scholarly journals Immunohistochemical markers of CYP3A4 and CYP3A7: a new tool towards personalized pharmacotherapy of hepatocellular carcinoma

2016 ◽  
Vol 60 (2) ◽  
Author(s):  
D. Fanni ◽  
M. Manchia ◽  
F. Lai ◽  
C. Gerosa ◽  
R. Ambu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitor ◽  
Standard Of Care ◽  
Normal Liver ◽  
Individual Variability ◽  
Immunohistochemical Markers ◽  
Liver Cancers ◽  
Individualized Approach ◽  
Viral Hepatitis Infection ◽  
Global Health Problem

<p>Hepatocellular carcinoma (HCC) represents a major global health problem, since more than 90% of primary liver cancers worldwide are HCC. Most cases of HCC are secondary to viral hepatitis infection (hepatitis B or C), alcoholism and cirrhosis. Sorafenib, an oral tyrosine kinase inhibitor that suppresses tumor proliferation and angiogenesis, emerged as the first effective systemic treatment for HCC after 30 years of research, and is currently the standard-of-care for patients with advanced HCC. Sorafenib is metabolized by cytochrome P450 (CYP450), particularly from the 3A4 isoform, producing two main metabolites: the N-oxide and the N-hydroxymethyl metabolite. We studied 11 HCC sample showing the presence of CYP3A4 and CYP3A7 in most of the samples analyzed. Specifically, the immunoreactivity of CYP3A4 was more strong and widespread than that of CYP3A7. The CYP3A4 immunoreactivity was observed in surrounding hepatocytes in 8 out of 11 cases; while the CYP3A7 immunostaining was found in normal liver cells, in 7 out of 11 cases. These results suggest the existence of a marked inter-individual variability regarding the presence of the isoforms of CYP3A. In addition, since sorafenib is metabolized by CYP3A4, but not by CYP3A7, an overexpression of CYP3A4 may lead to an increase in the degradation of the drug and then to clinical ineffectiveness. These results might implicate the necessity of an individualized approach in the treatment of HCC as positivity to CYP3A4 in HCC liver samples might predict a scarce response to sorafenib.</p>

scholarly journals Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab

2021 ◽  
Vol 13 ◽  
pp. 175883592110311
Author(s):  
Chiun Hsu ◽  
Lorenza Rimassa ◽  
Hui-Chuan Sun ◽  
Arndt Vogel ◽  
Ahmed O. Kaseb
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Healthcare Providers ◽  
Safety Data ◽  
Standard Of Care ◽  
Antiangiogenic Agents ◽  
Efficacy And Safety ◽  
First Line

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

scholarly journals Oncopharmacogenomics of Hepatocellular Carcinoma - A Therapy Related Review

2021 ◽  
Vol 17 (5) ◽  
Author(s):  
Prem Ravi Varma P K
Keyword(s):  
Hepatocellular Carcinoma ◽  
Complex Disease ◽  
Kinase Inhibitor ◽  
Current Knowledge ◽  
Clinical Investigation ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Molecular Classification ◽  
Molecular Pathways ◽  
Molecular Targeted Drug

Hepatocellular carcinoma (HCC) remains a highly complex disease resistant to commonly used chemotherapy and radiotherapy. As the fifth most common cancer worldwide with the third highest mortality rate and very poorly understood molecular pathways driving hepatocarcinogenesis, new treatment strategies are urgently needed for this devastating disease. The multi kinase inhibitor Sorafenib was the first molecular targeted drug in HCC that led to significant survival benefit in patients with advanced tumors. It is the first drug to be considered standard of care for advanced HCC and supports the importance of molecular therapies in the treatment of this cancer. Analysis of genetic and epigenetic alterations as well as different molecular pathways involved in the development of HCC help to identify potential new druggable targets. A variety of novel compounds are already under preclinical or clinical investigation, and accumulating evidence suggests that combination therapy targeting different pathways will potentiate anti-tumoral effects and will become the future therapeutic approach. In addition, the establishment of a robust molecular classification will pave the way for a more personalized treatment scheme in HCC. In this article a review of the current knowledge of the molecular pathogenesis of HCC and an overview of molecular targeted therapies in the management of HCC are provided.

Elasticity Characterization of Liver Cancers Using Shear Wave Ultrasound Elastography: Comparison Between Hepatocellular Carcinoma and Liver Metastasis

2017 ◽  
Vol 33 (6) ◽  
pp. 481-488 ◽  
Author(s):  
Kah Lai Choong ◽  
Yin How Wong ◽  
Chai Hong Yeong ◽  
Gnana Kumar Gnanasuntharam ◽  
Khean Lee Goh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Metastasis ◽  
Shear Wave ◽  
Liver Tissue ◽  
Normal Liver ◽  
Ultrasound Elastography ◽  
Normal Liver Tissue ◽  
Tissue Elasticity ◽  
Liver Cancers

Purpose: This was a feasibility study of shear wave ultrasound elastography for characterization of liver tumors and to compare the tissue elasticity values of hepatocellular carcinoma (HCC), liver metastases, and normal liver tissues. Methods: Forty-one patients and 30 healthy volunteers were recruited and categorized into HCC, liver metastasis, and control groups based on their computed tomography and sonographic examinations. Elasticity values of different groups were compared statistically. Results: Mean (standard deviation) elasticity values for HCC, liver metastasis, and normal liver tissue were 51.45 (14.96), 49.89 (13.82), and 6.63 (1.65) kilopascal, respectively. Statistically significant differences were found between the elasticity values of HCC and liver metastasis with normal liver tissue. Based on the receiver operating characteristics analysis, 18.25 kilopascal may differentiate the malignant focal liver lesions from the normal liver tissue with both sensitivity and specificity of 100%. Conclusion: Shear wave ultrasound elastography may be able to differentiate HCC and liver metastasis from normal liver tissue based on the tissue elasticity values.

Treatment Approaches for Hepatocellular Carcinoma

2007 ◽  
Vol 1 ◽  
pp. 117955490700100
Author(s):  
Khaldoun Almhanna ◽  
Richard Kim ◽  
Sujith Kalmadi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Tumor Resection ◽  
Standard Of Care ◽  
The United States ◽  
Multidrug Resistant ◽  
High Rate ◽  
Treatment Modalities ◽  
Multiple Risk Factors

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and it is responsible for up to one million deaths annually. Although multiple risk factors for HCC have been identified, and despite preventive measures, the incidence of HCC continues to rise to epidemiologic proportions in the United States. In general, tumor resection and orthotopic liver transplantation are the treatment with the best outcome; however, HCC is generally diagnosed late in its course when patients are not eligible for curative treatment options. HCC is a relatively Chemo-refractory tumor secondary to heterogeneity of the tumor and the high rate of multidrug resistant gene expression. There are no standard treatments for HCC, multiple palliative treatment modalities have been used for patients with unresectable disease. None of these modalities have shown any superiority; and the retrospective nature of these available data has confounded any reasonable conclusions. Different institutions use different treatment schema dependent on the center expertise. Sorafenib, a tyrosine kinase inhibitor, has recently demonstrated a survival advantage in metastatic HCC, and if approved by the FDA, might become the standard of care. In this article we will review the rationale behind the currently available treatment options for HCC.

scholarly journals Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2499
Author(s):  
Lisanne Noordam ◽  
Zhouhong Ge ◽  
Hadiye Özturk ◽  
Michail Doukas ◽  
Shanta Mancham ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Normal Liver ◽  
Occult Metastasis ◽  
Recurrence Rates ◽  
Curative Intent ◽  
Cancer Testis Antigens ◽  
Negative Prognostic Factor ◽  
Increased Risk ◽  
Hcc Recurrence ◽  
Cancer Testis

High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis. Tumor and paired tumor-free liver (TFL) tissues of HCC-patients and healthy tissues were assessed for mRNA expression of 49 CTAs by RT-qPCR and protein expression of five CTAs by immunohistochemistry. Twelve CTA-mRNAs were expressed in ≥10% of HCC-tumors and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA-expression in TFL was an independent negative prognostic factor for post-resection HCC-recurrence and survival. We established a panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients. The increased risk of HCC-recurrence in patients with CTA expression in TFL, suggests that CTA-expressing (pre-)malignant cells may be a source of HCC-recurrence, reflecting the relevance of targeting these to prevent HCC-recurrence.

scholarly journals SUMO-Activating Enzyme Subunit 1 (SAE1) Is a Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular Carcinoma

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 178
Author(s):  
Jiann Ruey Ong ◽  
Oluwaseun Adebayo Bamodu ◽  
Nguyen Viet Khang ◽  
Yen-Kuang Lin ◽  
Chi-Tai Yeh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Metabolism ◽  
Interaction Analysis ◽  
Normal Liver ◽  
Diagnostic Value ◽  
Vital Role ◽  
Regulation Of Transcription ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Characteristic Analysis

Hepatocellular carcinoma (HCC) is one of the most diagnosed malignancies and a leading cause of cancer-related mortality globally. This is exacerbated by its highly aggressive phenotype, and limitation in early diagnosis and effective therapies. The SUMO-activating enzyme subunit 1 (SAE1) is a component of a heterodimeric small ubiquitin-related modifier that plays a vital role in SUMOylation, a post-translational modification involving in cellular events such as regulation of transcription, cell cycle and apoptosis. Reported overexpression of SAE1 in glioma in a stage-dependent manner suggests it has a probable role in cancer initiation and progression. In this study, hypothesizing that SAE1 is implicated in HCC metastatic phenotype and poor prognosis, we analyzed the expression of SAE1 in several cancer databases and to unravel the underlying molecular mechanism of SAE1-associated hepatocarcinogenesis. Here, we demonstrated that SAE1 is over-expressed in HCC samples compared to normal liver tissue, and this observed SAE1 overexpression is stage and grade-dependent and associated with poor survival. The receiver operating characteristic analysis of SAE1 in TCGA−LIHC patients (n = 421) showed an AUC of 0.925, indicating an excellent diagnostic value of SAE1 in HCC. Our protein-protein interaction analysis for SAE1 showed that SAE1 interacted with and activated oncogenes such as PLK1, CCNB1, CDK4 and CDK1, while simultaneously inhibiting tumor suppressors including PDK4, KLF9, FOXO1 and ALDH2. Immunohistochemical staining and clinicopathological correlate analysis of SAE1 in our TMU-SHH HCC cohort (n = 54) further validated the overexpression of SAE1 in cancerous liver tissues compared with ‘normal’ paracancerous tissue, and high SAE1 expression was strongly correlated with metastasis and disease progression. The oncogenic effect of upregulated SAE1 is associated with dysregulated cancer metabolic signaling. In conclusion, the present study demonstrates that SAE1 is a targetable cancer metabolic biomarker with high potential diagnostic and prognostic implications for patients with HCC.

Knockout of Ajuba Attenuates the Growth and Migration of Hepatocellular Carcinoma Cells

2020 ◽  
Vol 160 (11-12) ◽  
pp. 650-658
Author(s):  
Yichen Le ◽  
Yi He ◽  
Meirong Bai ◽  
Ying Wang ◽  
Jiaxue Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Cancer Progression ◽  
Normal Liver ◽  
Cell Growth And Migration ◽  
And Migration ◽  
Hcc Cells

Ajuba has been found to be mutated or aberrantly regulated in several human cancers and plays important roles in cancer progression via different signaling pathways. However, little is known about the role of Ajuba in hepatocellular carcinoma (HCC). Here, we found an upregulation of Ajuba expression in HCC tissues compared with normal liver tissues, while a poor prognosis was observed in HCC patients with high Ajuba expression. Knockout of Ajuba in HCC cells inhibited cell growth in vitro and in vivo, suppressed cell migration, and enhanced the cell apoptosis under stress. Moreover, re-expression of Ajuba in Ajuba-deficient cells could restore the phenotype of Ajuba-deficient cells. In conclusion, these results indicate that Ajuba is upregulated in HCC and promotes cell growth and migration of HCC cells, suggesting that Ajuba could possibly be a new target for HCC diagnosis and treatment.

scholarly journals FXYD6 overexpression in HBV-related hepatocellular carcinoma with cirrhosis

2020 ◽  
Vol 15 (1) ◽  
pp. 259-266
Author(s):  
Xiongfei Chen ◽  
Lishuang Ding ◽  
Deshuai Kong ◽  
Xiulei Zhao ◽  
Lili Liao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Normal Liver ◽  
Early Recurrence ◽  
Tumor Diameter ◽  
Tumor Number ◽  
B Virus ◽  
Expression Rate ◽  
Polymerase Chain ◽  
And Gender ◽  
Liver Tissues

AbstractObjectiveThe aim of this study was to investigate the expression of FXYD domain-containing ion transport regulator 6 (FXYD6) mRNA and protein in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) tissues with cirrhosis, the corresponding paracancerous tissues and the normal liver tissues, and to explore the clinical significance of FXYD6 expression in HBV-related HCC with cirrhosis.MethodsThe FXYD6 mRNA and protein were examined by semi-quantitative reverse transcription polymerase chain reaction and immunohistochemistry, respectively.ResultsThe FXYD6 mRNA in HBV-related HCC tissues was significantly higher than that in the cirrhosis tissues or that in the normal liver tissues. The positive expression rate of FXYD6 protein was statistically higher in HBV-related HCC tissues than that in HBV-related cirrhosis or that in normal liver tissues. There was no significant correlation between the expression of FXYD6 protein and gender, age, histological differentiation, tumor diameter, tumor number, integrity of tumor capsule or not and alpha fetoprotein (AFP) concentration in serum, but the protein expression was associated with microvascular invasion, pathological stage, and early recurrence after operation within 1 year.ConclusionFXYD6 might be involved in hepatocyte carcinogenesis and tumor progression in HBV-related HCC with cirrhosis and indicated a poor prognosis.

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