Male Hepatocellular Carcinoma Patients Research Articles

A Potential Pneumothorax Induced by Immune Checkpoint Inhibitors: A Case Report and Literature Review

Background and Objectives: Immune checkpoint inhibitors (ICIs), which target immune checkpoints in cancer cells, are increasingly used as a mainstay in anticancer treatment. The combination of atezolizumab and bevacizumab is also a first-line treatment for hepatocellular carcinoma (HCC). However, ICIs can cause immune-related adverse events (IrAEs) which range from mild to severe, potentially leading to the need for discontinuing immunotherapy. We report a case of a pneumothorax, a rare side effect caused by IrAEs. Materials and Methods: This paper reports a case of a 78-year-old male HCC patient who developed a recurrent pneumothorax, suspected to be an adverse effect of ICIs. Results: The patient was a current smoker with a 30 pack-year smoking history. Prior to initiating ICIs, a chest CT scan showed mild emphysema and fibrosis attributable to smoking. Following ICI treatment, the patient developed a recurrent pneumothorax. Further tests revealed no underlying cause for the pneumothorax other than the ICIs and smoking, and there were no signs of intrapulmonary metastasis or pneumonitis. Conclusions: When a pneumothorax occurs in a patient undergoing immunotherapy, it is important to consider it as a potential adverse effect of the treatment. Special attention should be given to the possibility that immunotherapy may exacerbate underlying lung conditions. Patients should be advised on the importance of smoking cessation. As there are currently no guidelines for resuming immunotherapy after a pneumothorax, it is crucial to weigh the risks and benefits and consider dose reduction or discontinuation of the medication.

Myosteatosis and muscle loss impact liver transplant outcomes in male patients with hepatocellular carcinoma.

Sarcopenia is associated with unfavourable long-term survival in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). However, the impact of myosteatosis and muscle loss on patient prognosis has not been investigated. Seven hundred fifty-six HCC patients who received LT at 3 transplant centres were included. Computed tomography (CT) images of recipients were collected to measure skeletal muscle index (SMI) and skeletal muscle radiodensity (SMRA). The impact of myosteatosis on the prognosis of sarcopenic and non-sarcopenic patients was studied separately. Muscle status was evaluated based on the presence of sarcopenia and myosteatosis. The muscle loss of 342 males was calculated as the relative change of SMI between pre- and post-LT evaluations. Cox regression models were used to identify predictors of overall survival (OS) and recurrence-free survival (RFS). The study comprised 673 males and 83 females. The median follow-up time was 31months (interquartile range, 19-43months). Prior to LT, 267 (39.7%) and 187 (27.8%) males were defined as sarcopenic (low-SMI) and myosteatotic (low-SMRA), respectively. For sarcopenic recipients, the presence of myosteatosis was followed by a 23.6% decrease in 5year OS (P<0.001) and a 15.0% decrease in 5year RFS (P=0.014). Univariate and multivariate analyses revealed that muscle status was an independent predictor of OS [hazard ratio (HR), 1.569; 95% confidence interval (CI), 1.317-1.869; P<0.001] and RFS (HR, 1.369; 95% CI, 1.182-1.586; P<0.001). Postoperatively, a muscle loss >14.2% was an independent risk factor for poor OS (HR, 2.286; 95% CI, 1.358-3.849; P=0.002) and RFS (HR, 2.219; 95% CI, 1.418-3.471; P<0.001) in non-sarcopenic recipients (N=209). Pre-transplant myosteatosis aggravated the adverse impact of sarcopenia on liver transplant outcomes in male HCC patients. Post-transplant muscle loss might assist in prognostic stratification of recipients without pre-existing sarcopenia, intriguing new insights into individualized management.

A systematic analysis with the hierarchical cluster analysis strategy on the complex interaction of TERT and CTNNB1 somatic mutations in Vietnamese hepatocellular carcinoma patients

Telomerase reverse transcriptase (TERT) and β-catenin (CTNNB1) mutations may occur following the hepatocellular carcinoma (HCC) pathway signal. We conducted a Hierarchical cluster analysis study on 408 patients diagnosed with HCC by pathological surgery, identifying TERT promoter and CTNNB1 exon 3 mutations by sequencing. The overall preclinical characteristics, cumulative cut-point values, and the factors associated with these somatic mutations were analyzed in uni/multidimensional scaling model. HBV(+) HCV(−) HCC male patients who were older than 62.74 years old and have TERT promoter mutation as well as AFP > 489.78 ng/ml got a higher risk of HCC grade more than two from 27 % to 200 % with p < 0.05 (RR are from 1.27 [1.09–1.47] to 3.06 [2.04–4.61]). This mutation was a good indicator of grade 2 risk (HR = 0.37 [2.72–0.16], β = −1.00, p = 0.019). TERT promoter and CTNNB1 exon 3 mutations independently influenced tumor size and tumor site status in grade 3 and HBV(−) HCV (−) male HCC patients, where the hazard rates, respectively, were 0.28 [0.09–0.89], 0.023 [0.0023–0.23] and 0.06 [0.012–0.32] (β < 0 and p < 0.01). These two mutations inversely impacted each other the tumor sites status, especially in male HCC patients with grade 2 without B, C hepatitis virus (RRCTNNB1 exon 3 mutate - TERT promoter wildtype = 1.12 [1.04–1.20], p < 0.05). Consequently, the mutations in TERT promoter and CTNNB1 exon 3 may synchronize with other factors or independently impact the hepatocarcinogenesis and are important indicators for HCC prognostic in male patients with very high AFP levels or with moderately as well as poorly differentiated in tumor. Our results serve as the basis for further studies to understand the impact of different factors on the outcome of HCC, especially in monitoring and assessing the cancer risk of patients infect HBV and carry mutations.

Abstract 822: A retrospective study on the disparities of hepatocellular carcinoma

Abstract Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the third leading cause of cancer-related deaths worldwide. Studies report that the incidence of, and mortality from HCC vary significantly by age, sex, and race/ethnicity; however, disparities in the expression level of tumor biomarkers, liver functions, lipid profiles, and comorbidities have not been thoroughly investigated among subpopulations of patient with HCC. Methods: A retrospective study was conducted to review 247 serial HCC cases enrolled in the University of Mississippi Medical Center during June 2000 to May 2023. The entire HCC population was stratified into subpopulations by race, gender, age and BMI. Then comparisons were performed between two corresponding subpopulations in the expression level of HCC-related biomarkers including Alpha-FP, liver functions including albumin, ALT, AST, and ALP, plasma lipid profiles including cholesterol, and comorbidity conditions including cirrhosis in benign liver tissues, smoking, alcohol using, and illness with viral hepatitis. Two-tailed Student’s T-test was used to calculate the difference in mean values, and Chi-Square Test was used to compare the difference in rates or percentages. The significant p value was set at p&amp;lt;0.05. Results: In total 247 HCC cases, males were 178 (72.1%) and females were 69 (27.9%) with a male to female ratio of 2.6:1; black patients were 108 (43.7%), white patients were 127 (51.4%), and others were 4.9%. The mean age was 59.6 years and mean BMI was 27.04. AFP was the only one of detected tumor biomarkers showing disparities: it was significantly higher in patients of male (p=0.026), younger age (p&amp;lt;0.0001), lower BMI (p=0.039), smokers (p=0.0325) and illness with viral hepatitis (p=0.0007). Disparities in liver functions included: 1) AST was significantly higher in Black HCC patients (p=0.027); 2) no statistical difference of liver functions in gender; 3) younger HCC patients had significantly lower level of Albumin (p=0.006), and higher levels of ALT (p=0.014) and AST (p=0.0032); 4) HCC patients with lower BMI also had lower level of Albumin (p=0.015), and higher levels of AST (p=0.0480 and ALP (p=0.0057). There was no statistical difference of plasma lipid profiles between subpopulations, Black HCC patients except that Black HCC patients had significantly higher levels of cholesterol (p=0.0006) and HDL (p=0.048). In comorbidity, Black HCC patients had higher rates of alcohol using and existence of cirrhosis; and male HCC patients had higher rates of smoking, alcohol usage and viral hepatitis. Conclusions: HCC patients are greatly disparate in the expression level of tumor biomarkers, liver functions, plasma lipid profiles and comorbidity conditions between subpopulations stratified by race, gender, age and BMI. These results could provide useful information for clinical management and prognosis of patients with HCC. Citation Format: Xinchun Zhou, Barrett Aldridge, Nazar Rahmanov, Zhirong Liu, Jinghe Mao, Neha Varshney. A retrospective study on the disparities of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 822.

Prognostic analysis of sex and age in hepatocellular carcinoma: a SEER study.

This study aimed to explore the impact of sex on clinical features and survival among hepatocellular carcinoma (HCC) patients. HCC case data from the Surveillance, Epidemiology, and End Results (SEER) database for the period 2010 to 2015 were selected for analysis. Kaplan-Meier curves displayed overall survival. Univariate cox regression examined the prognostic characteristics of individual features, and multivariate Cox regression assessed hazard ratios. This study comprised 3486 HCC patients, with 2682 males and 804 females. Across all age groups, there was a higher prevalence of males compared to females. Survival curves among female patients showed no significant differences across various age groups. However, among male patients, those under 60 demonstrated notably higher survival rates compared to those aged 60 and above. Regarding various ethnicities, TNM staging systems, tumor sizes, the presence of lung/bone/brain metastases, location in Purchased/Referred Care Delivery Areas, SEER historic stages, tumor grades, and individuals receiving chemotherapy, the proportion of male patients consistently exceeded that of female patients. Within the female patient group, individuals receiving chemotherapy exhibited significantly higher survival rates compared to those who did not. However, the administration of chemotherapy showed no significant impact on the survival rate of male patients. Multivariate Cox regression analysis revealed age, gender, and the administration of chemotherapy key factors influencing the overall survival prognosis. Age, gender, and the administration of chemotherapy are influential factors in the prognosis of both male and female HCC patients.

Hepatitis B virus serology in first-degree relatives and spouses of patients with hepatocellular carcinoma at a Nigerian hospital

Abstract Background: The link between hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) has been well established. There is a dearth of scientific data on the important phenomenon of familial clustering of these diseases in sub-Saharan Africa. This study evaluated the prevalence and risk of HBV infection in first-degree relatives and spouses of patients with HCC. Materials and Methods: This case–control study was conducted in a Nigerian hospital. A total of 211 first-degree relatives and spouses of confirmed 110 patients with HCC and 212 matched controls were consecutively recruited. All participants were screened for the HBV serological markers using the Aria lateral immunoassay kits. Logistic regression was used to determine the odds ratio while bivariate analysis was used to calculate χ2. Results: The prevalence of HBsAg was higher in the first-degree relatives and spouses of patients with HCC than in the controls (17.1% versus 3.3%, P &lt; 0.001, odds ratio 5.9, 95% confidence interval (CI): 2.6–13.7). Among the relatives, the prevalence of HBsAg positivity was highest in the parents and siblings of HCC patients compared with the children and spouses (P &lt; 0.0001). Furthermore, the relatives of female index patients had a higher prevalence of HBV than the relatives of the male HCC patients (75.0% versus 27.0%, p = 0.012). Significant risks for HBV infection included lower vaccination rate, low educational status and tattoo acquisition (p = 0.006, 0.010 and 0.023 respectively). Conclusion: This study provides important local-based population data (perhaps the first of its kind) supporting the scientific postulation of familial clustering of HBV infection and HCC. It also underscores the importance of targeting first-degree relatives and spouses of patients with HCC for HBV screening to reduce the infection and its sequelae.

Gender dimorphism in hepatocarcinogenesis-DNA methylation modification regulated X-chromosome inactivation escape molecule XIST.

Sex disparities constitute a significant issue in hepatocellular carcinoma (HCC). However, the mechanism of gender dimorphism in HCC is still not completely understood. 5-Hydroxymethylcytosine (5hmC)-Seal technology was utilised to detect the global 5hmC levels from four female and four male HCC samples. Methylation of XIST was detected by Sequenom MassARRAY methylation profiling between HCC tissues (T) and adjacent normal liver tissues (L). The role of Tet methylcytosine dioxygenase 2 (TET2) was investigated using diethylnitrosamine (DEN)-administered Tet2-/- female mice, which regulated XIST in hepatocarcinogenesis. All statistical analyses were carried out by GraphPad Prism 9.0 and SPSS version 19.0 software. The results demonstrated that the numbers of 5hmC reads in the first exon of XIST from female HCC tissues (T) were remarkably lower than that in female adjacent normal liver tissues (L). Correspondingly, DNA methylation level of XIST first exon region was significantly increased in female T than in L. By contrast, no significant change was observed in male HCC patients. Compared to L, the expression of XIST in T was also significantly downregulated. Female patients with higher XIST in HCC had a higher overall survival (OS) and more extended recurrence-free survival (RFS). Moreover, TET2 can interact with YY1 binding to the promoter region of XIST and maintain the hypomethylation state of XIST. In addition, DEN-administered Tet2-/- mice developed more tumours than controls in female mice. Our study provided that YY1 and TET2 could interact to form protein complexes binding to the promoter region of XIST, regulating the methylation level of XIST and then affecting the expression of XIST. This research will provide a new clue for studying sex disparities in hepatocarcinogenesis. XIST was significantly downregulated in HCC tissues and had gender disparity. Methylation levels in the XIST first exon were higher in female HCC tissues, but no significant change in male HCC patients. The TET2-YY1 complex regulate XIST expression in female hepatocytes. Other ways regulate XIST expression in male hepatocytes.

Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice

Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men, but the underlying mechanism remains to be further explored. Here, we report that ubiquitinated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is responsible for HCC tumorigenesis in males. Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation. Activated GAPDH interacts with TRAF2, leading to upregulation of the canonical and noncanonical NF-κB pathways, and increases PD-L1 and AR-VRK2 expression, followed by induction of immune evasion, HCC tumorigenesis, and metastasis. Notably, the GAPDH inhibitor koningic acid (KA) activates immune response and protects against FBXW10-driven HCC invivo. In HCC clinical samples, the expression of active GAPDH is positively correlated with that of FBXW10 and VRK2. We propose that the FBXW10/AR/VRK2/GAPDH/NF-κB axis is critical for HCC tumorigenesis in males. Targeting this axis with KA is a potential therapeutic strategy for male HCC patients.

Hepatocellular carcinoma as predominant cancer subgroup accounting for sex differences in post-hepatectomy liver failure, morbidity and mortality.

Experimental evidence suggests sex dependent differences in liver regeneration. Limited evidence is available examining sex differences in post-hepatectomy liver failure (PHLF) and postoperative outcomes. Our aim was to assess the influence of sex on the outcomes after liver resection. The hepatectomy targeted National Surgical Quality Improvement Program (NSQIP) database was assessed for associations between sex and outcomes. A total of 13,401 patients underwent elective hepatic resection between 2014-2017. PHLF was highest among male patients with hepatocellular carcinoma (HCC) (OR=2.81,95%CI:1.40-5.62). Male sex was independently associated with increased PHLF (OR=1.47,95%CI:1.15-1.88), major complications (OR=1.25,95%CI:1.08-1.45), mortality (OR=1.61,95%CI:1.03-2.50), and if only major resections were assessed (OR=1.38,95%CI:1.03-1.84). Diagnosis specific subgroup analyses revealed that effects of sex were predominantly HCC associated. This is the largest series investigating the effects of gender on outcomes after hepatic resection. We documented that women undergoing liver resection have significantly lower risk of PHLF. This difference seemed influenced by the striking increase of PHLF in male HCC patients. These hypothesis suggest that sex might play a role in preoperative risk stratification.

Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression

ObjectsThe incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in...

Sex differences in hepatocellular carcinoma indicated BEX4 as a potential target to improve efficacy of lenvatinib plus immune checkpoint inhibitors.

Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer, and significant sex disparities have been observed in HCC. We aim to explore the potential sex-biased mechanisms involved in hepatocarcinogenesis.Methods: Based on TCGA data, we compared clinical features, genetic alterations, and immune cell infiltrations between male and female HCC patients. In addition, we performed sex-based differential expression analysis and functional enrichment analysis. Finally, GSE64041 dataset and another HCC cohort were engaged to validate our findings.Results: Significant differences of genetic alterations and TME were observed between male and female HCC patients. Enhanced metabolism of lipids was associated with hepatocarcinogenesis in men, while ECM-organization-related pathways were correlated to HCC development in women. BEX4 was upregulated in female but downregulated in male HCC patients, and was positively correlated with immune checkpoint molecules and infiltrated immune cell. These findings were further validated in dataset GSE64041 and our HCC cohort. More importantly, a negative correlation was found between BEX4 expression and lenvatinib sensitivity.Conclusion: Distinct biological processes were involved in sex-biased tumorigenesis of HCC. BEX4 can be targeted to improve the efficacy of lenvatinib plus immune checkpoint inhibitors.

Hepatocellular adenoma in men: A nationwide assessment of pathology and correlation with clinical course.

Background & AimsHepatocellular adenomas (HCA) rarely occur in males, and if so, are frequently associated with malignant transformation. Guidelines are based on small numbers of patients and advise resection of HCA in male patients, irrespective of size or subtype. This nationwide retrospective cohort study is the largest series of HCA in men correlating (immuno)histopathological and molecular findings with the clinical course.MethodsDutch male patients with available histological slides with a (differential) diagnosis of HCA between 2000 and 2017 were identified through the Dutch Pathology Registry (PALGA). Histopathology and immunohistochemistry according to international guidelines were revised by two expert hepatopathologists. Next generation sequencing (NGS) was performed to confirm hepatocellular carcinoma (HCC) and/or subtype HCA. Final pathological diagnosis was correlated with recurrence, metastasis and death.ResultsA total of 66 patients from 26 centres fulfilling the inclusion criteria with a mean (±SD) age of 45.0 ± 21.6 years were included. The diagnosis was changed after expert revision and NGS in 33 of the 66 patients (50%). After a median follow‐up of 9.6 years, tumour‐related mortality of patients with accessible clinical data was 1/18 (5.6%) in HCA, 5/14 (35.7%) in uncertain HCA/HCC and 4/9 (44.4%) in the HCC groups (P = .031). Four B‐catenin mutated HCA were identified using NGS, which were not yet identified by immunohistochemistry and expert revision.ConclusionsExpert revision with relevant immunohistochemistry may help the challenging but prognostically relevant distinction between HCA and well‐differentiated HCC in male patients. NGS may be more important to subtype HCA than indicated in present guidelines.

Genome-wide long noncoding RNA and mRNA expression profiles demonstrate associations between exposure to inorganic elements and the risk of developing hepatocellular carcinoma

BackgroundLong noncoding RNAs (lncRNAs) are closely associated with the development of hepatocellular carcinoma (HCC). The present study conducted a genome-wide microarray analysis and qPCR validation to obtain comprehensive insights into this issue.MethodsThirty male HCC patients with chronic HBV infection were included in the present study. Primary HCC tissue and normal tissue were collected. Double-stranded complementary DNA synthesized from 10 pairs of samples was labeled and hybridized to a microarray chip. Further analyses, such as hierarchical clustering, gene ontology (GO) and pathway analyses, were performed. In addition, qPCR validation was performed on tissue samples and additional serum samples.ResultsThe microarray analysis identified 946 upregulated and 571 downregulated lncRNAs and 1720 upregulated and 1106 downregulated mRNAs. Among these RNAs, ENST00000583827.1 (fold change: 21) and uc010isf.1 (fold change: 18) were the most over- and underexpressed lncRNAs in the HCC tissues, respectively. For the mRNAs, KIF20A (fold change: 26) and HEPACAM (fold change: 50) were the most over- and underexpressed in the HCC tissues, respectively. The GO analysis demonstrated that the most differentially expressed mRNAs were related to the response of metal ions. The pathway analysis also suggested that the most enriched pathway was mineral absorption.ConclusionsThe subsequent qPCR validation exhibited high consistency with the microarray analysis, except for three lncRNAs. The qPCR analysis also demonstrated that TCONS_00008984 had a 767-fold overexpression level in HCC tissues when compared with normal tissues, and this finding was confirmed in the serum samples; therefore, TCONS_00008984 has the potential to serve as a diagnostic marker or prognostic indicator. The GO and pathway analyses indicated that exposure to inorganic elements may be involved in HCC risk.

The association of the serum levels of myostatin, follistatin, and interleukin-6 with sarcopenia, and their impacts on survival in patients with hepatocellular carcinoma.

Background/AimsThe role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival.MethodsUsing prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017.ResultsThe median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm2/m2 (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients.ConclusionsThe serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.

The Loss of Masculine With Declined Serum DHT Is Associated With High Risk of Hepatocellular Carcinoma in Chinese Men.

Background: Hepatocellular carcinoma (HCC) is a male-predominant cancer. However, the relationship between 5α-dihydrotestosterone (DHT), the active form of testosterone, and HCC risk has not been established yet.Methods: We performed a serum epidemiological study in the Chinese population. From 2010 to 2012, 106 male HCC patients and 318 age-matched controls were detected for their serum DHT and estradiol (E2). The odds ratios (ORs) and 95% confidence interval (CI) were estimated by logistic regression analysis with adjustment for potential risk factors. Bivariate Pearson correlations between hormone concentrations and liver function index were investigated.Results: Serum DHT levels were lower (to 1/3 of control), and E2 levels were higher (to 1.5-fold of control) in HCC patients. Compared with the low DHT level, men with a medium level had an adjusted multiple OR of 0.15 (95% CI 0.05–0.43, p trend < 0.01), and men with a high level had an OR of 0.05 (95% CI 0.01–0.21, p trend < 0.01). Notably, DHT concentration, but not E2, is correlated with liver injury.Conclusion: The data suggest that serum DHT is closely associated with HCC risk, providing a reference in order to accurately predict liver cancer and study the pathogenesis of this disease.

Two elder cases of hepatocellular carcinoma adjacent to intrahepatic vessels successfully treated by carbon ion radiotherapy

The treatment for hepatocellular carcinoma (HCC) adjacent to the portal vein and/or bile duct requires considerable caution to avoid the complications, such as hepatic infarction and obstructive jaundice. Carbon ion radiotherapy (CIRT) has been attempted for HCC and has become accepted as a promising modality for minimizing hepatic damage with good local tumor control. We experienced two elder cases of HCC adjacent to intrahepatic vessels successfully treated by CIRT. Case 1, a 75-year-old man, was treated by CIRT for a 2-cm HCC near the porta hepatis adjacent to the right first portal branch. The treatment was sufficiently effective, and no vascular damage was demonstrated after CIRT. The liver function transiently deteriorated after CIRT, but recovered quickly. Alpha-fetoprotein transiently increased after the treatment and decreased thereafter. Tumor stain persisted for 3 months after CIRT, so a liver tumor biopsy was performed. However, no viable carcinoma cells were detected. There was no local recurrence or complications for 17months. Case 2, 76-year-old male HCC patient, showed dilation of the peripheral bile duct in the left lobe, suggesting tumor invasion to the duct. The tumor was hypovascular and was found to be well-differentiated HCC by a tumor biopsy. He was treated with CIRT, because he had a history of cerebral infarction and was being administered an antiplatelet agent daily. He achieved complete remission, and no adverse events were observed after the treatment for 3 years.

Glutathione S-Transferase P1 Polymorphism on Exon 6 and Risk of Hepatocellular Carcinoma in Thai Male Patients

Introduction: Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the fourth leading cause of cancer-related deaths worldwide. HCC cases are two to four times more common in males than in females, and the highest incidence is found in Asia and Sub-Saharan Africa. This gender disparity is the result of different behavioral risk factors, such as smoking and drinking alcohol. Glutathione S-Transferase P1 (GSTP1) is an enzyme that is involved in the detoxification of carcinogenic electrophiles. GSTP1 codon 105 in exon 5 and codon 114 in exon 6 polymorphisms result in decreased enzyme detoxification activity, which is the cause of many cancers. Objectives: This study aims to investigate the associations between GSTP1 polymorphism, HCC patients, and the risk factors for HCC. It is hoped that this research will provide useful knowledge on the effects of genetic GSTP1 polymorphism in Thai HCC patients. Methods: DNA from 44 Thai HCC patients and 52 healthy controls was analyzed for GSTP1 exon 5 and exon 6 polymorphisms by PCR-RFLP. The associations between GSTP1 polymorphism, the control group, and clinicopathological parameters were determined. Results:The results show that GSTP1 exon 6 polymorphism genotypes (C/T) were correlated with an increased risk of HCC susceptibility (OR = 4.40). Moreover, exon 6 polymorphism genotypes (C/T) were associated with the gender of patients (p = 0.015), but no relationships were found between GSTP1 exon 5 polymorphism and the clinicopathological data of patients. Conclusions: The results suggest that the GSTP1 exon 6 polymorphism genotype was associated with an increase in the risk of HCC in male patients and that it tended to be related to cancer differentiation. No association was found between GSTP1 exon 5 polymorphism and the risk of HCC.

Association of TNFRSF12A Methylation With Prognosis in Hepatocellular Carcinoma With History of Alcohol Consumption.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death worldwide with a poor prognosis. Alcoholic liver disease accounts for approximately one-third of all HCC cases. Current evidence proved that aberrant over-expression of TNFRSF12A correlates with the severity of disease, making it a likely indicator of disease a more aggressive and worse prognosis outcome. Emerging studies have confirmed that epigenetic changes are critical events in the development and progression of liver cancer. The study to investigate the mechanisms by which alcohol abuse mediated changes in the methylation level of TNFRSF12A affect the occurrence, development and prognosis of HCC were under warranted. Thus, in this study we mined two publicly available datasets to detect the association between DNA methylation level of CpG sites in gene TNFRSF12A and the development of HCC in those with alcohol abuse history. Finally, we discovered that the hypomethylation of two methylation sites—cg00510447 and cg26808293—could identify HCC from other non-HCC liver diseases. Also, hypomethylation of these two sites could identify alcoholic cirrhosis from other non-hepatocellular carcinoma liver diseases. Most important, the prognostic analysis revealed that the hypomethylation of cg00510447 and cg26808293 in HCC patients with alcohol abuse history could predict poor prognosis. Further stratified analyses by gender discovered that in male HCC patients with alcohol abuse history, hypomethylation of cg26808293 signified poor prognosis. The further mechanism analysis revealed that the DNA methyltransferases DNMT3L might regulate TNFRSF12A methylation and affect the occurrence, development and prognosis of HCC, especially in patients with a history of alcohol abuse. These findings provide new insights into the role of epigenetic mechanisms in the transformation of alcoholic liver disease into HCC.

Identification of metabolism-associated pathways and genes involved in male and female liver cancer patients

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. HCC is influenced by sex and multiple metabolic abnormalities. The present study aimed to compare the overall metabolic changes between male and female HCC patients and identify key metabolic genes. Metabolic genes and pathways were identified based on analyses of publicly available data. Differential expression analysis, gene set enrichment analysis, survival analysis and transcriptional regulation analysis were employed to explore sex differences and identify key metabolic genes in HCC. The results suggested that female patients had more severe metabolic gene expression abnormalities and pathway deregulation than male patients. This study identified 9 key metabolic genes, and only upregulated ALDH1A2 independently increased overall survival risk in patients. Bioinformatic analyses suggest that upregulated GATA3 and TAL1 activate ALDH1A2 and then disrupt amino acid and carbohydrate metabolism, which may increase the risk of HCC. This study identified a novel contribution of upregulated ALDH1A2 to HCC. Future studies are needed to elucidate the potential metabolic mechanism of the role of ALDH1A2 in HCC.

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors.

Telomerase reverse transcriptase (TERT) mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). Our aims were to investigate whether TERT mutations can be detected in circulating cell‐free DNA (cfDNA) of patients with HCC and/or cirrhosis and characterize clinical parameters associated with these mutations. We retrieved data on TERT C228T and C250T promoter mutations in 196 HCCs from The Cancer Genome Atlas. We measured these TERT mutations in plasma cfDNA in 218 patients with HCC and 81 patients with cirrhosis without imaging evidence of HCC. The prevalence of TERT mutations in The Cancer Genome Atlas HCC specimens was 44.4%. TERT mutations were detected with similar prevalence (47.7%) in plasma cfDNAs from 218 patients with HCC. TERT mutations, either within the HCC or in cfDNA, were associated with male sex, hepatitis C virus (HCV), alcoholic cirrhosis, family history of cancer, and poor prognosis. The high prevalence of TERT mutations in HCCs in male patients with cirrhosis caused by HCV and/or alcohol was confirmed in an independent set of HCCs (86.6%). Finally, TERT mutations were detected in cfDNA of 7 out of 81 (8.6%) patients with cirrhosis without imaging evidence of HCC, including 5 male patients with cirrhosis due to HCV and/or alcohol. Genes involved in xenobiotic and alcohol metabolism were enriched in HCCs with TERT mutations, and vitamin K2 was identified as an upstream regulator. Conclusion: TERT mutations are detectable in plasma cfDNA. Long‐term imaging surveillance of patients with cirrhosis with cfDNA TERT mutations without evidence of HCC is required to assess their potential as early biomarkers of HCC. (Hepatology Communications 2018;2:718‐731)