Aim: Increased serum alpha-fetoprotein (AFP) levels are associated with specific molecular sub-classes of hepatocellular carcinoma (HCC), supporting AFP as a predictive or therapeutic biomarker for precision treatment of this disease. Considering recent efforts to validate HCC molecular classification systems across different populations, we applied existing signature-based classification templates to Hawaii cohorts and examined whether associations between HCC molecular sub-class, AFP levels, and clinical features found elsewhere can also be found in Hawaii, a region with a unique demographic and risk factor profile for HCC.

Methods: Whole-genome expression profiling was performed on HCC tumors collected from 40 patients following partial hepatectomy. Tumors underwent transcriptome-based categorization into 3 molecular sub-classes (S1, S2, and S3). Patient groups based on molecular sub-class and AFP level were then compared with regards to clinical features and survival. Differences associated with AFP level and other clinical parameters were also examined at the gene signature level by gene set enrichment analysis.

Results: Statistically confident (false discovery rate < 0.05) sub-classifications were made in 98% (39/40) of tumors. Patient sub-groups differed significantly with regards to serum AFP level, with significantly lower levels in the S3 sub-group as compared to S1 (P = 0.048) and S2 (P = 0.010). Serum AFP > 400 ng/mL predicted significant tumor enrichment for genes corresponding to MYC target activation, high cell proliferation, poor clinical prognosis, and the S2 sub-class. AFP > 400 ng/mL and non-S3 tumor classification were found to be significant predictors of overall survival.

Conclusion: Distinct sub-classes of HCC associated with different molecular features and survival outcomes can be detected with statistical confidence in a Pacific Island cohort. Molecular classification signatures and other predictive markers for HCC that are valid for all patient populations are needed to support multi-center efforts to develop targeted therapies for HCC.

Aim: The Barcelona Clinic Liver Score (BCLC) currently limits hepatic resection only for small, solitary tumors measuring 2-3 cm with no signs of portal hypertension (PHT) or macrovascular invasion. The aim of this study was to show the benefit of surgical resection, and to compare the peri-operative and long-term outcomes between laparoscopic liver resection (LLR) and open liver resection (OLR) for hepatocellular carcinoma (HCC) classified as intermediate stage (B) under BCLC.

Methods: From 2004 to 2013, 49 patients staged as intermediate (BCLC B) and who underwent hepatic resection was included. These patients were divided into LLR or OLR. Demographics, tumor characteristics, recurrence rates and overall survival (OS) were compared between the 2 groups.

Results: Forty-nine patients were included and grouped into LLR (n = 28) and OLR (n = 21). The average tumor number was 2 ± 1 for both groups, while the mean tumor size was 4.4 ± 1.7 cm and 5.3 ± 2.6 cm for the LLR and OLR group, respectively. When compared with OLR, LLR had lower post-operative complications (14.3% vs. 33.3%, P = 0.114), and a statistically significant shorter hospital stay than the OLR group (9 vs. 21 days, P = 0.023). The LLR group also achieved a statistically significant difference in complete R0 resection as compared with the OLR group (P = 0.016). The OS and disease-free survival (DFS) at 1, 3 and 5 years were comparable between LLR and OLR (OS: 89.1% vs. 76.2%; 70.4% vs. 55.9%; 58.6% vs. 43.5%, P = 0.583; DFS: 59.3% vs. 51.0%; 20.2% vs. 44.6%; 16.2% vs. 37.2%, P = 0.947, respectively).

Conclusion: LLR showed comparable outcomes compared to OLR in the treatment of HCC staged BCLC B. Therefore, LLR as well as OLR can be considered in selective patients in the BCLC B group.

Aim: This study aims to analyze the particularities of hepatitis C induced hepatocellular carcinoma (HCC), developed during or after treatment with direct-acting antivirals.

Methods: We conducted an observational prospective study on 278 patients, who underwent treatment for hepatitis C related liver cirrhosis and respectively for F3 chronic hepatitis C. Liver status was assessed using biological parameters and imagistic evaluation (ultrasonography, computed tomography scan, magnetic resonance imaging).

Results: The follow-up time was 14 months. Before therapy, 69.3% of the cirrhotic patients and 26.7% of those with F3 degree of liver fibrosis had high levels of alpha-fetoprotein, with no imagistic evidence of HCC. During treatment, HCC was confirmed in 5 patients, 2 of them presenting portal vein thrombosis (PVT). Antiviral therapy was not interrupted. Two patients developed HCC at the end of treatment, while 4 of them were diagnosed with HCC after three months of ending the treatment. Excepting the ones with PVT, all patients underwent trans-arterial chemoembolization.

Conclusion: All patients acquired sustained virological response. The screening for HCC should not be stopped after achievement of sustained virological response. Patients who develop HCC after antiviral treatment often need to be evaluated by magnetic resonance imaging in order to detect the extension of the disease.

Qidong hepatitis B virus (HBV) infection cohort (QBC) is a prospective community-based study designed to investigate causative factors of primary liver cancer (PLC) in Qidong, China, where both PLC and HBV infection are highly endemic. Residents aged 20-65 years, living in seven townships of Qidong, were surveyed using hepatitis B surface antigen (HBsAg) serum test and invited to participate in QBC from June 1991 to December 1991. A total of 852 and 786 participants were enrolled in HBsAg-positive and HBsAg-negative sub-cohorts in May 1992, respectively. All participants were actively followed up in person, received HBsAg, alanine aminotransferase, alpha-fetoprotein tests and upper abdominal ultrasonic examination, and donated blood and urine samples once or twice a year. The total response rate was 99.6%, and the number of incident PLC was 201 till the end of February 2017. The ratio of incidence rates was 12.32 [95% confidence interval (CI): 7.16-21.21, P < 0.0001] in HBsAg-positive arm compared with HBsAg-negative arm. The relative risk of PLC was 13.25 (95% CI: 6.67-26.33, P < 0.0001) and 28.05 (95% CI: 13.87-56.73, P < 0.0001) in the HBsAg⁺/HBeAg^- group and the HBsAg⁺/HBeAg⁺ group, respectively, as compared to the HBsAg^-/HBeAg^- group. A series of novel PLC-related mutations including A2159G, A2189C and G2203W at the C gene, A799G, A987G and T1055A at the P gene of HBV genome were identified by using samples from the cohort. The mutation in HBV basal core promoter region of HBV genome has an accumulative effect on the occurrence of PLC. In addition, the tripartite relationship of aflatoxin exposure, P53 mutation and PLC was also investigated. QBC will be used to develop dynamic prediction model for PLC risk by using its long-term follow-up information and serial blood samples. This model is expected to improve the efficiency of PLC screening in HBV infection individuals.

Hepatocellular carcinoma (HCC) is recognized as a major global healthcare burden. Although there have been tremendous improvements in cancer screening and treatment, HCC mortality rate remains high. Many patients with HCC present late to medical attention and thus are not candidates for curative treatment. They typically have high tumor burden at presentation showing heterogeneity in anatomical factors and biochemical profile. Despite the relatively poor prognosis for these patients, significant improvements can still be made in survival if the optimal treatment modality is chosen. Currently, there is no international consensus on how to manage this group of heterogeneous, high-burden HCC. In this article, we will address this question by reviewing the latest available evidences. Our definition of “high-burden HCC” will be based on three factors: size, number of tumors and the presence of macrovascular invasion. The different treatment modalities, namely surgery, intra-arterial therapy, radiotherapy and systemic therapy, and their respective supportive evidences, will be discussed. In the end, we will summarize with our views on the future direction of research priorities for the management of high-burden HCC.

Direct antiviral therapy has dramatically changed our possibility to eradicate hepatitis C virus (HCV) infection in all stages of chronic liver disease, with sustained virological response rates well above 90%. HCV eradication should lead to a better prognosis even after cirrhosis has established, including a reduced risk of developing hepatocellular carcinoma (HCC). Unfortunately, during the last two years different reports have raised the concern about a possible increased risk of developing HCC in cirrhotic patients treated with direct antivirals. In this review, we have evaluated the principal published data and have reached a few conclusions: (1) direct antiviral therapy does not seem to increase the cumulative annual rate of HCC de novo occurrence or recurrence; (2) direct antiviral therapy seems to accelerate the development of HCC, soon after the end of treatment, in those patients at higher risk of HCC occurrence or recurrence; and (3) preliminary reports seem to indicate that HCC developed after direct antiviral therapy has more aggressive features. These findings clearly indicate the need for aggressive and close monitoring of cirrhotic patients during and after antiviral treatment, to detect and treat HCC at their earliest occurrence.

We present a case of absence of the portal vein and Laennec’s cirrhosis in a 51-year-old female who was diagnosed with hepatocellular carcinoma (HCC). Only 101 cases of this malformation of the splanchnic vasculature have been reported of which 4 were reported to have HCC. Patient had disease progression while waiting for a liver transplant. Patient was treated with 3 separate conventional transarterial chemoembolization procedures at an outside hospital. At our institution, radioembolization of the right hepatic lobe was performed. She succumbed to liver insufficiency 8 years after being diagnosed with HCC. The features of this patient’s clinical course are reviewed.

Aim: Sorafenib has been shown to improve time to tumor progression (TTP) and overall survival (OS) in patients with hepatocellular carcinoma (HCC); however, post-progression survival (PPS) has not been well characterized in these patients. This study aimed to evaluate the predictors of PPS by using time-dependent and dynamic changes in radiologic progression patterns, liver function, and performance status (PS) in patients with advanced HCC receiving sorafenib treatment.

Methods: We retrospectively analyzed the clinical characteristics of 128 advanced HCC patients with Child-Pugh scores ≤ 7 at the initiation of sorafenib treatment.

Results: The median TTP, OS, and PPS were 3.8, 15.6, and 9.9 months, respectively. At the time of confirmation of radiologic progressive disease (PD), a total of 46 (35.6%) patients showed impairments in their PS of ≥ +1 points over time. For the Child-Pugh score, 27 (21.1%) and 26 (10.9%) patients exhibited an impairment of ≥ +1 and ≥ +2 points, respectively. Multivariate analysis identified the following independent predictors of PPS: impairment in the PS score of ≥ +1 point [hazard ratio (HR) 1.81, 95% confidence interval (CI) 1.16-2.82], impairment in the Child-Pugh score of ≥ +2 points (HR 3.70, 95% CI 1.68-8.15), radiologic pattern of progression (target lesion growth and emergence of a new lesion) (HR 2.91, 95% CI 1.79-2.91), a TTP < 4 months (HR 1.87, 95% CI 1.21-2.91), second-line treatment after radiologic confirmation of PD (HR 0.16, 95% CI 0.08-0.32), and continuous sorafenib treatment after radiologic confirmation of PD (HR 1.76, 95% CI 1.06-3.00).

Conclusion: PPS in patients with advanced HCC can be characterized by using time-dependent dynamic changes in clinical parameters.

Aim: The present study was aimed to determine the modulatory role of lycopene enriched tomato extract (LycT) during initiation of N-nitrosodiethylamine (NDEA) induced hepatocellular carcinoma (HCC).

Methods: Female Balb/c mice were divided into 4 groups: control, NDEA (200 mg NDEA/kg b.wt, cumulative dose), LycT (5 mg/kg b.wt, thrice a week) and LycT + NDEA. LycT administration was commenced 2 weeks prior to NDEA administration in LycT + NDEA group.

Results: NDEA treatment caused histopathological alterations in hepatic tissue and was associated with enhanced serum levels of inflammatory markers, i.e., tumor necrosis factor-alpha, interleukin (IL)-6 and IL-β. NDEA treatment also induced functional alterations in liver as evident by slow ^99mTc-mebrofenin hepatic excretion. LycT administration to NDEA mice showed improved hepatic functional status as demonstrated by normal ^99mTc-mebrofenin excretion. NDEA treatment also caused alterations in the hematological parameters such as hemoglobin, red blood cells, platelets and total leucocyte counts. A significant increase in plasma lipid peroxidation and decrease in reduced glutathione levels with alterations in various enzymatic antioxidants were observed upon NDEA treatment. LycT pre-treatment aided in boosting the antioxidant defense system and ameliorated the inflammatory and hematological alterations.

Conclusion: As evident by improved functional, hematological and biochemical markers, it may be inferred that LycT has the potential to delay HCC initiation.

After decades of frustrating nihilism due to lack of innovative therapeutic solutions, the onco-hepatological community is facing up to important novelties for the treatment of intermediate and advanced stages of liver cancer. Four new drugs have been investigated and resulted in positive data: lenvatinib resulted not inferior to the standard of care sorafenib in first line, regorafenib and cabozantinib demonstrated prolonging survival in patients progressed to sorafenib and nivolumab approved by FDA as option after first-line. Contemporary, the knowledge acquired after ten years’ experience of sorafenib in patient selection and adverse events management revealed an increase of the outcomes. Physicians dedicated to treat advanced and intermediated liver cancer are close to live a new era where systemic treatments could have a huge impact on the disease. The aim of this review is to anticipate this new approach at the disease, summarizing data currently available for these therapies to identify therapeutic strategies of sequences and choosing drugs according to the patient profile.

Aim: Hepatitis C virus (HCV) cirrhosis is an important cause of hepatocellular carcinoma (HCC). This study aimed to identify factors of HCC presence among HCV cirrhotic patients with and without small diameter HCC (≤ 3 cm).

Methods: A case control transversal study between 1998 and 2003 including 93 patients: 31 with small diameter HCC and 62 without HCC. Groups were matched by age and gender. Multiple logistic regression analysis using Akaike Information Criteria to estimate the probability of HCC was performed. A model score was generated and bootstrap analysis was performed for internal validation.

Results: Three significant laboratorial variables for HCC presence were found: alanine aminotransferase > 37 U/L [odds ratio (OR): 7.43 (1.61-34.19), P = 0.01], alpha-fetoprotein > 20 ng/mL [OR: 16.2 (4.17-63.01), P < 0.001] and platelet count < 100,000/mm³ [OR: 3.62 (1.43-9.14), P = 0.007]. A model score with an area under curve of 0.79 (95% CI: 0.7-0.89) was built based on these variables. The negative predictive value of those classified as at low risk of HCC was 99.1%.

Conclusion: An easy and practical model score was generated. It may be an auxiliary tool for identification of HCV patients with low probability of small diameter HCC at initial evaluation composed of three serum examinations used in routine outpatient clinical practice.

Aim: We aimed to elucidate whether beta2-glycoprotein I (β2GPI) cooperation with hepatitis B surface antigen (HBsAg) promoted hepatocellular carcinogenesis enhanced by the lipopolysaccharide (LPS) via activation of nuclear factor kappa B (NF-κB) and expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and alpha fetal protein (AFP) in liver cancer cells.

Methods: Liver cancer cells (SMMC-7721) were transiently transfected with β2GPI and/or HBsAg and were subjected to LPS treatment. TNF-α, IL-1β, and AFP expression were measured in all groups by ELISA. NF-κB activation was assessed by non-radioactive electrophoretic mobility shift assay (EMSA) and was quantified in all groups.

Results: Cells transfected with β2GPI and/or HBsAg induced activation of NF-κB, with the highest activation seen in the doubly β2GPI- and HBsAg-transfected cells treated with LPS. Non-transfected cells treated with LPS exhibited lower activation compared to either β2GPI- or HBsAg-transfected cells with LPS treatment. In addition, cells transfected with β2GPI and/or HBsAg induced significantly increased expression of TNF-α, IL-1β and AFP, with the highest levels again seen in the doubly β2GPI- and HBsAg-transfected cells treated with LPS.

Conclusion: These observations suggest that the activity of NF-κB induced by β2GPI and HBsAg was enhanced by LPS. Expression of TNF-α, IL-1β and AFP increased in β2GPI and HBsAg cotransfected liver cancer cells.

Aim: To evaluate the effect of neoadjuvant hepatic arterial infusion chemotherapy (HAIC) on the survival of patients with resectable hepatocellular carcinoma (HCC).

Methods: Between January 2003 and January 2014, 80 patients underwent hepatic resection for HCC. Of these patients, we evaluated 49 patients who met the following inclusion criteria: (1) preserved liver function (Child-Pugh A); (2) resectable HCC (≤ 3 nodules, regardless of the size); and (3) HCC with high-grade malignant potential. Among them, 13 patients underwent neoadjuvant HAIC and curative hepatectomy (treatment group). The remaining 36 patients underwent curative hepatic resection without neoadjuvant therapy (control group). Survival after hepatic resection was compared retrospectively between the groups.

Results: During follow-up, 2 (15.4%) patients in the treatment group and 25 (69.4%) patients in the control group developed recurrence. The 1-, 3-, and 5-year disease-free rates (100%, 78.6%, and 78.6%, respectively vs. 65.8%, 33.7%, and 26.6%, respectively; P = 0.003) and overall survival rates (100%, 100%, and 100%, respectively vs. 91.7%, 77.8%, and 55.3%, respectively; P = 0.037) were significantly better in the treatment group than in the control group.

Conclusion: Neoadjuvant HAIC decreased the risk of recurrence and improved survival in patients with HCC with high malignant potential.

Hepatocellular carcinoma (HCC) is a kind of malignancy with high potential of metastasis and multicentric occurrence. The treatment of recurrent hepatocellular carcinoma (RHCC) and multinodular hepatocellular carcinoma (MHCC) is always a nodus because of the diverse clonal origin of RHCC/MHCC. Theoretically, the RHCC/MHCC can originate from intrahepatic metastasis (IM type) or multicentric occurrence (MO type). Our previous study proposed that there are at least 6 subtypes of clonal origin patterns in RHCC. RHCC and MHCC with different clonal origins have variant biological behaviors, clinical prognosis as well as treatment strategy. Generally speaking, patients with IM type HCC have a poorer prognosis compared with those with MO type HCC. Therefore, it is essential to emphasize the distribution of the clonal origin in HCC in order to determine the choice of clinical treatment. Undoubtedly, the detection of clonal origin pattern will become a promising breakthrough in the molecular pathological diagnosis of HCC. We should attach more attention to the establishment of a standardized molecular pathological clonal origin detection method and a new stratification of clinical treatment choice for RHCC/MHCC in future.

Aim: The present study evaluated the frequency of hepatocellular carcinoma (HCC) in patients without cirrhosis.

Methods: HCC patients were recruited from two reference centers for liver disease in Northeast Brazil from 2010 to 2016. The diagnosis of HCC and cirrhosis was based on international criteria.

Results: A total of 169 patients were included, and 16% (27) of the patients did not have hepatocellular carcinoma in non-cirrhosis (HCC-NC). The mean age of HCC-NC was 64.4 ± 11.3 years, and 74.1% of the patients were male. The main risk factors were hepatitis C virus (HCV) in 29.6% (8), nonalcoholic steatohepatitis (NASH) in 14.8% (4) and hepatitis B virus (HBV) in 11.1% (3). Histological HCC diagnosis was performed in 81.5% (22) of the patients, and in 18.5% (5) of these patients, the diagnosis was performed by ultrasonography, computed tomography or nuclear magnetic resonance imaging methods. Single nodules were found in 56% of HCC-NC (14) when assessed by imaging methods.

Conclusion: The frequency of HCC-NC was elevated and more common in males. HCV, NASH and HBV were the most frequent risk factors. These data contribute to discussion on future protocols and criteria for the early diagnosis and treatment of HCC in patients with chronic liver disease without cirrhosis.

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). While multiple treatment modalities are available, liver transplantation remains the sole curative treatment for advanced stages of HCC, and hence new treatment approaches are required to fulfill this unmet need of curative HCC therapy. Our first-in-man proof-of-concept adoptive T-cell immunotherapy against HBV related hepatocellular carcinoma metastases has shown promising results. Here, we review the development of T-cell immunotherapy targeting HBV antigens for the treatment of HBV-HCC and discuss the practical considerations for the safe and effective use in clinics.

Hepatitis B virus (HBV) infection is a primary cause of hepatocellular carcinoma (HCC). Under selection pressures of host immunity and/or immunoprophylaxis and antiviral therapies, HBV evolves by accumulating mutations in its genome. Several studies highlighted the considerable importance of HBV surface (HBs) protein mutants (pre-S/S variants) in tumorigenesis. Among those mutants, pre-S2 mutants have been recognized as "precursor lesions of HCC" and as risk factors for post-operative recurrence of HCC. Pre-S2 mutants play important roles in tumor progression and induce various mechanisms of tumorigenesis. These roles include that the cytoplasmic orientation of the pre-S2 domain is essential for the transcriptional activator C-terminally truncated middle surface protein (MHBst) which participates in the development of hepatocellular carcinoma. Pre-S2 mutants may also play important roles in HBV tumorigenesis by inducing both endoplasmic reticulum stress-dependent and endoplasmic reticulum (ER) stress-independent pathways. Because HCC has poor prognosis and its incidence is increasing, methods for the prevention and treatment of HCC should be comprehensive. Emerging treatments based on ER stress may provide a new strategy.

Hepatocellular carcinoma has been known to arise commonly in the setting of chronic liver disease. Due to its association with cirrhosis, patients with hepatocellular carcinoma often present with markedly diminished hepatic functional reserve, making them poor surgical candidates. For such patients, image-guided percutaneous ablative modalities have provided a viable alternate curative therapy. Although treatment allocation is a decision based on a number of factors, patients eligible for percutaneous ablation generally include those with early stage disease, hepatocellular carcinoma with disease limited to the liver and no extra-hepatic metastases. While percutaneous ethanol injection is the seminal technique, newer developments have led to it being replaced by percutaneous radiofrequency ablation as the most commonly employed procedure, due to a better efficacy as well as safety profile. Other ablative modalities including microwave ablation, laser ablation and cryotherapy are not as widely available. Furthermore, data comparing their effectiveness with well-established procedures like radiofrequency ablation is limited.

Mitochondria are the center of energy production in eukaryotic cells and are crucial for several cellular processes. Dysfunctional mitochondria have been associated with cancer progression. Mitochondria contain their own circular DNA (mtDNA), which codes for 13 proteins, 2rRNA, 22tRNA and non-coding RNAs. Recent evidence showed the presence of 5-methylcytosine and 5-hydroximethylcytosine in mtDNA suggesting that the level of gene expression could be modulated like a nuclear DNA by direct epigenetic modifications. Mitoepigenetics is a bidirectional phenomenon in the epigenetic regulation of mitochondrial genes encoded in both the nucleus and the mitochondrion. This process is affected by SAM-mediated methylation and hydroxymethylation of mtDNA and by nuclear chromatin modulators from mitochondria, such as Acetyl-CoA and NAD⁺. There is some information about physiological and pathological methylated profiles, but information is scarce for hepatocellular carcinoma (HCC). The aim of this review is to summarize the mitoepigenetic knowledge in HCC already reported so far, through a keywords search in Medline. In addition, the deregulation of energy intermediaries needed for the mitoepigenetic regulation is described. As this is a new area of study, a rigorous analysis and careful interpretation and integration of results are needed.

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that could develop at any level from the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar and distal on the basis of its anatomical location. Of note, these three CCA subtypes have common features but also important inter-tumor and intra-tumor differences that can affect the pathogenesis and outcome. A unique feature of iCCA is that it recognizes as origin tissues, the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, which are furnished by two distinct stem cell niches, the canals of Hering and the peribiliary glands, respectively. The complexity of iCCA pathogenesis highlights the need of a multidisciplinary, translational and systemic approach to this malignancy. This review will focus on the advances of iCCA epidemiology, histo-morphology, risk factors, molecular pathogenesis, revealing the existence of multiple subsets of iCCA.

Clear evidence exists for genetic susceptibility to hepatocellular carcinoma (HCC). Genome-wide association studies have identified multiple candidate susceptibility loci. These loci suggest that genetic variation in the immune system may underpin HCC susceptibility. Genes for the antigen processing and presentation pathway have been observed to be significantly enriched across studies and the pathway is identified directly through genome-wide studies of variation using pathway methods. Detailed analysis of the pathway indicates both variation in the antigen presenting loci and in the antigen processing are different in cases in controls. Pathway analysis at the transcriptional level also shows difference between normal liver and liver in individuals with HCC. Assessing differences in the pathway may prove important in improving immune therapy for HCC and in identifying responders for immune checkpoint therapy.

The multiplicity and phenotype of intratumoral immune infiltrate have been shown to influence the clinical outcome of hepatocellular carcinoma (HCC), thus providing a strong rationale to therapeutic interventions aimed at restoring the dysfunctional immune response against the tumor. Improving the knowledge of the complex interactions between transformed hepatocytes, nonparenchymal resident cells, and infiltrating immune cells (characterizing the HCC microenvironment) will be instrumental to increase the success rate of existing immunotherapeutic strategies and to identify new potential targets for intervention or biomarkers to optimize the selection of candidate patients.

Present study reports an update on the molecular interaction of antiviral drugs with viral and host cell components during hepatitis C virus (HCV) infection. In addition to the traditional therapeutic drug regimen, termed as standard of care, some recent drugs have been added in the existing regimen used for HCV infection. These drugs were categorized as direct-acting antivirals (DAAs) agents and “other agents”, with their efficacious impact in the control of HCV infection. They target both viral proteases and host cell receptor proteins/enzymes involved in HCV entry into the cell, replication, and assembly to check their propagation both in situ as well as in cell to cell transmission. Recent studies have reported a significant rise in sustained virological response after the use of these drugs both alone and in combination with pegylated interferon-α (PegIFN-α) plus ribavirin. Recently, DAAs have been reported to be highly effective in eradication of HCV infection, especially liver cirrhosis, reducing but not avoiding the occurrence of liver cancer. Some studies have demonstrated that the presence of resistant HCV variants, arising during viral replication, may be controlled by the new drug regimen. It is important to note here that all these drugs are influenced by viral as well as host factors including basic viral load, HCV genotypes, IFN action, interleukin 28B polymorphism and some liver and metabolic diseases, etc. This is an area with on-going investigations to explore more antiviral agents that may address new challenges in HCV therapy.

Given the high prevalence of viral hepatitis in the Eastern Mediterranean countries, hepatitis B and C infections are the major causes of hepatocellular carcinoma (HCC) in the region. Most cases are associated with cirrhosis related to hepatitis B or C infection. Environmental, host genetic and viral factors can affect the risk of HCC in patients with hepatitis B and C infection. Understanding the epidemiology and viral risk factors in the region provides the implementation of strategies for prevention and treatment of viral hepatitis. Herein, we reviewed the epidemiology, burden of disease and viral risk factors for HCC.

New regimens with direct-acting antivirals (DAAs) agents have changed both efficacy and safety of hepatitis C virus (HCV)-treatment, as almost all patients can be treated and cured at any stage of liver disease. The rates of sustained virological response to currently available combinations exceed 95% in real-life practice. However, conflicting results have been produced on the occurrence/recurrence of hepatocellular carcinoma (HCC) in patients with HCV-associated cirrhosis treated with DAAs. In this review we analyse the data available in the literature in order to elucidate the impact of DAAs on the risk of HCC occurrence in patients without previous history of tumor, and of recurrence after successful treatment of the tumor. Data on “de novo” HCC incidence were quite homogeneous, suggesting that the treatment with DAAs does not modify the risk of HCC developing during the first 6-12 months after HCV eradication. On the contrary, HCC recurrence rates after DAAs were extremely variable across different studies, reflecting a large heterogeneity in this clinical setting. The possibility that treatment with DAAs may favour tumour growth and spread in individual patients with active HCC foci is supported by some observations but remains unproven.

Hepatocellular carcinoma (HCC) is one of the most rapidly growing and prevalent cancers in the whole world. The characterized hypoxia region inside the HCC tumors has been recently found as the key driver of HCC malignance and treatment failure, leading to a variety of hypoxia-related biological consequences including angiogenesis, metastasis, metabolism deregulation and drug resistance, which ultimately resulted in treatment failure of HCC. This review will summarize the signaling pathways involved in hypoxia-mediated malignance of HCC and discuss current advances of hypoxia-targeted therapies.

Aim: Plasmacytoma variant translocation 1 (PVT1), a long intergenic non-coding RNA, was overexpressed in liver cancer. A single nucleotide polymorphism (SNP) rs4733586 was identified as an expression quantitative trait loci (eQTL) for PVT1 using bioinformatics analysis. This study was to assess the association of PVT1 eQTL with hepatocellular carcinoma (HCC) prognosis.

Methods: A case-only study was performed to assess the association between SNP and HCC overall survival in 331 HCC patients with hepatitis B virus. Cox proportional hazard regression models were conducted for survival analysis with adjustment for age, gender, smoking status, drinking status, Barcelona-Clinic Liver Cancer stages, and chemotherapy or transcatheter hepatic arterial chemoembolization (TACE) status.

Results: The variant genotype C allele of rs4733586 was significantly associated with a higher death risk compared with T allele (adjusted hazard ratio = 1.26, 95% confidence intervals = 1.05-1.51, P = 0.012 in the additive model). By stepwise Cox proportional hazard analysis, four variables (age, drinking status, chemotherapy or TACE status, PVT1 eQTL) were remained in the final regression model. In the stratified analysis, no heterogeneity was observed among different subgroups.

Conclusion: These findings suggest that eQTL SNP for PVT1 may be susceptibility marker for the HCC overall survival.

Hepatocellular carcinoma (HCC) is one of the most relevant sanitary problems for its prevalence and poor prognosis. This tumor is characterized by highly heterogeneous features, both at clinical and molecular level. SerpinB3 (squamous cell carcinoma antigen-1 or SCCA1) is a serine-protease inhibitor that protects cells from oxidative stress conditions, but in chronic liver damage it may lead to HCC through different strategies, including inhibition of apoptosis, induction of epithelial to mesenchymal transition, cell proliferation and invasiveness. Mechanisms of tumor growth promotion induced by SerpinB3 encompass the inhibition of intratumor infiltration of natural killer cells and the up-regulation of Myc oncogene. Recently this serpin has also been identified as a Ras-responsive factor and modulator of metabolic pathways. In the liver SerpinB3 is undetectable in normal hepatocytes, but its expression progressively increases in chronic liver diseases, dysplastic nodules and hepatocellular carcinoma, especially in those with poor prognosis, in which it could also exert immunomodulatory effects. In serum SerpinB3/4 isoforms (or SCCA) circulate bound to IgMs (SCCA-IgM) in patients with HCC, and in patients with cirrhosis their levels have been found correlated to the risk of HCC development. Preliminary findings in patients with HCC revealed that SCCA-IgM levels are predictive of HCC prognosis.

Primary liver cancer is one of the leading causes of cancer-related deaths worldwide. China has more than 55% liver cancer cases globally. The development of hepatocellular carcinoma (HCC) was caused by a variety of risks factors, including chronic inflammation by virus, alcohol consumption and non-alcoholic steatohepatitis. Emerging evidence has notarized inflammation as a critical component of HCC progression. The development of HCC is a multistep process which may originate from liver chronic injury and inflammation to subsequent fibrosis and/or cirrhosis and finally HCC. A large number of studies indicate that chemokines and cytokines are candidates linking molecules between inflammation and liver cancer. Here, we will describe a few of the key cytokines and chemokines and signal pathways which are involved in the inflammation of HCC. Inhibitors of inflammation for the prevention and overcoming antitumor immunity for treatment of liver cancer are promising candidates for the future management of patients with HCC.

Hepatocellular carcinoma (HCC) is still one of the most common and rapidly fatal malignancies worldwide with a multi-factorial, multi-step, complex process, and poor prognosis. Early discovery and effective therapy of HCC are of utmost importance. Recent studies demonstrated that Wnt/β-catenin pathway play important roles in occurrence and development of HCC including hepatocytes malignant transformation, metastasis, chemoresistance and liver cancer stem cells. Oncogenic wingless-type MMTV integration site family member 3a (Wnt3a) signaling is a promising biomarker in diagnosis and prognosis for HCC. This review presents current data on mechanisms of hepatocarcinogenesis involving participation of the Wnt canonical pathway, and focuses on the Wnt3a expression in HCC progression and its clinical application.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second cause of cancer related death due to latent liver disease, late diagnosis and non-available therapeutic treatment. Liver biopsy is still the gold standard in order to know the molecular biology of the tumor, its behaviour and invasive characteristics. Conventional diagnosis methods for HCC detection include imaging and serological tests with low sensitivity and specificity. In this review, we focus on the potential utility of certain serum biomarkers and a new approach, “liquid biopsy”, in the management of HCC patients.

Staphylococcal nuclease and tudor domain containing 1 (SND1) is a protein that regulates a complex array of functions. It controls gene expression through transcriptional activation, mRNA degradation, mRNA stabilization, ubiquitination and alternative splicing. More than two decades of research has accumulated evidence of the role of SND1 as an oncogene in various cancers. It is a promoter of cancer hallmarks like proliferation, invasion, migration, angiogenesis and metastasis. In addition to these functions, it has a role in lipid metabolism, inflammation and stress response. The participation of SND1 in such varied functions makes it distinct from most oncogenes that are relatively more focused in their role. This becomes important in the case of hepatocellular carcinoma (HCC) since in addition to typical cancer drivers, factors like lipid metabolism deregulation and chronic inflammation can predispose hepatocytes to HCC. The objective of this review is to provide a summary of the current knowledge available on SND1, specifically in relation to HCC and to shed light on its prospect as a therapeutic target.

Liver transplantation has now been an established treatment for hepatocellular carcinoma and cirrhosis. The Milan criteria have been accepted and applied widely in the world as an indication for deceased donor liver transplant. Due to the severe organ shortage, however, living donor liver transplant (LDLT) has accounted for the majority of transplantations in Japan and the other Asian countries/regions. LDLT cannot be limited by the restrictions imposed by the allocation system but depends on institutional criterion or case-by-case considerations. Accumulating data from a nationwide survey and each center experience have indicated that extending the Milan criteria is warranted.

The neuropeptide somatostatin has been shown to control the secretion of several hormones and growth factors, but also to inhibit the proliferation of several tumor cells. Hepatocellular carcinoma (HCC) is a leading cause of death all over the world due to very limited treatment modalities. Early reports showed that somatostatin may influence HCC growth, making somatostatin a potential therapeutic candidate. The introduction of somatostatin analogues with long half-lives has made this prospect feasible. In this review, experimental data regarding the presence of somatostatin receptors and their functional significance in HCC are presented. Potential mechanisms of direct anti-tumoral activity of somatostatin, including effects on tumor cell proliferation and apoptosis, inhibition of various trophic factors and angiogenesis are also reviewed, as well as indirect actions affecting liver fibrosis, inflammation and macrophage-associated innate immunity. Data on the use of somatostatin analogues for the treatment of induced HCC in experimental animals are presented and human studies of somatostatin treatment of advanced HCC are critically analyzed. Reasons and pitfalls for treatment failures are identified and indications for the proper use of somatostatin, either alone or as an adjunct to other modalities in future trials are proposed.

Aim: Evaluate the effect of sorafenib in a rat model of non-alcoholic fatty liver disease (NAFLD) related to hepatocellular carcinoma (HCC) by quantifying the correlation between changes in glucose metabolism on PET imaging and degree of tumor differentiation.

Methods: NAFLD related HCC was induced by the combination of high fat and choline deficient diet with diethylnitrosamine (100 mg/L) for 16 weeks. Then carcinogenic stimuli were suspended, liver nodules were identified by abdominal ultrasound and two groups were randomized: control (n = 10) and sorafenib (n = 20). Rats received daily gavage administration of 1 mL saline or sorafenib (5 mg/kg/day) for more 3 weeks. After treatment, [¹⁸F]FDG PET scan was performed on animals.

Results: [¹⁸F]FDG uptake was lower in the sorafenib group than that in the control group (3.3 ± 0.48 vs. 5.5 ± 1.5, P = 0.01). Direct correlation was found between poorly-differentiated HCC and TumorSUVmax/MuscleSUVmax ratio (R² = 0.54, P = 0.006). Treatment was associated with significantly more residual tumors that were well differentiated (Grades I/II) than in the untreated control group (39% vs. 5%, respectively, P = 0.01).

Conclusion: Sorafenib shows promise as a treatment for reducing the aggressiveness of HCC as demonstrated by [¹⁸F]FDG PET and immunohistochemistry.

Globally, hepatocellular carcinoma (HCC) is the second leading cause of cancer related death. Hepatitis C virus infected patients with cirrhosis or bridging fibrosis are particularly at risk. The risk is reduced among patients who achieve viral clearance with interferon-based regimens. Direct-acting antivirals (DAA) have revolutionized the management of HCV as the treatment is well tolerated, convenient to administer and is highly effective. Earlier studies showed conflicting results in the effect of DAA induced sustained virologic response (SVR) on the subsequent development or recurrence of HCC, with some studies showing an increased risk. More recently, two large retrospective studies provided convincing evidence that DAA induced SVR reduces the risk of HCC development. Irrespective of viral clearance, patients with cirrhosis and advanced fibrosis and those with treated HCC continue to be at increased risk requiring long-term surveillance studies.

Alternative splicing is a highly regulated process that plays a critical role in diversification of the transcriptome and proteome in the cell. Several diseases, including different types of cancers, have been associated with aberrant regulation of alternative splicing. Thus, correcting alternative splicing is an attractive strategy to restore normal cell physiology in patients with cancer including hepatocellular carcinoma (HCC). This review summarizes the role of alternative splicing events related to HCC and potential therapeutic applications for it.

Obesity and diabetes are associated with the onset of hepatocellular carcinoma (HCC). These two illnesses correlate also with the development of non-alcoholic fatty liver disease (NAFLD). Currently, NAFL is considered the leading form of chronic liver disease in the Western industrialized countries. Insulin resistance is the common pathogenic factor among these three pathologies. NAFL is characterized by fat accumulation in the liver that involves greater than 5% of the liver parenchyma with no evidence of hepatocyte injury. However, NAFL may progress toward non-alcoholic steatohepatitis that in turn may lead to advanced fibrosis, cirrhosis and HCC. It is alarming that NAFLD related HCC has been, at present, considered as a growing burden worldwide, and its prevalence is tending to further increase together with the increasing incidence of obesity and diabetes. Worthy of note is that in the presence of chronic accumulation of fat in the liver it has been reported the emergence of HCC during chronic liver disease in absence of liver cirrhosis, usually the major risk factor for the development of HCC. Thus, in the future NAFLD related HCCs will place a growing strain on health-care systems from the need for their management. Unfortunately, most of the NAFLD related HCC patients are diagnosed at advanced stages and are characterized by a poor prognosis, because they are ineligible to radical treatments. Thus, it is urgent to boost up new screening policies to make early diagnoses, as well as to develop preventive-therapeutic strategies.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. There are two major challenges for HCC, the first being that early detection is generally not applicable, and secondly, it is usually fatal within several months after diagnosis. HCC is an inflammation-induced cancer. It is known that chronic inflammation leads to oxidative/nitrosative stress and lipid peroxidation, generating excess oxidative stress, together with aldehydes which can react with DNA bases to form promutagenic DNA adducts. In this review, the evidence between oxidative stress and liver carcinogenesis is summarized. We focused on the potential of using DNA adducts as oxidative stress biomarkers for liver carcinogenesis.

Cancer is a major disease threatening human health. The overall prognosis for hepatocellular carcinoma (HCC) patients is poor, with a dismal 5-year survival rate of approximately 5%-30%. The dysfunction of immune system plays a pivotal role in the development of cancer, which has attracted attention of several researchers. Recent advances in immunotherapy have led to various inspired achievements and refreshed our concepts about cancer treatments. In this article, several types of immune-based therapies for treating HCC are reviewed. Their underlying mechanisms, preclinical and clinical study results, potential prospects, and deficiencies are discussed, and an outline for future research directions is proposed.

Aim: Hepatitis C virus (HCV) infection is a global health problem that affects more than 180 million people worldwide. HCV is associated with several hepatic and other hepatic disorders including malignancies. HCV is a small enveloped positive-single strand RNA virus that belongs to Hepacivirus in the family Flaviviridae. Here we aim to provide a new therapeutic strategy via treatment of infected HepG2 cells with heat shock (HS).

Methods: The potential inhibitory effect of HS on HCV replication was assessed by the relative gene expression of NS5A and its corresponding protein by flowcytometry which has been additionally used to monitor other cellular factors.

Results: HS treatment of infected HepG2 cells has the ability to disturb HCV replication possibly via stimulation of the Alu non-coding element which inhibits gene expression of ribosomal L22. Ribosomal protein L22 (RPl22) is one of the abundant RNA-binding proteins that are known to facilitate synthesis and translation of viral RNA and to participate in balancing the protein components of the ribosome itself.

Conclusion: HS treatment of infected cells leads to up-regulation of long RNA-Alu molecule that regulates the expression of RPL22 and subsequently reduces HCV replication in HepG2 cells.

Development of hepatocellular carcinoma (HCC) is very complex and occurs through a multistep biological process of malignant transformation of normal hepatocytes in which various factors, including genetic and epigenetic alterations, regulation of oxidative stress, inflammation, and immunity are involved. To date, numerous studies have described the molecular pathogenesis of HCC, but the precise molecular mechanisms of HCC development remain unclear. Emerging single-cell transcriptome analysis technology is a powerful tool for defining sub-populations within heterogeneous bulk tumor tissue and allows molecular characterization of each cell. This breakthrough method can unveil the molecular mechanisms of HCC. In this article, I discuss recent advances in the molecular pathogenesis of HCC through this newly emerging concept of single-cell analysis.

Hepatitis C virus (HCV) has emerged as a leading cause of hepatocellular carcinoma (HCC). In most cases, the virus causes HCC in the presence of chronic hepatic inflammation, advanced fibrosis, and cirrhosis. A combination of viral, environmental, and genetic factors are likely to determine the host immune response to the infection as well as the progression to HCC. Clinical and epidemiologic studies have identified many of the risk factors associated with HCC development in patients with chronic hepatitis C. Male sex and older age are considered as independent risk factors for HCC, while alcohol consumption accelerates fibrosis, increasing the risk for progression to HCC. Obesity, diabetes mellitus, nonalcoholic fatty liver disease, aflatoxin exposure and occult hepatitis B infection, all contribute to a higher HCC risk. HCV patients infected with HCV genotype 3 are also more likely to develop HCC and genetic variations such as single nucleotide polymorphisms, which may also alter the risk. Sustained virological response to the antiviral therapy results in significantly more favorable long-term outcomes. The incidence of HCC after HCV eradication is similar between patients treated with peginterferon plus ribavirin and direct-acting antiviral therapy.

Hepatocellular carcinoma (HCC) commonly presents at an advanced stage due to the lack of efficient early screening tools. Early, non-invasive biomarkers useful in the diagnosis and prognosis of HCC would be of significant benefit for HCC management. Development of exosome-based liquid biopsy as a non-invasive method for the management of HCC has gained much traction. Exosomes are small membranous vesicles secreted by most cell types including HCC cells. Exosomes serve as couriers for the intercellular transfer of important biomolecules, including, protein, nucleic acids and lipids to nearby and distant cells in the body. The molecular cargos carried by exosome have been described to play significant roles in cancer progression. Herein, we will dissect how HCC-derived exosomes confer aggressive traits such as tumour growth, invasion, immune remodelling and drug resistance to HCC cells. We review the current literature concerning exosomes as biomarkers in a diagnostic setting, evaluating their prognostic, predictive and monitoring capabilities. This review will highlight and discuss emerging research in the utility of exosome-based liquid biopsies therapeutic tools in HCC management. Here we will also focus on advances in exosome biology in preclinical studies.

Globally 71 million people are living with hepatitis C virus (HCV) out which 7.1 million (10%) are present in Pakistan. Genotype 3 is the most common HCV type in the country. World Health Organization is working with health authorities in different countries for effective control of HCV, to reduce its incidence by 90% and to reduce hepatitis related mortality by 65% by the year 2030. There are several challenges that hinder elimination of HCV from Pakistan including the lack of patient awareness about the causes and transmission of disease, lack of affordability for investigations and drug treatment and lack of experienced healthcare professionals. Other major contributors to achieve HCV elimination are lack of effective drugs and delayed regulatory approvals combined with compromised monitoring by health authorities and lack of robust epidemiological data. Efforts are needed to educate the public about the modes of transmission and prevention of HCV infection, and massively upscale screening along with treatment. There is a dire need to prevent more than 200,000 new infections that occur each year in Pakistan. Given the scale of the problem, it is very unlikely that the government alone can handle it.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related to worldwide death with a great geographical variation. To be eligible for curative therapy at the time of diagnosis is important. However, the majority of cases are diagnosed at late stages. This can be achieved with applicable screening modalities. Until now, many organizations around the world have developed guidelines according to their own evidence-based data for screening of HCC. The purpose of this article is to review the screening modalities of HCC to assist gastroenterologists and providers involved in the management of HCC.

Hepatocellular carcinoma (HCC) represents the most common indication of laparoscopic liver resection (LLR). It must be acknowledged that most series concern minor hepatectomies for peripheral lesions located in favorable segments, and such procedures are now performed in the majority of HPB centers. However, there are growing reports concerning major hepatectomies (i.e., 3 segments or more) and complex resections such as anatomical resections in difficult segments (i.e., postero-superior). Retrospective comparative studies, including some with propensity score matching, and meta-analyses showed that LLR is associated with short-term benefits including reduced blood loss, length of stay and morbidity with identical oncological results and survival rates. In addition, laparoscopy leads to less post-operative abdominal adhesions, improving operative outcomes in case of repeat hepatectomy or secondary liver transplantation. Despite the lack of results of randomized-controlled trials in HCC, a consensus exists that the laparoscopic approach can improve the outcome of major liver resections, provided it is performed in experienced centers. This requires specific high-quality training.

Liver fibrosis is a wound-healing response of liver cells to chronic injuries caused by viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), toxins, and alcohol abuse. The ability to stage diseases for treatment naïve patients to initiate proper medical procedures and predict the clinical causes of the disease or the treatment response is important given the increased prevalence of liver fibrosis caused by HBV, HCV and fatty liver diseases. CHI3L1 (chitinase-3-like protein 1, also known as YKL-40), which belongs to the chitinase family but lacks chitinolytic activity and is highly expressed in the liver, seems to fulfill this role. CHI3L1 is a non-invasive staging marker for liver fibrosis caused by HBV, HCV and non-alcoholic fatty liver disease as well as a predictor of the clinical causes and fibrotic changes after treatments. CHI3L1 predicts histological progression of liver fibrosis and fibrosis progression rate (fibrosis unit/year), rapid fibrosis progression after liver transplantation and response to interferon and recent direct acting antiviral therapy in chronic HCV patients. CHI3L1 also predicts response to antiviral therapy in chronic HBV patients.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The prognosis for patients who present with inoperable primary liver tumors is poor with median survival times of 12 months or less. Tumor-related liver failure is a common cause of mortality, underscoring the importance of local control. Recent advancements in external beam radiation therapy delivery techniques have enabled dose escalation that in turn has significantly improved local control and has allowed radiation therapy to emerge as an effective modality in this setting. In this review, we outline the critical practical aspects of treating liver tumors with radiation including choice of fractionation, motion management, image guidance and use of intensity-modulated radiation therapy vs. proton beam therapy. We review our approach to ablative radiation therapy for HCC with consideration of underlying cirrhosis and provide a brief overview of the current literature.

Hepatic resection has become the standard treatment of primary liver cancer. Indications for hepatic resection in patients with hepatocellular carcinoma (HCC) vary greatly between Japan and other countries because the clinical practice guidelines for HCC defined by the Japan Society of Hepatology differ from the EASL-EORTC clinical practice guidelines. Hepatic resection is not recommended as a treatment for the patients at Barcelona Clinic Liver Cancer (BCLC) stage B. Otherwise, there are many surgeons/clinicians who believe that not all HCC patients at BCLC stage B should be excluded from an indication for hepatectomy because many reports showed good prognosis after hepatic resection for HCC patients over BCLC stage B. The survival rate is expected to increase with better outcomes of hepatectomy in the future. This paper has described indications for hepatectomy for patients with HCC through comparison of domestic guidelines with overseas guidelines, focusing on their differences.

Most hepatocellular carcinomas (HCCs) arise on a background of chronically inflamed liver, and thus are considered typical immunogenic cancers. Although there have been advances in treatment options for HCC, many patients still struggle with a limited chance of survival requiring further innovative approach. Especially for the advanced HCC, many other molecular targeted therapies had been evaluated without success. Based on the immunological mechanisms thought to be acting during HCC development, the effects of diverse immunomodulatory regimens such as therapeutic vaccination, immune checkpoint inhibitors, and adoptive cellular immunotherapy have been investigated. Notably, many strategies have been developed in adoptive cellular immunotherapy, including dendritic cells, cytotoxic T cells, natural killer cells, cytokine-induced killer (CIK) cells, and genetically engineered T cells. In recent clinical trials, adjuvant CIK cell immunotherapy increased progression free survival after curative treatment of HCC. Most recently, new immunomodulatory agents were introduced for oncological treatment, eventually leading to the clinical breakthrough of checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). To date, very promising published evidence with checkpoint inhibitors in HCC has been reported in the clinical trials with anti-CTLA-4 agent tremelimumab and a large phase II trial with anti-PD-1 agent nivolumab. Further investigations of immuno-oncology potentially popularized the applications of immunotherapy in the various stages of HCCs, and thus immune-based therapies are the promising innovative approach for patients with HCC. Hopefully, the immuno-oncology will bring about a paradigm shift of anti-cancer treatment for HCC.

Hepatocellular carcinoma is the third most common cause of cancer-related death globally and portends a poor prognosis. The fibroblast growth factor receptor (FGFR) pathway is increasingly acknowledged to play a role in the pathogenesis of hepatocellular carcinoma (HCC) and is postulated to be upregulated as a mechanism of resistance to anti-VEGF treatment. We attempt to review the importance of the FGFR pathway in HCC oncogenesis, as well as the current clinical evidence on the efficacy and safety of FGFR pathway inhibitors in HCC.

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide. Surgery is the mainstay of treatment, but less than 20%-30% of patients are good candidates. Actually, thermal ablation is considered the best treatment with curative intent for cirrhotic patients with unresectable HCC ≤ 3 cm. Unfortunately, radio frequency efficacy in obtaining the complete ablation of HCC nodules diminishes with increasing tumor size and local tumor progression is more frequent in larger nodules. To overcome these problems, higher-powered generators, different devices and techniques have been attempted. Furthermore, microwave ablation has been introduced with the promise of a large ablative capacity. The aim of this review is to describe the role of thermal ablation for the treatment of large unresectable HCC.

Hepatitis C virus (HCV) was discovered in 1989, before that it was commonly known as transfusion associated non A non B hepatitis. It rapidly assumed the role of leading cause of cirrhosis and liver cancer and a leading indication for liver transplant globally. For over two decades the treatment was suboptimal with the use of pegylated interferon and ribavirin combination across all genotypes. The vaccine development also failed for over two decades. However a major breakthrough happened in December 2013 when the Food and Drug Administration (FDA) approved the first pan genotypic oral directly acting drug Sofosbuvir. Since then many new directly acing drugs have been approved through fast track by the FDA. Today we have directly acting antiviral agents for all HCV patients providing cure rates of over 90%. Looking into this success the World Health Organization has set targets for 2030 for HCV elimination. There are several countries which have formed strategies to achieve this goal and others are still thinking to develop their own strategies. The availability of generics have reduced the prices substantially, however the problem is so gigantic that unless proper operational strategies for elimination are developed by the developing world especially by China and Pakistan, the two counties having the largest existing pool of HCV patients, the goals of elimination may not come true.

Hepatocellular carcinoma (HCC) is the main tumor of the liver and is the sixth most frequently diagnosed tumor in the world. It is the evolution of chronic hepatic injury secondary to different etiologies. Chronic hepatitis B virus and hepatitis C virus infection, chronic alcoholic hepatitis, as well as non-alcoholic fatty liver disease are the most common causes behind the development of HCC. The introduction of effective prophylaxis and treatment against hepatitis B, the recent use of highly effective hepatitis C treatments, as well as lifestyle changes observed in recent decades in the general population causing an increase in obesity and metabolic syndrome have led to significant epidemiological change in HCC in relation to the changed etiologic prevalence of liver injury. Increasing evidence was emerging, emphasizing how the development of HCC is a complex and multifactorial process. The knowledge of the molecular mechanisms involved is important for the understanding of the basic factors of the development of hepatocarcinogenesis and of possible therapeutic approaches. Several pathogenic mechanisms and clinical expression of HCC occur in relation to the different etiologies of the underlying liver disease. The different clinical behavior of HCC often makes diagnosis difficult at an early stage, that is necessary for an effective therapeutic approach. This review analyzes the possible different pathogenic mechanisms involved in the development of HCC and emphasizes the different epidemiological and clinical aspects of HCC observed in the most common forms of liver diseases of viral and non-viral origin.

Aim: To investigate the potential effects of recipient ethnicity on the short and long-term outcomes of patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) in the United States. We performed a retrospective study using the standard transplant analysis and research (STAR) files with the primary aim of assessing short and long-term survival of different ethnic groups undergoing LT for HCC in the United States.

Methods: The study population was represented by adults (age ≥ 18) who received a first-time cadaveric LT for HCC between 1 Jan 2002 and 30 Jun 2013. Recipients of LT for other primary and secondary malignancies were excluded. Other exclusion criteria were: transplants from grafts recovered from living or donors after cardiac death, split grafts, multi-visceral or redo transplants, and LT performed across ABO incompatible blood groups. Survival analysis stratified by recipient ethnicity was performed using the Kaplan-Meier method. Proportional hazard model analysis was used to assess the effect of predictors of survival. Characteristics utilized in the Cox regression model were selected a priori.

Results: The study population was represented by 6048 recipients with an average age of 58 years and 20% being females. The majority of patients were Caucasians (67%), followed by Hispanics (14.2%), African Americans (8.8%) and Asians (8.6%). Overall 30-, 60-, 90-day and 1-year mortality was 1.7%, 2.3%, 3.0% and 8.8% respectively with no statistically significant differences among ethnicities. Log-rank comparisons however showed that African American had the lowest 5-year survival with statistically significant differences in comparison to all other ethnic groups (P ≤ 0.001). At multivariate Cox-regression analysis, African American ethnicity remained an independent predictor for increased mortality (HR = 1.524; 95% CI: 1.283-1.803; P < 0.001) after adjusting for the recipient and donor age, recipient sex, recipient history of diabetes and recipient functional status at the time of transplantation.

Conclusion: Short-term outcomes of African Americans undergoing cadaveric LT for HCC are similar to other ethnic groups. However, African American ethnicity is an independent predictor of lower 5-year overall survival when compared to all other ethnic groups.

Primary liver cancer represents the 4th most common tumor in males (4% of all cancers) and the 7th most common tumor in females (2.3% of all cancers), with a prevalence of 53/100,000 in males and 22/100,000 in females (male-to-female ratio = 2:1). In the majority of the cases, hepatocellular carcinoma (HCC) develops in patients with cirrhosis and thus the risk factors for HCC and chronic liver disease are overlapping. Viral infections (hepatitis B virus, hepatitis C virus), alcohol and fat (nonalcoholic fatty liver disease/non-alcoholic steatohepatitis) represent the main risk factors for development of HCC on cirrhotic liver. Several prospective studies reported that at present HCC does represent the first cause of death of cirrhotic patients, while in the past morbidity and mortality in cirrhosis were mainly determined by other non-neoplastic complications of the disease. From a clinical point of view, staging systems in HCC should define outcome prediction and treatment assignment. Due to the nature of HCC, the main prognostic variables are the tumor stage, liver function and performance status. The most accepted clinical classification of HCC has been proposed by the Barcelona Clinic Liver Cancer. The BCLC staging system has come to be widely accepted in clinical practice and is also being used for many clinical trials of new drugs to treat HCC. Therefore, it has become the de facto staging system that is used.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths in the world. In contrast to other cancers, survival of patients with HCC is determined by the extent of the tumor in addition to underlying liver disease and its functional reserve. From risk factors to management, HCC reveals a considerable geographic and institutional variation throughout the world. Although many staging and/or scoring systems have been proposed, each prognostic system has several benefits and limitations on its own. Therefore, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. In this review, currently available staging systems for assessing the prognosis of HCC, their uses, limitations, and future prospects are revisited.

The development of second generation ultrasound (US) contrast-medium and specific imaging techniques with dedicated softwares, allows to observe the liver perfusion in real time, becoming an useful and less invasive method to describe precisely the vascularization of hepatic lesions. This significantly increased the ability of US to detect and characterize focal liver lesions. The aim of this review article is to evaluate the role of contrast enhancement US in the diagnosis of hepatocellular carcinoma in cirrhotic liver, with reference to the guidelines of American Association for the Study of Liver Diseases, European Association for the Study of the Liver and European Federation of Societies for Ultrasound in Medicine and Biology.

Liver transplantation (LT) is recognized as best treatment option in patients with early hepatocellular cancer (HCC) in underlying liver cirrhosis. Apart from tumor size and number implemented in the Milan criteria, which are current worldwide standards for patient selection, several biological tumor factors have been identified to affect cancer-specific outcome. In particular, grading and vascular tumor invasions were shown to correlate with aggressive biological tumor behavior and poor survival following LT. Identifying tumors with favorable biology is one important approach for expanding the pool of eligible liver recipients beyond the Milan burden limits. Improving the immunological state and condition for appropriate defense against circulating cancer cell attack may be another important prognostic aspect. Therefore, there is increasing interest in non-cancer factors related to the peritransplant period that may influence the oncological outcome by providing negative immunomodulatory actions. Considering and modulation of these non-HCC factors of prognosis might contribute in safely expanding the HCC LT selection criteria.

Aim: Disturbed alternative splicing of far upstream element-binding protein-interacting repressor (FIR) was found to be unable to repress c-Myc transcription and so it might be important for suppressing tumor development. FIR is a splicing variant of poly (U)-binding-splicing factor (PUF60), and forms complex with other splicing factors. FIR/PUF60 is a splicing factor of U2 small nuclear ribonucleoprotein auxiliary factor family, Thus FIR/PUF60 is a multifunctional protein. The expression of exon2-lacking splicing variant of FIR, FIRΔexon2, is elevated in many cancer tissues and promotes tumor development by disabling FIR-repression to sustain c-Myc activation. FIRΔexon2, as a dominant negative of FIR, opposed apoptosis in cancer cells. FIR/FIRΔexon2 interacts with degron pocket of F-box and W (Typ) D (Asp) repeat domain-containing 7 and inhibits proteolysis of substrates proteins. Recently, FIR/PUF60 was identified as a versatile regulator of transcriptional and post-transcriptional steps in expression of hepatitis B virus (HBV) pregenomic RNA (pgRNA) expression.

Methods: Small molecular chemical compounds against FIR and FIRΔexon2 were screened among 2,3275 chemicals by natural product depository array (RIKEN, Wako, Saitama, Japan).

Results: Nine chemicals against FIR and four chemicals against FIRΔexon2 were identified as candidates of interacting chemicals. Interestingly, BK697 contains WD -like structure. Among them, BK697 against FIRΔexon2 inhibited hepatoma cell growth.

Conclusion: Therefore, FIR (PUF60)/FIRΔexon2 is multifunctional and applicable for clinical use for HBV suppression and hepatoma treatment. Together, one clue to the development of hepatome diagnosis and therapies directed against FIR/FIRΔexon2/PUF60 with small molecular weight chemicals that inhibit HBV cccDNA replication.

Aim: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) for chronic hepatitis B (CHB) can be associated with reappearance of hepatitis B surface antigen (HBsAg). The current study determined the significance of HBsAg qualitatively and quantitatively using a highly sensitive assay in recurrent HCC after transplantation.

Methods: Consecutive patients with HBV-related HCC with LT were included. Oral nucleos(t)ide analogues without hepatitis B immune globulin were used as hepatitis B virus (HBV) prophylaxis. Quantitative HBsAg levels were performed at time of transplant, at 1 month, 3 and 6 months post transplant using a highly sensitive (hs)-HBsAg assay.

Results: One hundred and fourteen patients were included, with a median follow-up of 80 months, with 24 cases of HCC recurrence, and a cumulative rate of 20.7% at 5 years. There was significant correlation between time of tumor recurrence and time of HBsAg reappearance (r = 0.551, P = 0.027). Early HCC recurrence was associated with higher median level of hs-HBsAg at the time of transplant (72.85 vs. 69.70 IU/mL, P = 0.018). Using a hs-HBsAg cut-off level of 0.0005 IU/mL, patients with levels above this threshold at 3 and 6 months were associated with higher rate of early HCC recurrence (28.6% vs. 3.0% and 26.9% vs. 2.9% respectively, both P = 0.0006). There was no significant difference in HCC recurrence between positive and negative HBsAg using the conventional qualitative HBsAg assay.

Conclusion: Serum hs-HBsAg levels of ≥ 0.0005 IU/mL at 3 to 6 months after LT is associated with higher rates of early HCC recurrence, and may be useful as an early tumor marker.

Alpha-fetoprotein (AFP) has been increasingly recognised as a valuable marker in predicting HCC recurrence post-liver transplantation. Moreover, its secretion has been associated with poor histological tumour characteristics as it reflects an aggressive tumour biological behaviour. This review aims to summarise the emerging evidence on the use of AFP either as an independent marker, or as a variable incorporated into prognostic models. For this purpose, an electronic PubMed literature search was performed. Due to the heterogeneity of the reported studies, drawing clear conclusions about the optimum AFP cut-off level to predict recurrence is difficult. Models that include AFP at different cut-offs have been shown be superior to Milan criteria in predicting disease recurrence, but need to be prospectively validated in order to confirm their prognostic value. Until more refined methods for selecting patients become available, existing evidence support the use of AFP in decision models for liver transplantation.

Hepatitis C virus (HCV) remains a major public health threat worldwide, responsible for 500,000 deaths annually; hepatocellular carcinoma (HCC) remains one of the major causes of HCV-related mortality. The global prevalence of HCV is approximately 1.0%, and in developed countries, injecting drug use continues to be the primary risk factor in incident cases. Targeted treatment of people who inject drugs (PWID) is important for achieving the WHO goals of eliminating viral hepatitis, which will have a significant impact on reducing HCC rates. Due to the close relationship between injecting drug use, incarceration and chronic HCV, the prevalence of HCV is up to 40 times greater within correctional facilities compared with the community. However, very few prisoners are treated for HCV while incarcerated. This is a result of financial, logistical and prisoner barriers to HCV care within correctional facilities. In the era of direct acting antiviral (DAA) therapy which is highly efficacious, time-efficient and safe, modelling studies have identified the benefit of increasing HCV treatment uptake amongst PWIDs to reduce community prevalence via treatment-as-prevention. Despite this, there are few real-world data evaluating DAA therapy within prison settings. In this article, we review the barriers to HCV care within prison systems, the outcomes of traditional HCV treatment programs within prisons and emerging data regarding the benefit of DAA therapy within correctional facilities. We present the mathematical modelling regarding the impact of treatment as prevention amongst PWIDs to eliminate HCV as a public health threat and how the prison fits into this paradigm.

Hepatocellular carcinoma (HCC) is a significant cause of mortality in patients with chronic liver disease around the world. Development of biomarkers for early HCC detection is a primary public health goal to decrease mortality. The ideal biomarkers should be highly sensitive and specific for surveillance of high-risk populations and early detection of HCC and also be able to predict therapeutic outcome and provide a prognosis on survival. Currently, the new biomarkers do not perform better than the conventional ones such as alpha-fetoprotein in such a way that they could be widely adopted in clinical practice. Another problem is the low sensitivity of these biomarkers in the detection of HCC. Further work on the development of novel biomarkers and on a combination of them is necessary. Advances in identifying unique molecular signatures including genomic, proteomic, metabolomic, and glycomic profiles have improved our understanding of many biological processes involved in HCC. This review focuses on the role of old and new biomarkers in surveillance, diagnosis, prognosis, and prediction of response to therapeutic targets for HCC and provides up-to-date data to health-care providers which would be applied in clinical practice.

Aim: Worldwide, hepatocellular cancer (HCC) is the fourth leading cause of cancer death and occurs 3 times more commonly in males than females. Current surveillance practices do not fully address gender differences in HCC.

Methods: Clinical characteristics and survival were compared between males and females using a prospectively collected database of HCC patients.

Results: In a cohort of 1206 patients, 307 (25%) were female who presented with older age, more non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), family history of HCC, and hypertension. Males (75%) were more likely to use alcohol and cigarettes. Females were more likely to undergo HCC surveillance, have smaller tumor size at diagnosis, and less vascular involvement. Males who met Milan criteria were more likely to undergo liver transplant than women who met the criteria. Median/mean survival was similar between the genders. Multivariate analysis showed that NAFLD/NASH was predictive of mortality for both males and females, age and smoking were predictive of mortality for males, and transplant was predictive of survival for males.

Conclusion: Gender differences in HCC appear related to both behavioral risk factors and biologic factors. Older females with HCC have more NAFLD/NASH and may be overlooked by current surveillance guidelines. These gender disparities may lend support to future studies of gender-based HCC screening.

Aim: We report an update of our experience on endolymphatic immunotherapy in patients with advanced hepatocellular carcinoma (HCC) not eligible for surgery.

Methods: From 2003 to 2009 we enrolled 39 patients with advanced HCC not suitable for surgery. Patients underwent monthly endolymphatic injections of 1.5 × 10⁶-3.0 × 10⁶ IL-2-activated peripheral autologous lymphocytes and 250U of IL-2. Blood biochemistry every 3 months and imaging studies every 6 months were performed. Evaluation of the results was done according to clinical and pathological characters mainly including etiology, Child-Pugh class, size and number of lesions, α-fetoprotein, lymphadenopathy, vascular invasion, Response Evaluation Criteria in Solid Tumours criteria for tumour burden, biochemical parameters and survival rates.

Results: Ten patients completed 12 therapy cycles, 6 received 6 infusions, 10 only 3-4 injection and 13 patients received less than 3 injections and where considered not suitable for evaluation. No clinically significant adverse reactions occurred. Imaging studies showed no significant decrease in tumour mass. Survival of treated patients was significantly higher with respect to control group (P < 0.0001). The 1-year survival was 0% in the control group vs. 50% in the treated group. In addition survival of patients who completed 12 therapy cycles appeared higher with respect to patients who underwent less than 6 cycles without reaching statistical significance due to the small number of patients. All patients with 12 completed cycles showed an improvement of 9 parameters or more.

Conclusion: Endolymphatic administration of immunotherapy appeared safe, easy to perform and effective in terms of survival. This study should encourage future large scale studies in order to reach a firmer conclusion and define uniform inclusion criteria.

With increasing awareness of the HCC epidemic around the globe, early diagnosis of tumors provides a greater opportunity to benefit patients from liver-directed treatments including surgical resection, ablation, catheter-based therapies and external beam radiation. Development of new approaches and refinement of existing techniques have improved our capabilities to provide efficacious and safe means of local disease control. The choice of treatment for individual patients hinges heavily on factors related to the tumor, underlying hepatic function, and existing co-morbidities. Recent advances in minimally invasive therapies across all disciplines have augmented our ability to eradicate the tumor while preserving liver parenchyma. In this review, we discuss and summarize current minimally invasive options that are available to treat HCCs that are confirmed to the liver, especially in their early stages. Emerging evidence suggest that resection, ablation and radiation can all provide excellent local control, and this opens more options for patients to best suit their needs.

Heterogeneity is a cardinal hallmark of cancer, including primary liver cancer (PLC), and occurs at different layers including putative cell-of-origin. Current evidence suggests that within cellular subpopulations in PLC there are stem-like cells, the cancer stem cells (CSCs). The CSC concept has been recently proposed as an explanation of such intra-tumor heterogeneity. According to this model, CSCs are responsible for tumor initiation, recurrence, metastasis as well as drug-resistance. However, although the CSC hypothesis is intriguing and supported by a large number of experimental studies, there are still open questions regarding the origin of putative CSCs. Since chemo-resistance and recurrence represent major issues in PLC treatment, the development of new therapeutic strategies is needed, for which a good understanding of tumor behavior and in particular of CSCs biology is an imperative prerequisite. In this review we summarize the regulatory pathways that support CSC features in PLC. Moreover, we highlight the key features of hepatic CSC, in terms of enhanced drug-resistance, increased metastatic potential and metabolic rearrangement. Knowledge of the molecular mechanisms underlying CSC biology may provide novel options for PLC combination therapies.

Since the widespread adoption of new direct-acting antiviral agents (DAAs), the approach to hepatitis C virus (HCV) infection has changed profoundly as almost all patients can be cured regardless of the stage of their liver disease. On the other hand, there are a few conflicting reports on the risk of hepatocellular carcinoma (HCC) occurring and recurring in patients given DAA-based therapy. The present review focuses on the latest and most relevant literature providing evidence on the occurrence and recurrence of HCC after HCV antiviral treatment with the new DAAs. Retaining the distinction between HCC occurrence and recurrence, we also discuss its patterns of presentation and speculate on the possible pathogenic mechanisms. We offer our personal viewpoints on this important issue, which has kept clinicians second-guessing in real-world clinical practice, when dealing with HCV eradication in the setting of advanced liver disease in this interferon-free era.

Aim: Genotype 3 is the most prevalent genotype in Pakistan. Despite a revolution in the treatment of Hepatitis C, genotype 3 is still thought to be difficult to treat genotype. The price of patent direct acting antivirals was thought to a great limiting factor especially for low income countries. In Pakistan low cost generics of daclatasvir and sofosbuvir are easily available for treatment. The aim of our study is to provide real life local data to determine their efficacy and safety.

Methods: This open-label, non-randomized, uncontrolled study was carried out at Center for Liver and Digestive Diseases, Holyfamily Hospital, Rawalpindi. We enrolled patients from March 2016 through March 2018 who were 18 years or older having chronic hepatitis C infection with detectable polymerase chain reaction (PCR), regardless of whether they were treatment naïve or have experienced Interferon in the past. The patients were offered generic sofosbuvir 400 mg and daclatasvir 60 mg once daily with or without ribavirin for a period of 12 to 24 weeks. Follow-up PCRs were performed at 4th week of treatment, end of treatment and 12 weeks post treatment. All those patients were included in the study that had at least one follow-up PCR during or after the course of treatment.

Results: A total of 102 patients were enrolled in the study with a mean age of 48.11 ± 12.70 including 63% males and 37% females. All patients were genotype 3. On 4th week follow up, 31/36 (86.11%) patients had quantitative PCR negative. Out of 102 patients, 78 patients had follow up PCR at the completion of therapy with an end of treatment response of about 96.1%. Thirty patients had a follow up at 12 weeks post treatment with a SVR12 of 83.33% (25/30) amongst which treatment Naïve had a response rate of 84% (21/25), treatment experience 80% (4/5), non-cirrhotics 85.71% (12/14), cirrhotics 81.25% (13/16) and decompensated chronic liver disease patients have a SVR12 of about 83.33% (10/12) respectively. The combination was well tolerated with few side effects, 18.6% patients had itching, 10.8% had insomnia, 8.8% had oral ulcers and 6.9% had fatigue.

Conclusion: Generic sofosbuvir and daclatasvir are cheap, safe and efficacious with a SVR12 of about 83.33% amongst genotype 3 patients. These generics will act as a pivot in the eradication of hepatitis C infection from developing world.

Aim: Hepatocellular carcinoma (HCC) is a common cancer worldwide, especially in Asia, with high mortality. Curative options are only available for early-stage HCC, which are usually asymptomatic and best diagnosed through surveillance. Risk factors associated with HCC include liver cirrhosis due to alcohol, chronic viral hepatitis infections and nonalcoholic steatohepatitis. We review the evidence supporting the benefits and drawbacks of HCC surveillance as well as new surveillance modalities.

Methods: A MEDLINE and Cochrane Database search with defined search phrases was performed. Studies published from Jan 2000 to Jul 2018 were reviewed and publications focusing on the benefits and harms of HCC surveillance were qualitatively synthesized. Modalities of HCC surveillance were also reviewed.

Results: A total of 5 randomized controlled trials (RCTs) and 24 cohort studies with sample size of more than 100 each were selected. Significant mortality reduction was demonstrated in 1 RCT. Cohort studies showed overall improved outcomes in the surveillance group with 61.3%-88% of HCC being detected in an early-stage and with up to 80% eligible for curative treatments. A quarter (27.5%) of the surveillance patients experienced additional scans or procedures due to false-positive results. Combination of ultrasound with alpha-fetoprotein increases HCC detection rate. Novel serum markers and liquid biopsy are attractive tools for surveillance as they are non-invasive and convenient.

Conclusion: The current evidence supports HCC surveillance as it detects earlier stage of tumor, allows more curative treatment and improves survival. Further research on hepatocarcinogenesis and novel surveillance modalities will continue to refine surveillance guidelines to reduce HCC-related mortality.

Aim: The incidence of non-virus-related nonB-nonC hepatocellular carcinoma (NBNC-HCC) is on the rise. However, screening at-risk individuals using imaging methods is complicated by the large size of the at-risk patient pool. The aim of this study is to develop an effective simple screening method, using blood tests.

Methods: The diagnostic value of aspartate aminotransferase (AST), alpha-fetoprotein (AFP), and des-gamma-carboxy prothrombin (DCP) was analyzed using sera from 203 NBNB-HCC patients and 106 diabetes mellitus patients.

Results: Areas under receiver operating characteristic curves for AST, AFP, and DCP were 0.844, 0.901, and 0.914, respectively. The optimal cut-offs for diagnosing NBNC-HCC based on Youden indices were 30 IU/L, 3.6 ng/mL, and 25 mAU/mL, respectively. On selecting patients who were positive at least one parameter (AST, AFP, or DCP), the sensitivity was 97.5%. This high sensitivity was preserved (98.0%) even in cases of non-advanced HCC (≤ 3 cm, ≤ 3 nodules). Specificity was 72.6%.

Conclusion: This simple triple screen for AST, AFP, and DCP appears to have diagnostic value in NBNC-HCC and could be used to select candidates for further testing using imaging.

Hepatitis C virus (HCV) is a major cause of liver morbidity and mortality worldwide with increasing disease burden projected for the next several decades. The timely advent of direct-acting antivirals (DAAs) sparked significant public health responses aimed at HCV elimination by 2030. This review will focus on the implications of the DAAs in terms of medical progress, barriers to HCV elimination as a public health threat, and current gaps that will require further innovation. We utilized PubMed searches with the relevant keywords for articles published in the last 5 years, as well as personal collections of relevant publications. DAAs have proven to be safe and effective. DAAs are well suited for nearly all infected patients, and many countries worldwide have taken on initial treatment scale-up strategies. These unprecedented efforts, albeit significant, face extraordinary challenges related to the high infection burden, stigma, and financial constraints. Currently, few countries are progressing towards HCV elimination, as this attainable public health goal requires explicit, adequately resourced, and coordinated public health prioritization at all levels.

To implement an adequate treatment strategy for solitary hepatocellular carcinoma (HCC), the prediction of microvascular invasion (MVI) is crucial. Metastatic recurrences after curative treatments can result from occult metastasis derived from invisible MVI. For predicting MVI, poorly differentiated or non-singular nodular HCC with a high risk of MVI should be evaluated by common imaging modalities such as ultrasound, contrast enhanced computed tomography (CECT), or magnetic resonance imaging (MRI). Summarizing these predictabilities in previous reports, the accuracies for predicting MVI were 78% in contrast enhanced ultrasonography (CEUS), 76%-89% in CECT, and 62%-77% in MRI. Those for predicting poor differentiation were 69%-92% in CEUS, 52%-90% in CECT, and 71%-75% in MRI. Those for predicting non-singular nodular type were 92%-95% in CEUS, 81%-89% in MRI, and 91%-93% in the combination of MRI and CECT. Among common imaging modalities, MRI can provide tissue characterization of the HCC using signal intensity. Gadolinium-ethoxybenzyl diethylenetriamine penta-acetic acid-enhanced MRI including diffusion imaging is the most informative imaging modality to predict MVI. Combination of MRI with other imaging modalities or tumor markers may provide a more accurate predicting for MVI. HCC with a high risk of MVI should be treated as advanced HCC even after curative treatment.