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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.