AFP Level Research Articles

Effect of Radiofrequency Ablation with Interventional Therapy of Hepatic Artery on the Recurrence of Primary Liver Cancer and the Analysis of Influencing Factors.

Background The probability of liver cancer recurring in patients after surgery is a serious threat to liver cancer patients. Radiofrequency ablation is widely employed in liver cancer cases. We explored the therapeutic effects and influencing factors of radiofrequency ablation combined with hepatic artery intervention in patients with recurrence of primary liver cancer surgery. Methods 90 patients with primary liver cancer postoperative recurrence admitted to our hospital from January 2014 to February 2017 were selected as the research objects. The patients were randomly divided into the control group (n = 45) and combined treatment group (n = 45). The combined treatment group received radiofrequency ablation combined with hepatic artery interventional therapy, and the control group received hepatic artery interventional therapy. The short-term efficacy, AFP levels before and after treatment, and long-term survival results of the two groups were compared. Single-factor and multifactor analyses of the clinical information of the combined treatment group were carried out to find out the factors affecting the therapeutic effect of radiofrequency ablation combined with hepatic artery intervention on patients with recurrence of primary liver cancer. Results The total effective rate of short-term curative effect of the combined treatment group was higher than the control group, and there was a statistically significant difference existing (P < 0.05). After treatment, two groups of patients' AFP levels were greatly lower than before treatment, the AFP levels of the combined treatment group were significantly lower than the control group, and there was a statistically significant difference (P < 0.05). The survival rates of patients in the combined treatment group at the sixth month, the first year, and the second year after treatment were significantly higher than those of the control group, and there was a statistically significant difference (P < 0.05). The univariate results showed that, in the combined treatment group, there were statistically significant differences between the effective group and the ineffective group in tumor diameter, intact capsule, liver cirrhosis, intrahepatic spread, and tumor adjacent to large blood vessels (P < 0.05). The outcomes of multivariate analysis indicated that tumor diameter ≥ 3 cm, incomplete capsule, intrahepatic spread, and tumor adjacent to large blood vessels were risk factors for ineffective recurrence of patients with primary liver cancer after radiofrequency ablation combined with hepatic artery intervention (P < 0.05). Discussion. Tumor diameter ≥ 3 cm, incomplete capsule, intrahepatic spread, and tumor adjacent to large blood vessels are risk factors for the ineffectiveness of radiofrequency ablation combined with hepatic artery interventional therapy for patients with recurrence of primary liver cancer. It is necessary to increase the range of radiofrequency treatment, increase the temperature of the radiofrequency needle, and strengthen postoperative follow-up interventions based on the specific conditions of the patient's tumor.

Serum soluble cluster of differentiation 163 (sCD163), matrix metalloproteinase 9 (MMP9) and cytokeratin 18 (CK18) levels as biomarkers for liver fibrosis in Egyptian chronic hepatitis C patients

Abstract Liver fibrosis is a pathological disease in which extracellular matrix proteins, such as collagen, build up in the liver, causing tissue remodeling and the creation of persistent scar tissue. It has been associated to HCV infection, As a result, the objective of this study is to evaluate the levels of sCD163, MMP9, and CK18 as noninvasive biomarkers . A total of 100 subjects were divided into 4 groups for investigation. Group 1 consisted of healthy control subjects (Control group). Patients with HCV infection were divided into 3 groups based on their fibrosis grade: Group 2 (F0), Group 3 (F1-F2), and Group 4 (F3-F4). The ELISA technique was used to assess the levels of direct serum indicators sCD163, MMP9, CK18, and AFP. A complete blood count, serum ALT, AST, albumin, total bilirubin, and INR were measured. In addition, as indirect biomarkers, the FIB-4 score and the AST/ALT Ratio (AAR) were reported. Results indicated that the levels of sCD163, CK18, and AFP were increased significantly in all HCV infected groups, compared to controls, with the highest levels in the advanced groups. MMP9 was decreased in low grade fibrotic HCV groups, but significantly increased in advanced liver fibrosis group. FIB-4 and AAR showed a significant increase in all HCV patients, compared to control group. From the obtained data, the performance of MMP9 was the most accurate direct blood biomarker for evaluating the advanced fibrosis (Group 4). In addition, CK18 and sCD136 showed promising results.

Clinical Implication of E2F Transcription Factor 1 in Hepatocellular Carcinoma Tissues.

Background: To date, the clinical management of advanced hepatocellular carcinoma (HCC) patients remains challenging and the mechanisms of E2F transcription factor 1 (E2F1) underlying HCC are obscure. Materials and Methods: Our study integrated datasets mined from several public databases to comprehensively understand the deregulated expression status of E2F1. Tissue microarrays and immunohistochemistry staining was used to validate E2F1 expression level. The prognostic value of E2F1 was assessed. In-depth subgroup analyses were implemented to compare the differentially expressed levels of E2F1 in HCC patients with various tumor stages. Functional enrichments were used to address the predominant targets of E2F1 and shedding light on their potential roles in HCC. Results: We confirmed the elevated expression of E2F1 in HCC. Subgroup analyses indicated that elevated E2F1 level was independent of various stages in HCC. E2F1 possessed moderate discriminatory capability in differentiating HCC patients from non-HCC controls. Elevated E2F1 correlated with Asian race, tumor classification, neoplasm histologic grade, eastern cancer oncology group, and plasma AFP levels. Furthermore, high E2F1 correlated with poor survival condition and pooled HR signified E2F1 as a risk factor for HCC. Enrichment analysis of differentially expressed genes, coexpressed genes, and putative targets of E2F1 emphasized the importance of cell cycle pathway, where CCNE1 and CCNA2 served as hub genes. Conclusions: We confirmed the upregulation of E2F1 and explored the prognostic value of E2F1 in HCC patients. Two putative targeted genes (CCNE1 and CCNA2) of E2F1 were identified for their potential roles in regulating cell cycle and promote antiapoptotic activity in HCC patients.

Differences in the presentation and treatment of primary liver tumors at a hepatology center and an oncology center.

Primary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates. A retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012-2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients. Of the total population, 93% (n = 102) presented with cirrhosis, 86% (n = 94) had HCC (HC: 58%, UCAC: 42%), and 14% (n = 15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I-II, BCLC A-B, and AFP levels < 100 ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels > 1,000 ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation. The most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.

Vitronectin (VTN): A Novel Diagnostic and Prognostic Marker for Hepatocellular Carcinoma (HCC) On Top Of Chronic Hepatitis C Virus Related Diseases

Abstract Background Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the most common form of primary liver cancer. Aim of the study to study the level of serum vitronectin (VTN) compared to AFP in diagnosis and prognosis of hepatocellular carcinoma on top of HCV-related liver diseases. Patients and Methods This prospective observational study included a total number of 60 subjects who were divided into 4 groups: Group 1: include 10 normal persons. Group 2: included 10 patients who have Hepatitis C Virus infection. Group 3: included 20 cirrhotic patients. Group 4: included 20 patients with HCC (on top of hepatitis C virus related cirrhosis), in which we tested them for vitronectin before first intervention and after intervention within 3 months. Results The mean age of the cases showed high statistically significant difference between the study groups (P &amp;lt; 0.001).There were a total number of 29 males and 31 females with significant difference in the sex distribution between the study groups. 80% of the cases in HCC group were males. This sex distribution can be attributed to high prevalence of risk factors like smoking, DM and HCV in males in addition to possible role of sex hormones. On analyzing laboratory characters of the studied groups, we found statistically significant difference between cirrhosis group and non-cirrhotic groups with low platelets count, high serum creatinine, high INR, lower serum albumin, high bilirubin and higher AST. The median level of AFP in group 4 (HCC patients) was 110 IU/ml which was higher than its median value in the other study groups with high level of significance between the study groups. The median level of vitronectin levels in the different study groups didn’t reveal a statistically significant difference between the different study groups. Serum level of vitronectin in group 3 (cirrhotic patients) has no statistically significant difference between the three subgroups according to child's classification. By the analysis of serum level of AFP and vitronectin level in group IV (HCC patients) before and after treatment, the median level of AFP was significantly lower than its level before intervention, while the decrease in vitronectin level was statistically insignificant after intervention. Conclusions Chronic HCV infection and its serious complicatons specially HCC are still representing a health challenge in Egypt, reflecting wide HCV prevalence and late diagnosis. Serum AFP alone has an unreliable role in HCC surveillance as it has low sensitivity because it may be normal in up to 40% of HCC cases especially early stages of the tumor, and low specificity as its levels may be elevated in conditions other than HCC as cirrhosis or exacerbation of chronic hepatitis or even in some cases of cholangiocarcinoma. AFP is useful in clinical practice in screening and diagnosis of HCC in association with US and CT. According to our study, we can't use Vitronectin alone in diagnosis and prognosis of HCC on top of cirrhosis related to HCV +ve infection. It didn’t reveal a statistically significant difference between the different study groups ,so it may require further study and research.

S2859 Metastatic Hepatocellular Carcinoma After Sustained Virologic Response to Hepatitis C in a Non-Cirrhotic

Introduction: Hepatitis C has long been one of the most common causes of cirrhosis and resultant hepatocellular carcinoma (HCC). There is evidence demonstrating an increased risk of development of HCC in non-cirrhotic patients who have had sustained virologic response (SVR) after direct acting antiviral (DAA) treatment of hepatitis C. We present a case of a non-cirrhotic 72-year-old male who attained SVR with DAA treatment in 2018. After presenting to the hospital two years later with significant weight loss and fatigue, he was found to have metastatic HCC. Case Description/Methods: A 71-year-old male with a history of tobacco use, hypertension, diabetes mellitus type 2, and chronic hepatitis C who completed Harvoni in 2017 was admitted due to unintentional weight loss of fifty-five pounds associated with early satiety, epigastric pain, and weakness. He was found to have hepatitis C antibodies in 1993 and underwent a liver biopsy in 2001 that showed stage one fibrosis. In 2015, he underwent a second liver biopsy that again showed stage one portal fibrosis. In July 2017, he underwent treatment and was found to have an undetectable viral load. During his 2021 admission, CT abdomen/pelvis showed heterogeneous enhancement throughout the right lobe of the liver with scattered hyper-enhancing foci. He underwent liver biopsy showing HCC. He was offered the option of immunotherapy versus hospice care. He then opted for hospice care. Discussion: While HCC can develop in patients who achieved sustained virologic response following HCV eradication, 20% of cases can develop in non-cirrhotics. Surveillance is not performed in these cases, so HCC can present at more advanced stages. Risk factors for HCC development after HCV clearance are older age at eradication, male sex, advanced fibrosis stage, AFP levels following IFN treatment, heavy alcohol use, diabetes mellitus, hypertension, and hyperlipidemia. Clearance by DAAs had no impact on short term development of HCC but noted sofosbuvir-based treatment without Ribavirin as adding additional risk. Other guidelines proposed following the level of fibrosis and SVR but acknowledged that implementation of this strategy cannot presently be achieved in clinical practice. Although abdominal ultrasound remains the gold standard, associating the development of HCC in patients with SVR and various SNPs could identify patients at increased risk. Our case further enforces the need for increased surveillance in this patient population.

Study of serum Fetuin-A level in pateints with post HCV liver cirhosis with and without hepatocellular carcinoma

Abstract Background Measurement and assessment of the levels of glycoprotein as fetuin-A which provides insights into the pathogenic mechanisms of various liver diseases and improved capability to identify disease- specific profiles of proteins leads to more accurate prediction of disease classes and development of novel treatments. Aim of the work Assessment of diagnostic value of Fetuin –A in cases of liver cirrhosis due to HCV with and without HCC. Patients and methods This study was conducted at the Internal Medicine, Faculty of Medicine, Zagazig University, during the period from November 2014 to Decmeber 2015 on 80 patients with liver cirrhosis due to chronic HCV infection. Two groups of post HCV patients with liver cirrhosis as a first group &amp; post HCV liver cirrhosis with HCC as a second group; each group included 40 patients. The study also included 20 healthy subjects as a control. Patients who were excluded, those who had received antiviral therapy within 6 months before the study, subjects with high triglyceride or had received lipid lowering drugs, HBV infected patients, patients with medical history of ESRD, diabetes mellitus. Results fetuin A was significantly lower in post HCV liver cirrhosis than a healthy control cases, fetuin-A was significantly lower in post HCV liver cirrhosis with HCC versus post HCV liver cirrhotic patients. Serum levels of fetuin A was a useful marker in post HCV liver cirrhosis with HCC, with AFP levels below cutoff value. Serum levels of AFP was a useful marker in post HCV liver cirrhosis with HCC, with fetuin-A levels above cutoff value. Conclusion Serum fetuin-A level is decreasing in post HCV liver cirrhosis and liver cirrhosis with HCC than in healthy control with the lowest level in HCC. Post HCV liver cirrhosis with HCC cases which are not diagnosed by alph-fetoprotein can be captured by Fetuin A and vice versa. Also, the results show no significant correlations of fetuin-A with the CP scores and MELD score in post HCV liver cirrhosis .

Potential Anti-carcinogenic Effect of Acetazolamide, a Carbonic Anhydrase Enzyme Inhibitor, in Diethylnitrosamine - Induced Hepatocarcinogenesis in Rats

Abstract Background Despite the progress achieved in early detection and treatment of HCC, it still accounts for a significant number of cancer-related deaths worldwide. Tumoral microenvironment acidity plays a pivotal role in tumoral cell survival, tumoral progression and metastasis. CA-IX and XII are two of several mechanisms by which tumor maintain optimal intracellular pH at the expense of the extracellular environment that turns into acidic pH. ACT is a CA inhibitor that is used in many medical indications. It is effective, safe and inexpensive. It has some side effects and it may be even contraindicated in some cases. Aim of the work To evaluate the possible anticarcinogenic role of ACT in DEN-induced HCC animal model. Materials and Methods This study showed that using DEN for 10 weeks caused significant increase in the levels of AST, ALT, total bilirubin, direct bilirubin and AFP and significant decrease in albumin level in DEN-induced HCC rat groups when compared to normal control rats. Administration of ACT for 3 weeks in ACT-treated DEN-induced HCC group caused marked improvement in the mentioned biochemical measurements (AST, ALT, total bilirubin, direct bilirubin and AFP) when compared to DEN-induced HCC rat group without ACT treatment, yet still higher than the lab values of normal control group. Results The present study demonstrated that using DEN in rat groups had induced polyhedral to round hepatocytes with dense, centrally located vesicular nuclei. The neoplastic areas showed poorly differentiated large cells with hyperchromatic nuclei and prominent nucleoli. The neoplastic cells showed anisokaryosis, anisocytosis, and deeply basophilic scanty cytoplasm and frequent mitotic figures mostly Grade III. The hepatic lobule displayed disorganization of hepatic cords with hyperplasia of Kupffer cells, multinucleated tumor giant cells with prominent basophilic nuclei and basophilic spindle cells. Conclusion Acetazolamide showed significant antitumor effect in DEN-induced HCC in rats, making it a promising agent to use against HCC either individually or in combination with any other therapeutic modalities. Further researches should be conducted in this anti HCC aspect.

A Diagnostic Value of Serum Level Cyclase-Associated Plasma Protein 2 Versus Alpha Fetoproteins as a novel Biomarker for Detection of Hepato-Cellular Carcinoma in Egyptian Patients with Liver Cirrhosis

Abstract Background HCC is the third deadliest and fifth most common cancer worldwide, despite the widespread use of surveillance programs in at risk populations, more than half of HCC cases are diagnosed late, and curative therapies such as surgical resection, radiofrequency ablation or TACE are possible in less than 30% of patients. Objective To assess the value of plasma cyclase-associated protein 2 level in diagnosis of hepatocellular carcinoma among the Egyptian patients with chronic hepatitis c virus. Patients and Methods This study has been carried out in the department of Internal Medicine and Gastroenterology in Ain Shams University Hospitals and Manshiet El-Bakry general hospital, Department of Gastrohepatology. This study evaluate the significance of Plasma CAP2 level as a new diagnostic marker for HCC patients with post hepatitis C liver cirrhosis where (80) persons, divided into three groups; Group A included (30) patients with post hepatitis C liver cirrhosis without HCC, Group B included (40) patients with post hepatitis C liver cirrhosis and HCC, and Group C included (10) healthy subjects as a control group. Results In this study CAP2 was significantly higher in HCC group than in cirrhotic and control groups (p &amp;lt; 0.001) with mean levels (30.7±12.4), (14.4±7.6), and (6.9±4.3) ng/ml respectively although in HCC patients with negative or low AFP levels. This finding could imply the role of CAP2 in diagnosing early and AFP negative HCC patients. Conclusion CAP2 is significantly elevated in HCC group than in cirrhotic and control groups with better sensitivity and specificity than AFP at cut off values ≥15.9 ng/ml and ≥53.2 ng/ml respectively. Such results support using of CAP2 as a better diagnostic marker for HCC. AFP and CAP-2 were higher in multiple lesions than in single lesions, but the differences were significant only in CAP-2 with ≥27.3 ng/ml in differentiating multiple from solitary lesions Considering the HCC if both of them were positive decreased sensitivity but had perfect specificity.

Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice

PurposeThe development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). Patients and methodsWe derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. ResultsIn the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. ConclusionDevelopment of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

Role of Apparent Diffusion Coefficient (ADC) Mapping in Assessment of Therapeutic Response of Hepatocellular Carcinoma Post Trans-Catheter Arterial Chemoembolization

Abstract Background: Trans-arterial chemoembolization (TACE) is widely used as an interventional procedure in treatment of HCCs. ADC value can be used in evaluating its efficacy in order to rule out or in residual tumor tissue. Aim of Study: To assess the role of DWI and ADC value in evaluating HCCs post TACE. Patients and Methods: A retrospective analytical study on 25 patients with hepatocellular carcinoma (HCC); to assess therapeutic response of (HCC) cases after TACE by ADC mapping MRI technique in comparison to dynamic contrast study (DCE-MRI), to evaluate its accuracy, sensitivity and specificity in detecting treatment response/residual tumor. Results: Comparative study between the 2 groups revealed; highly significant increase in ADC value, in active group; compared to inactive group; with highly significant statistical difference (p 0.05). Spearman's correla-tion analysis shows that; AFP level had a highly significant negative correlation with ADC value; with highly significant statistical difference (p < 0.01). By using ROC-curve analysis, DWI/ADC value at a cutoff point (91.33) detected patients with residual active lesions, with good accuracy (84%), sensitivity 84% and specificity 83% (p=0.0001). Conclusion: ADC maps can be used as a quantitative value to differentiate between active and inactive tumors and in monitoring response to treatment in oncological patients.

MicroRNA-199: A Potential Therapeutic Tool for Hepatocellular Carcinoma in an Experimental Model.

Hepatocellular carcinoma is one of the major health problems throughout the world with a very poor prognosis. MicroRNAs are small regulatory non-protein-coding RNA molecules. We aimed at investigating microRNA-199 as a potential therapeutic tool for HCC both in vitro and in an experimental model. A therapeutic strategy based on the effect of microRNAs to target genes responsible for liver cancer was adopted in this work. The ability of these small RNAs to potently influence cellular behavior was also investigated. The role of miR-199a in the development of liver cancer has been identified using a systematic literature search using miRBase. HepG2 cell line was used to test the effect of miRNA199a in vitro. Hepatocellular carcinoma was induced in Male Balb/C mice by diethylnitrosamine (DEN). Mice were treated with miRNA-199a and sacrificed after 16 weeks and blood samples and liver specimens were collected for biochemical and histopathological assessment. Histopathological examination of liver specimens after miRNA 199a treatment showed regression of Hepatocellular carcinoma with restoration of normal architecture. AFP, VEGF and TNFα levels decreased after treatment with miRNA 199a. Caspase 3 and 9; showed decreased expression in animals treated with miRNA 199a than non-treated ones.

Circular RNAs 0064286 and 0000475: Potential Diagnostic Biomarkers in Hepatocellular Carcinoma.

Objective:Hepatocellular carcinoma (HCC) is considered the highest recorded malignancy in Egypt. The shortage of appropriate biomarkers for early detection often results in the late diagnosis of the HCC. Circular RNAs (CircRNAs) are presented as long stranded non-coding RNA that combine covalently to make a sealed circular form which make them very stable. CircRNAs are known to have interpretative role in cancer development and metastasis. Aim:To examine the dysregulation of two new CircRNAs obtained from Circbase database (hsa_circ_0064286 and hsa_circ_0000475) in the serum of HCC patients as predictable diagnostic biomarkers of HCC and their correlation with some liver biochemical parameters. Methods:Sixty clinically diagnosed HCC Egyptian patients and 25 healthy volunteers were enrolled in the study. Expression levels of the selected CircRNAs was evaluated in subjects’ serum. Moreover, correlation with liver biochemical parameters, sensitivity, and specificity of studied CircRNAs were estimated. Results:Both circular RNAs were significantly down regulated in HCC patients, which was negatively correlated with ALP, ALT, AST, AFP, and bilirubin levels. Circ_0064286 showed more sensitivity and specificity (88.3% and 96%, respectively). Conclusion:As far as we know, this is the first study that shed light on the expression levels of both circRNAs in Egyptian HCC patients. They may serve as potential biomarkers for HCC diagnosis. Moreover, those circRNAs draw attention as therapeutic targets for HCC through targeting their sponge miRNAs.

MP40-04 NOVEL SELECTIVE LYSINE-SPECIFIC DEMETHYLASE 1 INHIBITORS, NCL1 AND NCD38, SUPPRESS TESTICULAR TUMOR CELL PROLIFERATION

You have accessJournal of UrologyPenile & Testicular Cancer I (MP40)1 Sep 2021MP40-04 NOVEL SELECTIVE LYSINE-SPECIFIC DEMETHYLASE 1 INHIBITORS, NCL1 AND NCD38, SUPPRESS TESTICULAR TUMOR CELL PROLIFERATION Toshiki Etani, Taku Naiki, Nobuhiko Shimizu, Yusuke Noda, Takashi Nagai, Satoshi Nozaki, Keitaro Iida, Ryosuke Ando, Noriyasu Kawai, Satoru Takahashi, Takayoshi Suzuki, and Takahiro Yasui Toshiki EtaniToshiki Etani More articles by this author , Taku NaikiTaku Naiki More articles by this author , Nobuhiko ShimizuNobuhiko Shimizu More articles by this author , Yusuke NodaYusuke Noda More articles by this author , Takashi NagaiTakashi Nagai More articles by this author , Satoshi NozakiSatoshi Nozaki More articles by this author , Keitaro IidaKeitaro Iida More articles by this author , Ryosuke AndoRyosuke Ando More articles by this author , Noriyasu KawaiNoriyasu Kawai More articles by this author , Satoru TakahashiSatoru Takahashi More articles by this author , Takayoshi SuzukiTakayoshi Suzuki More articles by this author , and Takahiro YasuiTakahiro Yasui More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002055.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lysine-specific demethylase 1 (LSD1), the first histone demethylase to be discovered, is a novel target in prostate cancer therapy. NCL1 and NCD38, novel selective cell-active inhibitors of LSD1, were discovered at our university. We analyzed the efficacy of LSD1 inhibitors in germ cell tumors in vitro and in vivo. METHODS: Various tests were used to uncover mechanism of germ cell tumor growth and anticancer effects of NCL1 and NCD38. Cell viability was assessed using a WST-8 assay with standard vehicle, NCL1 or NCD38 in NTERA2 and Tera-1 cells (human testicular embryonal carcinoma cell lines). Flow cytometry and western blotting were performed to assess apoptosis and the cell cycle after treatment of NTERA2 cells with NCL1 or NCD38. Subcutaneous and orthotopic tumors were induced by injecting nude mice with NTERA2 cells. Thereafter, mice were injected intraperitoneally with vehicle, NCL1 or NCD38, twice a week, and their subsequent growth recorded. TUNEL staining was used to detect apoptosis in tumors. Finally, tissue arrays were prepared from tissue specimens from 35 patients with seminoma who underwent orchiectomy. RESULTS: The WST assay revealed a reduction in the number of viable cells in a dose-dependent manner after NCL1 or NCD38 treatment. In western blotting, NCL1 or NCD38 treatment induced caspase-dependent apoptosis, while Oct 3/4 and SOX2 expression was decreased. In ChIP-qPCR analysis, LSD1 inhibition increased the methylation of promoter regions of SOX2 and Oct 3/4. In flow cytometry analysis, NCL1 or NCD38 significantly induced apoptosis in a dose-dependent manner. Subcutaneous tumor volumes and serum AFP levels were significantly lower in mice treated with NCL1 or NCD38 than in controls. TUNEL analysis showed that NCL1 and NCD38 treatment induced apoptosis in NTERA2 subcutaneous tumors. Tissue array analysis showed that LSD1 expression in human seminoma specimens was significantly higher than that in noncancerous specimens. CONCLUSIONS: Germ cell tumor growth was effectively suppressed with NCL1 or NCD38 treatment in vitro and in vivo without adverse events by regulating apoptosis and suppressing SOX2 and Oct4. These results indicate the potential of NCL1 and NCD38 as therapeutic agents for germ cell tumors. Source of Funding: Grants in Aid for Scientific Research (KAKENHI), Japan Society for the Promotion of Science (JSPS), Number 17K11152 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e715-e716 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Toshiki Etani More articles by this author Taku Naiki More articles by this author Nobuhiko Shimizu More articles by this author Yusuke Noda More articles by this author Takashi Nagai More articles by this author Satoshi Nozaki More articles by this author Keitaro Iida More articles by this author Ryosuke Ando More articles by this author Noriyasu Kawai More articles by this author Satoru Takahashi More articles by this author Takayoshi Suzuki More articles by this author Takahiro Yasui More articles by this author Expand All Advertisement Loading ...

A Radiomics Signature-Based Nomogram to Predict the Progression-Free Survival of Patients With Hepatocellular Carcinoma After Transcatheter Arterial Chemoembolization Plus Radiofrequency Ablation.

Objective: The study aims to establish an magnetic resonance imaging radiomics signature-based nomogram for predicting the progression-free survival of intermediate and advanced hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) plus radiofrequency ablationMaterials and Methods: A total of 113 intermediate and advanced HCC patients treated with TACE and RFA were eligible for this study. Patients were classified into a training cohort (n = 78 cases) and a validation cohort (n = 35 cases). Radiomics features were extracted from contrast-enhanced T1W images by analysis kit software. Dimension reduction was conducted to select optimal features using the least absolute shrinkage and selection operator (LASSO). A rad-score was calculated and used to classify the patients into high-risk and low-risk groups and further integrated into multivariate Cox analysis. Two prediction models based on radiomics signature combined with or without clinical factors and a clinical model based on clinical factors were developed. A nomogram comcined radiomics signature and clinical factors were established and the concordance index (C-index) was used for measuring discrimination ability of the model, calibration curve was used for measuring calibration ability, and decision curve and clinical impact curve are used for measuring clinical utility.Results: Eight radiomics features were selected by LASSO, and the cut-off of the Rad-score was 1.62. The C-index of the radiomics signature for PFS was 0.646 (95%: 0.582–0.71) in the training cohort and 0.669 (95% CI:0.572–0.766) in validation cohort. The median PFS of the low-risk group [30.4 (95% CI: 19.41–41.38)] months was higher than that of the high-risk group [8.1 (95% CI: 4.41–11.79)] months in the training cohort (log rank test, z = 16.58, p < 0.001) and was verified in the validation cohort. Multivariate Cox analysis showed that BCLC stage [hazard ratio (HR): 2.52, 95% CI: 1.42–4.47, p = 0.002], AFP level (HR: 2.01, 95% CI: 1.01–3.99 p = 0.046), time interval (HR: 0.48, 95% CI: 0.26–0.87, p = 0.016) and radiomics signature (HR 2.98, 95% CI: 1.60–5.51, p = 0.001) were independent prognostic factors of PFS in the training cohort. The C-index of the combined model in the training cohort was higher than that of clinical model for PFS prediction [0.722 (95% CI: 0.657–0.786) vs. 0.669 (95% CI: 0.657–0.786), p＜0.001]. Similarly, The C-index of the combined model in the validation cohort, was higher than that of clinical model [0.821 (95% CI: 0.726–0.915) vs. 0.76 (95% CI: 0.667–0.851), p = 0.004]. The calibration curve, decision curve and clinical impact curve showed that the nomogram can be used to accurately predict the PFS of patients.Conclusion: The radiomics signature was a prognostic risk factor, and a nomogram combined radiomics and clinical factors acts as a new strategy for predicted the PFS of intermediate and advanced HCC treated with TACE plus RFA.

Long-term Risk of Hepatocellular Carcinoma Following Direct-Acting Antiviral Therapy in Compensated Liver Cirrhosis Induced by Hepatitis C Virus Infection

Background: Considering the excellent safety profile and the high efficacy rates, great benefits were expected with the availability of the new direct-acting antivirals (DAAs) in treating hepatitis C virus (HCV) infection. Following the publication of two articles in 2016 on the high incidence rates of hepatocelullar carcinoma (HCC) following DAAs, several papers revealed contradictory results, thereby casting shadows on the role of DAAs in hepatocarcinogenesis. Objectives: The present study aimed to assess the incidence and risk factors of HCC in patients with HCV genotype 1b infection and compensated cirrhosis with the sustained virological response (SVR) following DAAs. Methods: This multicentric prospective study encompassed 479 patients with HCV genotype 1b compensated cirrhosis treated with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) +/- ribavirin (RBV) for 12 weeks in two tertiary centers in Northeastern Romania. The patients were prospectively followed up in the Institute of Gastroenterology Iasi, Romania, from November 2015 to December 2020. Results: During the follow-up period (mean 60.11 ± 3.87 months), 23 patients (4.8%) developed HCC. The 1-, 3-, and 5-year cumulative incidence rates of HCC were 1.1, 1.9, and 2.6%, respectively. At the time of the diagnosis, 15 patients (65%) had a single tumor, 12 patients (52.2%) were within the Milan criteria, and nine persons (39%) had Barcelona liver cancer stage 0-A. In this regard, the mean AFP level was 35.3 ± 93.1 ng/mL. A multivariate analysis, age above 65 years, and a cutoff point of AFP ≥ 10 ng/mL at the end of treatment were independent factors associated with HCC. A majority of the patients (n = 11, 47.8%) received curative treatment by surgical resection. In this study, histopathological examination identified a moderately differentiated tumor (G2) in 5 patients, five patients had a poorly differentiated tumor (G3), and only one patient had a well-differentiated tumor (G1). Conclusions: Our study revealed no evidence of the high incidence rate of HCC after the long-term follow-up of patients with HCV-related liver cirrhosis and SVR following DAA treatment. However, the cumulative 5-year risk remained above the cutoff point, and this makes the HCC screening cost-effective. The HCC occurrence appears to be associated with aging and a moderately increased AFP level at EOT (≥ 10 ng/mL).

Hepatic mRNA Expression Levels of the Oncogenes Alpha-Fetoprotein and Osteopontin as Diagnostics for Liver Cancer in a Murine Model of Diet-Induced Non-Alcoholic Steatohepatitis

Non-alcoholic steatohepatitis (NASH) is associated with an increased risk of hepatocellular carcinoma (HCC). Expression levels of hepatic oncogenes, alpha-fetoprotein (afp) and osteopontin (opn)/secreted phosphoprotein 1 (spp1), were investigated using a model of diet-induced NASH. Mice were randomized to a standard diet or a fast-food diet (FFD) for 17 months. Livers from the FFD cohort exhibited hallmark characteristics of NASH with liver fibrosis, with a subset of animals exhibiting HCC. Expression levels of hepatic afp and opn/spp1 were elevated ~2.5 and ~5-fold, respectively, in the FFD cohort. Hepatic opn/spp1 exhibited a direct (r = 0.65) and significant (p &lt; 0.01) correlation with liver hydroxyproline content. Receiver operating characteristic (ROC) curve analysis for hepatic afp, as a diagnostic for HCC, returned an area under (AU) ROC 0.84, a sensitivity of 87.5%, a specificity of 77% and a threshold of &gt;1.05-fold change in mRNA level. The use of hepatic opn/ssp1 as a diagnostic for HCC returned an AUROC 0.88, a sensitivity of 83.3%, a specificity of 86.7% and a threshold of &gt;2.4-fold change in mRNA level. These data point to a transformation of NASH to an oncotype with hepatic oncogene levels as a diagnostic for NASH.

DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer.

Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGFβ pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways.

The importance of the glucose-to-lymphocyte ratio in patients with hepatocellular carcinoma treated with sorafenib.

Aim: To show the prognostic significance of the glucose-to-lymphocyte ratio (GLR) in hepatocellular carcinoma (HCC). Patients & methods: A total of 150 patients with advanced HCC who were treated with sorafenib in our center between January 2011 and December 2019 were included in the studyretrospectively. Neutrophil-to-lymphocyte ratio, systemic immune-inflammation index, lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio, prognostic nutritional index andGLR were analyzed to assess their prognostic value using Kaplan-Meier and Cox regression analysis before and after propensity score matching (PSM). Results: In univariate analysis before and after PSM, albumin-bilirubin grade, neutrophil-to-lymphocyte ratio, systemic immune-inflammation index, lymphocyte-to-monocyte ratio, prognostic nutritional index, AFP level andGLR were found to be significantly associated with bothprogression-free and overall survival. In multivariate analysis before and after PSM, GLR, albumin-bilirubingrade andAFP were determined to be independent prognostic factors for progression-free and overall survival. Conclusion: The GLR prior to sorafenib treatment is a new prognostic biomarker that may predict survival in advanced HCC.

Burned-Out Testicular Tumors in Adolescents: Clinical Aspects and Outcome.

Purpose: Testicular germ cell tumors are the fourth most common neoplasm in adolescents, accounting for 8% of all tumors in the age group 15–19 years. On rare instances, the primary testicular lesion is not clinically or radiologically evident while nodal or visceral metastases represent the clinical manifestations of the disease. This phenomenon is described as “burned-out testicular tumor.” In this paper, the authors report a single-institution experience with burned-out testicular tumors in adolescents and discuss their clinical implications.Patients and Methods: All the patients diagnosed with metastatic testicular germ cell tumors at Bambino Gesù Children Hospital between January 1, 2010, and June 30, 2020, were included in the study. Patients were categorized into two groups: “primary testicular” and “burned out.” All the patients were staged and treated according to the AIEOP–TCGM 2004 protocol.Results: Eleven patients were classified as “primary testicular,” and five patients were classified as “burned out.” “Burned-out” tumors were associated with the presence of systemic symptoms compared to “primary testicular” tumors (80 vs. 0%; p = 0.0027) and higher aFP, hCG, and LDH levels (p < 0.00001). The “burned-out” population had a statistically significant higher incidence of relevant toxicity than the “primary testicular” population (80 vs. 18%; p = 0.0357) and a worse outcome in terms of both mean overall survival (15 vs. 43 months; p = 0.0299) and mean event-free survival (12 vs. 38 months; p = 0.0164).Conclusion: “Burned-out” testicular tumors seem to be a well-distinct clinical entity with a high treatment-related toxicity and poor prognosis. Further studies are needed to clarify the “burned-out phenomenon” and to identify more effective therapeutic strategies for these patients.