Hepatocellular carcinoma-the role of the underlying liver disease in clinical practice

Hepatocellular carcinoma(HCC)is one of the most common causes of cancerrelated mortality.This particular type of cancer has the distinctive characteristic of mostly happening in individuals with an underlying liver disease.This makes the management of patients more challenging,since physicians must take into consideration two different conditions,the chronic liver disease and the tumor.The underlying liver disease has several implications in clinical practice,because different kinds of chronic liver disease can lead to varying degrees of risk of developing HCC,obstacles in surveillance,and differences in the efficacy of the treatment against HCC.A shift in the prevalence of liver diseases has been evident over the last few years,with viral hepatitis gradually losing the leading position as cause of HCC and metabolic dysfunction-associated steatotic liver disease gaining importance.Therefore,in an era of personalized medicine,it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and its impact in the management of their tumors.

hsa-mir-183 is frequently methylated and related to poor survival in human hepatocellular carcinoma

To screen clinically relevant microRNAs (miRNAs) silenced by DNA methylation in human hepatocellular carcinoma (HCC).METHODSKnockdown of DNA methyltransferases (DNMTs) using siRNAs and miRNA profiling in HCC cell lines were performed to identify DNA hypermethylation-mediated miRNA downregulation. Confirmation using individual quantitative real-time PCR (qRT-PCR) assays was then performed followed by DNA methylation quantification at the promoter of the miRNA genes. Quantification of DNA methylation and miRNA expression was then performed in primary HCC tumor samples and related with clinicopathological variables.RESULTSmiRNA profiling after DNMT knockdown in HCC cell lines revealed upregulation of miR-23, miR-25 and miR-183. After qRT-PCR confirmation and CpG island methylation quantification of these miRNAs in cell lines, further analysis in primary HCC specimens showed that hsa-miR-183 is hypermethylated in 30% of HCC (n = 40). Expression of mature miR-183 showed an inverse correlation with DNA methylation levels. In HCC cells, DNMT knockdown and 5-aza-2’-deoxycytidine treatment reduced methylation and stimulated expression of miR-183. In HCC patients, hypermethylation at hsa-miR-183 promoter significantly correlates with poor survival (log-rank test P = 0.03). DNA methylation analysis in healthy liver, benign liver tumors (hepatocellular adenoma and focal nodular hyperplasia) and their corresponding adjacent tissues showed absence of hypermethylation supporting the notion that aberrant methylation at hsa-miR-183 is specific for the malignant transformation of hepatocytes.CONCLUSIONOur data indicate that hypermethylation of hsa-miR-183 is a frequent event in HCC and potentially useful as a novel surrogate diagnostic and prognostic marker.

Immune aspects of hepatocellular carcinoma:From immune markers for early detection to immunotherapy

Hepatocellular carcinoma(HCC)is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide.Most HCCs develop in an inflammatory microenvironment,and mounting evidence emphasizes the importance of immune aspects in hepatocarcinogenesis.In normal physiology,both innate and adaptive immune responses are responsible for eliminating malignantly transformed cells,thus preventing the development of liver cancer.However,in the setting of impaired natural killer cells and exhaustion of T cells,HCC can develop.The immunogenic features of HCC have relevant clinical implications.There is a large number of immune markers currently being studied for the early detection of liver cancer,which would be critical in order to improve surveillance programs.Moreover,novel immunotherapies have recently been proven to be effective,and the combination of atezolizumab and bevacizumab is currently the most effective treatment for advanced HCC.It is expected that in the near future different subgroups of patients will benefit from specific immunotherapy.The better we understand the immune aspects of HCC,the greater the benefit to patients through surveillance aiming for early detection of liver cancer,which allows for curative treatments,and,in cases of advanced disease,through the selection of the best possible therapy for each individual.

High rate of complete histopathological response in hepatocellular carcinoma patients after combined transarterial chemoembolization and stereotactic body radiation therapy

BACKGROUND Liver transplantation(LT)presents a curative treatment option in patients with early stage hepatocellular carcinoma(HCC)who are not eligible for resection or ablation therapy.Due to a risk of up 30%for waitlist drop-out upon tumor progression,bridging therapies are used to halt tumor growth.Transarterial chemoembolization(TACE)and less commonly stereotactic body radiation therapy(SBRT)or a combination of TACE and SBRT,are used as bridging therapies in LT.However,it remains unclear if one of those treatment options is superior.The analysis of explant livers after transplantation provides the unique opportunity to investigate treatment response by histopathology.AIM To analyze histopathological response to a combination of TACE and SBRT in HCC in comparison to TACE or SBRT alone.METHODS In this multicenter retrospective study,27 patients who received liver transplantation for HCC were analyzed.Patients received either TACE or SBRT alone,or a combination of TACE and SBRT as bridging therapy to liver transplantation.Liver explants of all patients who received at least one TACE and/or SBRT were analyzed for the presence of residual vital tumor tissue by histopathology to assess differences in treatment response to bridging therapies.Statistical analysis was performed using Fisher-Freeman-Halton exact test,Kruskal-Wallis and Mann-Whitney-U tests.RESULTS Fourteen patients received TACE only,four patients SBRT only,and nine patients a combination therapy of TACE and SBRT.There were no significant differences between groups regarding age,sex,etiology of underlying liver disease or number and size of tumor lesions.Strikingly,analysis of liver explants revealed that almost all patients in the TACE and SBRT combination group(8/9,89%)showed no residual vital tumor tissue by histopathology,whereas TACE or SBRT alone resulted in significantly lower rates of complete histopathological response(0/14,0%and 1/4,25%,respectively,P value<0.001).CONCLUSION Our data suggests that a combination of TACE and SBRT increases the rate of complete histopathological response compared to TACE or SBRT alone in bridging to liver transplantation.

Non-alcoholic fatty liver disease-related hepatocellular carcinoma:Is there a role for immunotherapy?

Hepatocellular carcinoma(HCC)is among the most common cancers and it is a major cause of cancer-related deaths.Non-alcoholic fatty liver disease(NAFLD)affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC.The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood.However,metabolic,fibrogenic,oncogenic,inflammatory and immunological pathways seem to be involved.First-line therapy of advanced HCC has recently undergone major changes,since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib.Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy.However,initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease,which seems to be particularly important in NAFLD-related HCC,as these tumors might not benefit from it.This article will review the mechanisms of NAFLD-related hepatocarcinogenesis,with an emphasis on its immune aspects,the efficacy of traditional systemic therapy for advanced NAFLD-related HCC,and the most recent data on the role of immunotherapy for this specific group of patients,showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.

Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.