular miRNAs expression is observed in diseases, and extracellular miRNAs have an important role in cancer cell microenvironment. In ChIP-Seq study, the expression of miR-2110 was found to be regulated by ZEB2. In this study, the effects of miR2110 on cell proliferation and migration of hepatocellular carcinoma (HCC) cells were examined. Material and Methods: SNU398 cells transfected with mimic miR2110 (20nM) (HMI0375, Sigma-Aldrich) and negative control miR (HMC0002, Sigma-Aldrich). MicroRNA isolation was accomplished with miRVANA isolation kit according to manufacturer instructions. cDNA synthesis was performed expression, respectively, and calibrated with Ct of controls. The real-time quantitative PCR (RT-qPCR) reaction was performed using the TaqMan Fast Advanced Master Mix (Thermo Sci.). Ct values of miR2110 were normalized to miR-186-5p and miR16-5p for the intracellular gene. Cell proliferation analysis was analyzed with the xCELLigence RTCA System. Wound healing assay was analyzed with the ImageJ program and relative fold change calculated. Results: The mimic-miR-2110 transfected SNU398 cells nearly nine-fold (log2) more miR-2110 expressed compared to negative control transfected cells. The mimic-miR-2110 transfected HCC cell proliferation significantly inhibited compared to the negative control cells. Furthermore, miR-2110-SNU398 cell migration capacity was relatively four-fold decreased compared to negative control-miR-SNU398 cells. Conclusion: Our results suggest the miR-2110 inhibited cell proliferation and also miR-2110 negatively affect cell migration compared to control groups in HCC cells. These data suggest the complexity of microRNA EMT transcription factors regulation. These initial results are pointed out the predictive biomarker capacity of miR-2110 in HCC.

Keywords: epithelial to mesenchymal transition, EMT, hepatocellular carcinoma cells, micro-RNA-2110, ZEB2

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Authors: Sila Akhan, Muge Toygar, Murat Sayan, Simge Fidan

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Chronic viral hepatitis B, C, and D can cause hepatocellular carcinoma (HCC), cirrhosis and death. The proper treatment reduce the risk of development of HCC importantly, but not to zero point. Materials and Methods: We analysed retrospectively our chronic viral hepatitis B, C and D patients who attended to our Infectious Diseases policlinic between 2004-2018. From 589 biopsy-proven chronic hepatitis patients 3 have hepatocellular carcinoma on our follow up. First case is 74 years old patient. His HCV infection diagnosis was made 8 years ago. First treatment was pegylated interferon plus ribavirin only 28 weeks, because of HCV RNA breakthrough under treatment. In 2013 he was retreated with telaprevir, pegylated interferon plus ribavirin 24 weeks. But at the end of the therapy HCV RNA was found 1.290.000 IU/mL. He has abdominal ultrasonography (US) controls and alpha-fetoprotein (AFP) at 6 months intervals. All seemed normal until 2015 then he has an abdominal magnetic resonance imaging (MRI) and found HCC by chance. His treatment began in Oncology Clinic after verified with biopsy of HCC. And then sofosbuvir/ledipasvir was given to him for HCV 24 weeks. Sustained virologic response (SVR) was obtained. He is on cure for HCV infection and under control of Oncology for HCC. Second patient is 36 years old man. He knows his HBV infection since 2008. HBsAg and HBeAg positive; HDV RNA negative. Liver biopsy revealed grade:4, stage 3-4 according modified Knodell scoring system. In 2010 tenofovir treatment was began. His abdominal US and AFP were normal. His controls took place at 6 months intervals and HBV DNA negative, US, and AFP were normal until 2016 continuously. AFP found 37 above the normal range and then HCC was found in MRI. Third patient is 57 years old man. As hepatitis B infection was first diagnosed; he has cirrhosis and was began tenofovir as treatment. In short time he has HCC despite normal AFP values. Conclusion: In Mediterranian countries including Turkey naturally occurring pre-S/S variants are more than 75% of all chronic hepatitis B patients. This variants may contribute to the development of progressive liver damage and hepatocarcinogenesis. HCV-induced development of HCC is a gradual process and is affected by the duration of disease and viral genotype. All the chronic viral hepatitis patients should be followed up in 6 months intervals not only with US and AFP for HCC. Despite they have proper treatment there is always the risk development of HCC. Chronic hepatitis patients cannot be dropped from follow up even treated well.

Keywords: HCC, HCV, HBV, DAA

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Authors: Hanan M. Hassan, Laila Abouzeid, Lamya H. Al-Wahaibi, George S. G. Shehatou, Ali A. El-Emam

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Cancer is a major public health problem and the second leading cause of death worldwide. In 2020, cancer diagnosis and treatment have been negatively affected by the coronavirus 2019 (COVID-19) pandemic. During the quarantine, because of the limited access to healthcare and avoiding exposure to COVID-19 as a contagious disease; patients of cancer suffered deferments in follow-up and treatment regimens leading to substantial worsening of disease, death, and increased healthcare costs. Thus, this study is designed to investigate the molecular mechanisms by which adamantne derivatives attenuate hepatocllular carcinoma experimentally and theoretically. There is a close association between increased resistance to anticancer drugs and defective apoptosis that considered a causative factor for oncogenesis. Cancer cells use different molecular pathways to inhibit apoptosis, BAX and Bcl-2 proteins have essential roles in the progression or inhibition of intrinsic apoptotic pathways triggered by mitochondrial dysfunction. Therefore, their balance ratio can promote the cellular apoptotic fate. In this study, the in vitro cytotoxic effects of seven synthetic adamantyl isothiorea derivatives were evaluated against five human tumor cell lines by MTT assay. Compounds 5 and 6 showed the best results, mostly against hepatocellular carcinoma (HCC). Hence, in vivo studies were performed in male Sprague-Dawley (SD) rats in which experimental hepatocellular carcinoma was induced with thioacetamide (TAA) (200 mg/kg, i.p., twice weekly) for 16 weeks. The most promising compounds, 5 and 6, were administered to treat liver cancer rats at a dose of 10 mg/kg/day for an additional two weeks, and the effects were compared with doxorubicin (DR), the anticancer drug. Hepatocellular carcinoma was evidenced by a dramatic increase in liver indices, oxidative stress markers, and immunohistochemical studies that were accompanied by a plethora of inflammatory mediators and alterations in the apoptotic cascade. Our results showed that treatment with adamantane derivatives 5 and 6 significantly suppressed fibrosis, inflammation, and other histopathological insults resulting in the diminished formation of hepatocyte tumorigenesis. Moreover, administration of the tested compounds resulted in amelioration of EGFR protein expression, upregulation of BAX, and lessening down of Bcl-2 levels that prove their role as apoptosis inducers. Also, the docking simulations performed for adamantane showed good fit and binding to the EGFR protein through hydrogen bond formation with conservative amino acids, which gives a shred of strong evidence for its hepatoprotective effect. In most analyses, the effects of compound 6 were more comparable to DR than compound 5. Our findings suggest that adamantane derivatives 5 and 6 are shown to have cytotoxic activity against HCC in vitro and in vivo, by more than one mechanism, possibly by inhibiting the TLR4-MyD88-NF-κB pathway and targeting EGFR signaling.

Keywords: adamantane, EGFR, HCC, apoptosis

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Authors: Umme Shahera, Saifullah Munshi, Munira Jahan, Afzalun Nessa, Shahinul Alam, Shahina Tabassum

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The development of HCC is a multi-stage process. Several extrinsic factors, such as aflatoxin, HBV, nutrition, alcohol, and trace elements are thought to initiate or/and promote the hepatocarcinogenesis. Alteration of p53 status is an important intrinsic factor in this process as p53 is essential for preventing inappropriate cell proliferation and maintaining genome integrity following genotoxic stress. This study was designed to assess the correlation of p53 gene expression with HBV-DNA and serum Alanine transaminase (ALT) in patients with cirrhosis and HCC. The study was conducted among 60 patients. The study population were divided into four groups (15 in each groups)-HBV positive cirrhosis, HBV negative cirrhosis, HBV positive HCC and HBV negative HCC. Expression of p53 gene was observed using real time PCR. P53 gene expressions in the above mentioned groups were correlated with serum ALT level and HBV viral load. p53 gene was significantly higher in HBV-positive patients with HCC than HBV-positive cirrhosis. Similarly, the expression of p53 was significantly higher in HBV-positive HCC than HBV-negative HCC patients. However, the expression of p53 was reduced in HBV-positive cirrhosis in comparison with HBV-negative cirrhosis. P53 gene expression in liver was not correlated with the serum levels of ALT in any of the study groups. HBV- DNA load also did not correlated with p53 gene expression in HBV positive HCC and HBV positive cirrhosis patients. This study shows that there was no significant change with the expression of p53 gene in any of the study groups with ALT level or viral load, though differential expression of p53 gene were observed in cirrhosis and HCC patients.

Keywords: P53, ALT, HBV-DNA, liver cirrhosis, hepatocellular carcinoma

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Authors: Chang Liang, Weizhi Gong, Yan Zhang

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Purpose: Hepatocellular carcinoma (HCC) is a malignant tumor with a high mortality rate and poor prognosis worldwide. Murine double minute 2 (MDM2) regulates the tumor suppressor p53, increasing cancer risk and accelerating tumor progression. Speckle-type POX virus and zinc finger protein (SPOP), a key of subunit of Cullin-Ring E3 ligase, inhibits tumor genesis and progression by the ubiquitination of its downstream substrates. This study aimed to clarify whether SPOP and MDM2 are mutually regulated in HCC and the correlation between SPOP and MDM2 and the prognosis of HCC patients. Methods: First, the expression of SPOP and MDM2 in HCC tissues were detected by TCGA database. Then, 53 paired samples of HCC tumor and adjacent tissues were collected to evaluate the expression of SPOP and MDM2 using immunohistochemistry. Chi-square test or Fisher’s exact test were used to analyze the relationship between clinicopathological features and the expression levels of SPOP and MDM2. In addition, Kaplan‒Meier curve analysis and log-rank test were used to investigate the effects of SPOP and MDM2 on the survival of HCC patients. Last, the Multivariate Cox proportional risk regression model analyzed whether the different expression levels of SPOP and MDM2 were independent risk factors for the prognosis of HCC patients. Results: Bioinformatics analysis revealed the low expression of SPOP and high expression of MDM2 were related to worse prognosis of HCC patients. The relationship between the expression of SPOP and MDM2 and tumor stem-like features showed an opposite trend. The immunohistochemistry showed the expression of SPOP protein was significantly downregulated while MDM2 protein significantly upregulated in HCC tissue compared to that in para-cancerous tissue. Tumors with low SPOP expression were related to worse T stage and Barcelona Clinic Liver Cancer (BCLC) stage, but tumors with high MDM2 expression were related to worse T stage, M stage, and BCLC stage. Kaplan–Meier curves showed HCC patients with high SPOP expression and low MDM2 expression had better survival than those with low SPOP expression and high MDM2 expression (P < 0.05). A multivariate Cox proportional risk regression model confirmed that a high MDM2 expression level was an independent risk factor for poor prognosis in HCC patients (P <0.05). Conclusion: The expression of SPOP protein was significantly downregulated, while the expression of MDM2 significantly upregulated in HCC. The low expression of SPOP and high expression. of MDM2 were associated with malignant progression and poor prognosis of HCC patients, indicating a potential therapeutic target for HCC patients.

Keywords: hepatocellular carcinoma, murine double minute 2, speckle-type POX virus and zinc finger protein, ubiquitination

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Authors: Lucian Mocan

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We present method of Nanoparticle enhanced laser thermal ablation of HepG2 cells (Human hepatocellular liver carcinomacell line), using gold nanoparticles combuned with a specific growth factor and demonstrate its selective therapeutic efficacy usig ex vivo specimens. Ex vivo-perfused liver specimens were obtained from hepatocellular carcinoma patients similarly to the surgical technique of transplantation. Ab bound to GNPs was inoculated intra-arterially onto the resulting specimen and determined the specific delivery of the nano-bioconjugate into the malignant tissue by means of the capillary bed. The extent of necrosis was considerable following laser therapy and at the same time surrounding parenchyma was not seriously affected. The selective photothermal ablation of the malignant liver tissue was obtained after the selective accumulation of Ab bound to GNPs into tumor cells following ex-vivo intravascular perfusion. These unique results may represent a major step in liver cancer treatment using nanolocalized thermal ablation by laser heating.

Keywords: HepG2 cells, gold nanoparticles, nanoparticle functionalization, laser irradiation

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Authors: Lena Lapidot, Amir Amnon, Rita Nosenko, Veitsman Ella, Cohen-Ezra Oranit, Davidov Yana, Segev Shlomo, Koren Omry, Safran Michal, Ben-Ari Ziv

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Introduction: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related mortality worldwide. Liver Cirrhosis is the main predisposing risk factor for the development of HCC. The factor(s) influencing disease progression from Cirrhosis to HCC remain unknown. Gut microbiota has recently emerged as a major player in different liver diseases, however its association with HCC is still a mystery. Moreover, there might be an important association between the gut microbiota, nutrition, life style and the progression of Cirrhosis and HCC. The aim of our study was to characterize the gut microbial signature in association with life style and nutrition of patients with Cirrhosis, HCC-Cirrhosis and healthy controls. Design: Stool samples were collected from 95 individuals (30 patients with HCC, 38 patients with Cirrhosis and 27 age, gender and BMI-matched healthy volunteers). All participants answered lifestyle and Food Frequency Questionnaires. 16S rRNA sequencing of fecal DNA was performed (MiSeq Illumina). Results: There was a significant decrease in alpha diversity in patients with Cirrhosis (qvalue=0.033) and in patients with HCC-Cirrhosis (qvalue=0.032) compared to healthy controls. The microbiota of patients with HCC-cirrhosis compared to patients with Cirrhosis, was characterized by a significant overrepresentation of Clostridium (pvalue=0.024) and CF231 (pvalue=0.010) and lower expression of Alphaproteobacteria (pvalue=0.039) and Verrucomicrobia (pvalue=0.036) in several taxonomic levels: Verrucomicrobiae, Verrucomicrobiales, Verrucomicrobiaceae and the genus Akkermansia (pvalue=0.039). Furthermore, we performed an analysis of predicted metabolic pathways (Kegg level 2) that resulted in a significant decrease in the diversity of metabolic pathways in patients with HCC-Cirrhosis (qvalue=0.015) compared to controls, one of which was amino acid metabolism. Furthermore, investigating the life style and nutrition habits of patients with HCC-Cirrhosis, we found significant correlations between intake of artificial sweeteners and Verrucomicrobia (qvalue=0.12), High sugar intake and Synergistetes (qvalue=0.021) and High BMI and the pathogen Campylobacter (qvalue=0.066). Furthermore, overweight in patients with HCC-Cirrhosis modified bacterial diversity (qvalue=0.023) and composition (qvalue=0.033). Conclusions: To the best of the our knowledge, we present the first report of the gut microbial composition in patients with HCC-Cirrhosis, compared with Cirrhotic patients and healthy controls. We have demonstrated in our study that there are significant differences in the gut microbiome of patients with HCC-cirrhosis compared to Cirrhotic patients and healthy controls. Our findings are even more pronounced because the significantly increased bacteria Clostridium and CF231 in HCC-Cirrhosis weren't influenced by diet and lifestyle, implying this change is due to the development of HCC. Further studies are needed to confirm these findings and assess causality.

Keywords: Cirrhosis, Hepatocellular carcinoma, life style, liver disease, microbiome, nutrition

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Authors: Suang K. Lau, Ismail Goolam, Rafid Al-Asady

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Background: The majority of patients with hepatocellular carcinoma (HCC) are not suitable for curative treatment, in the form of surgical resection or transplantation, due to tumour extent and underlying liver dysfunction. In these non-resectable cases, a variety of non-surgical therapies are available, including microwave ablation (MWA), which has shown increasing popularity due to its low morbidity, low reported complication rate, and the ability to perform multiple ablations simultaneously. Objective: The aim of this study was to evaluate the validity of MWA as a viable treatment option in the management of HCC and hepatic metastatic disease, by assessing its efficacy and complication rate at a tertiary hospital situated in Westmead (Australia). Methods: A retrospective observational study was performed evaluating patients that underwent MWA between 1/1/2017–31/12/2018 at Westmead Hospital, NSW, Australia. Outcome measures, including residual disease, recurrence rates, as well as major and minor complication rates, were retrospectively analysed over a 12-months period following MWA treatment. Excluded patients included those whose lesions were treated on the basis of residual or recurrent disease from previous treatment, which occurred prior to the study window (11 patients) and those who were lost to follow up (2 patients). Results: Following treatment of 106 new hepatic lesions, the complete response rate (CR) was 86% (91/106) at 12 months follow up. 10 patients had the residual disease at post-treatment follow up imaging, corresponding to an incomplete response (ICR) rate of 9.4% (10/106). The local recurrence rate (LRR) was 4.6% (5/106) with follow-up period up to 12 months. The minor complication rate was 9.4% (10/106) including asymptomatic pneumothorax (n=2), asymptomatic pleural effusions (n=2), right lower lobe pneumonia (n=3), pain requiring admission (n=1), hypotension (n=1), cellulitis (n=1) and intraparenchymal hematoma (n=1). There was 1 major complication reported, with pleuro-peritoneal fistula causing recurrent large pleural effusion necessitating repeated thoracocentesis (n=1). There was no statistically significant association between tumour size, location or ablation factors, and risk of recurrence or residual disease. A subset analysis identified 6 segment VIII lesions, which were treated via a trans-pleural approach. This cohort demonstrated an overall complication rate of 33% (2/6), including 1 minor complication of asymptomatic pneumothorax and 1 major complication of pleuro-peritoneal fistula. Conclusions: Microwave ablation therapy is an effective and safe treatment option in cases of non-resectable hepatocellular carcinoma and liver metastases, with good local tumour control and low complication rates. A trans-pleural approach for high segment VIII lesions is associated with a higher complication rate and warrants greater caution.

Keywords: hepatocellular carcinoma, liver metastases, microwave ablation, trans-pleural approach

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Authors: Xinxiu Li, Chuqian Zheng, Yanyan Qian, Hong Fan

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Objectives: In hepatocellular carcinoma (HCC), oncogenes are continuously and robustly transcribed due to aberrant expression of essential components of the trans-acting super-enhancers (SE) complex. Preclinical and clinical trials are now being conducted on small-molecule inhibitors that target core-transcriptional components, including as transcriptional bromodomain protein 4 (BRD4) and cyclin-dependent kinase 7 (CDK7), in a number of malignant tumors. This study aims to explore whether co-overexpression of BRD4 and CDK7 is a potential marker of worse prognosis and a combined therapeutic target in HCC. Methods: The expression pattern of BRD4 and CDK7 and their correlation with prognosis in HCC were analyzed by RNA sequencing data and survival data of HCC patients from TCGA and GEO datasets. The protein levels of BRD4 and CDK7 were determined by immunohistochemistry (IHC), and survival data of patients were analyzed using the Kaplan-Meier method. The mRNA expression levels of genes in HCC cell lines were evaluated by quantitative PCR (q-PCR). CCK-8 and colony formation assays were conducted to assess cell proliferation of HCC upon treatment with BRD4 inhibitor JQ1 or/and CDK7 inhibitor THZ1. Results: It was shown that BRD4 and CDK7 were often overexpressed in HCCs and were associated with poor prognosis of HCC by analyzing the TCGA and GEO datasets. BRD4 or CDK7 overexpression was related to a lower survival rate. It's interesting to note that co-overexpression of CDK7 and BRD4 was a worse prognostic factor in HCC. Treatment with JQ1 or THZ1 alone had an inhibitory effect on cell proliferation; however, when JQ1 and THZ1 were combined, there was a more notable suppression of cell growth. At the same time, the combined use of JQ1 and THZ1 synergistically suppresses the expression of HCC driver genes. Conclusion: Our research revealed that BRD4 and CDK7 coupled can be a useful biomarker in HCC prognosis and the combination of JQ1 and THZ1 can be a promising therapeutic therapy against HCC.

Keywords: BRD4, CDK7, cell proliferation, combined inhibition

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