Hepatocellular carcinoma: predisposing conditions and precursor lesions

The global incidence of HCC is rising; in the United States, its rise is in parallel to that of cirrhosis due to the HCV and obesity epidemics. The lack of adequate treatment for advanced HCC mandates both prevention and early detection of these lesions. The limitations of currently available histopathologic evaluations, serologic markers, and radiographic imaging modalities in detecting HCC and its precursors have been outlined in this review. Refinements of all of these may lead to better HCC detection, earlier intervention, and successful treatment. Randomized controlled trials are necessary to evaluate the most efficacious and cost-effective approach to screening.     

Generalized intraperitoneal seeding of hepatocellular carcinoma after microwave coagulation therapy: a case report.

We first describe a case of generalized intraperitoneal seeding of hepatocellular carcinoma (HCC) after microwave coagulation therapy (MCT). A 61 year-old man underwent operative MCT for an exophytic HCC, 60 mm in diameter, in segment IV of his cirrhotic liver. Despite successful tumor ablation, the serum alpha-fetoprotein levels continuously rose after MCT. Five months later, radiographic examinations delineated several perihepatic masses with hypervascularity, and the patient presented with constipation. At the second laparotomy, there were numerous small peritoneal metastases involving the entire peritoneal cavity and slightly bloody ascites. An omental mass, 50 mm in diameter, involved the transverse colon. Most of these intraabdominal masses were removed together with the involved colon. Histologically, the initial tumor was a moderately differentiated HCC, and the peritoneal masses were poorly differentiated HCCs. The patient died of rapid tumor progression and bleeding 2 months later. In conclusion, we should be aware of the possible occurrence of peritoneal seeding after MCT for HCC. Every effort should be made to prevent this serious complication, particularly in cases of superficial, large, and less differentiated HCCs.     

Correlating serum alpha-fetoprotein in hepatocellular carcinoma with response to Yttrium-90 transarterial radioembolization with glass microspheres (TheraSphere™)

BackgroundFew studies have assessed the relationship between serum alpha-fetoprotein (AFP) and yttrium-90 (Y-90) radioembolization response in hepatocellular carcinoma (HCC). The objective of the study was to evaluate whether peri-procedural serum AFP was correlated with Y-90 therapy response in HCC.MethodsPatients undergoing Y-90 radioembolization with glass microspheres (TheraSphere™) for HCC between 2006 and 2013 at a single center were evaluated. The relationship between AFP and 6-month radiographic improvement (complete or partial response by modified RECIST criteria), overall (OS), and disease-specific survival (DSS) were analyzed.ResultsSeventy-four patients underwent a total of 124 Y-90 infusions. Median age was 65 years, median AFP was 37 ng/mL (range: 2–112,593 ng/mL) and median model for end-stage liver disease score was 6.2 (range:1.8–11.2). Increased AFP was not associated with radiographic improvement (odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.75–1.30, p = 0.92). Median OS was 15.2 months and was increased in patients with low AFP compared to high AFP (30.8 months vs. 7.8 months, p < 0.001). On multivariable regression analysis, increased AFP was associated with worse OS (OR = 1.11, 95%CI = 1.01–1.22, p = 0.034) and DSS (OR = 1.13, 95%CI = 1.03–1.25, p = 0.018).ConclusionPre-infusion AFP independently predicted survival after Y-90 treatment for HCC, but not radiographic response, and can help guide treatment decisions.     

Zoledronic acid delays disease progression of bone metastases from hepatocellular carcinoma

Aim: We conducted a retrospective cohort study to investigate the efficacy of combination therapy with radiotherapy (RT) and zoledronic acid for bone metastases from hepatocellular carcinoma (HCC). Additionally, we investigated the efficacy of zoledronic acid for non‐irradiated bone metastases. Methods: This study consisted of 31 patients who had received RT for bone metastases. Twelve of these patients with 23 sites of bone metastases were also treated with zoledronic acid (Z group). In the Z group, 14 sites received RT and nine sites did not. Nineteen patients with 38 sites of bone metastases were not treated with zoledronic acid (non‐Z group). In the non‐Z group, 22 sites received RT and 16 did not. We compared survival, pain response, time to pain progression, radiographic response, time to radiographic progression, and safety between groups. Results: While pain response rates were similar between the two groups, time to pain progression rates of irradiated and non‐irradiated bone metastases was significantly lower in the Z (0% and 20% at 6 months, respectively) than in the non‐Z group (34% and 66% at 6 months, respectively) (P = 0.045 and P = 0.005). Further, while radiographic response rates were similar between the two groups, time to radiographic progression rate of non‐irradiated bone metastases was significantly lower in the Z (29% at 3 months) than in the non‐Z group (91% at 3 months) (P = 0.009). No significant side‐effects were documented. Conclusion: Zoledronic acid delayed the pain progression of both irradiated and non‐irradiated bone metastases and the radiographic progression of non‐irradiated bone metastases from HCC.     

Favorable response to second-line atezolizumab and bevacizumab following progression on nivolumab in advanced hepatocellular carcinoma: A case report demonstrating that anti-VEGF therapy overcomes resistance to checkpoint inhibition

Rationale:Advanced hepatocellular carcinoma (HCC) remains a deadly disease in part due to decades of limited therapeutic options. With recent advances in our understanding of the tumor biology, several promising treatment strategies involving targeted and immunotherapies have emerged. However, enhancing their modest efficacy in HCC and other gastrointestinal malignancies is essential to improving survival.Patient concerns:A man in his late 50s with a history of type 2 diabetes mellitus and morbid obesity initially presented with progressive abdominal pain and anorexia prompting an abdominal computed tomography scan that revealed a large solitary liver mass with extensive local involvement.Diagnoses:Although there were features consistent with a primary gastric tumor on subsequent endoscopic evaluation leading to early diagnostic uncertainty, his clinical picture, including a dominant liver mass, immunohistochemical staining profile, and significantly elevated alpha fetoprotein ultimately favored HCC.Interventions:The patient received palliative systemic therapy with infusional fluorouracil for a presumed gastric primary, however restaging scans after 3 cycles demonstrated disease progression. The consensus from a multidisciplinary discussion was that his pathology was more consistent with primary HCC. He was subsequently started on nivolumab with a partial response, although after 5 months, he progressed prompting initiation of second-line atezolizumab and bevacizumab with a favorable response.Outcomes:The addition of atezolizumab and bevacizumab led to a sustained biochemical and radiographic response that appeared to overcome the resistance to nivolumab monotherapy. Aside from several mild immune-related adverse effects, his quality of life has greatly improved and he has tolerated treatment well to date.Lessons:Our findings suggest that vascular endothelial growth factor inhibition can overcome resistance to checkpoint inhibition in advanced HCC by resulting in a unique synergy that has never before been described in patients. The biological rationale for this response is likely attributable to the immunomodulatory effects of antiangiogenic agents, promoting an immunostimulatory microenvironment that can be exploited by immune checkpoint inhibitors for more effective antitumor activity. Given the considerable benefit patients may derive following progression on first-line treatment, it is important to consider this strategic combination of therapies which can ultimately lead to improved patient outcomes.     

Biomarkers for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks high among the most common and fatal cancers in the world. HCC develops from chronic liver diseases, especially from hepatitis C virus-related and hepatitis B virus (HBV)-related liver diseases. In this sense, useful biomarkers for HCC detection for the patients at risk of HCC are quite important. Recently, new therapies for HCC have been developed, and the prognosis of the patients has improved. However, considering the recurrence rate of HCC after treatment is very high, biomarkers that detect recurrence at an early stage are also required. In addition, since new drugs such as multikinase inhibitors have been introduced to the clinical scene, surrogate biomarkers to predict the effectiveness of treatment will be required in the near future. So far, many biomarkers for HCC have been developed, and their clinical usefulness has been assessed. As a result, several biomarkers for HCC are widely used. However, investigations to discover more useful biomarkers that fit in clinical settings are under way. In this review article, biomarkers for HCC are overviewed to examine their clinical usefulness.     

Novel therapeutic approaches for hepatocellulcar carcinoma： Fact and fiction

Hepatocellular carcinoma （HCC） is the most common primary liver cancer and accounts for 80%-90% of this class of malignancy. So far, understanding of its pathogenesis and effective therapeutic methods are rather limited. In this issue, 11 invited review articles are published to address current advance of underlying molecular mechanisms for the deve-lopment of HCC, and novel therapeutic approaches for HCC. This series of review articles provide an in-depth unders-tanding of HCC that has led to or may lead to the development of novel therapies for HCC.     

Angiogenesis and immune checkpoint dual blockade: Opportunities and challenges for hepatocellular carcinoma therapy

The disease burden related to hepatocellular carcinoma (HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors (ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase III clinical trial IMBrave150 [atezolizumab (anti-programmed cell death ligand 1 antibody) combined with bevacizumab (anti-vascular endothelial growth factor monoclonal antibody)], showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of anti-angiogenics and ICIs, and point out the existing challenges of the combination therapy.     

Combined hepatocellular-cholangiocarcinoma (cHCC-CC): a distinct entity

Patients with hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, display a highly variable clinical course, suggesting that HCC encompasses several biologically distinct subtypes. This heterogeneity has the potential to impede both treatment decisions and prognostic predictions for patients with HCC. One distinct, albeit rare, subtype of HCC is combined hepatocellular-cholangiocarcinoma (cHCC-CC), which overall carries a poorer prognosis than HCC and cholangiocarcinoma (CC) alone. This review discusses predominantly the histopathologic and pathogenetic intricacies of this tumor and highlights the need for an accurate diagnosis of this specific HCC subtype.     

Molecular targeted therapy for hepatocellular carcinoma in the current and potential next strategies

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its incidence is still increasing. While the primary curative treatment for HCC is surgical resection, a major obstacle for the treatment of HCC is the high frequency of tumor recurrence even after curative resection. Effective palliative treatment is hindered by the evidence that HCC is frequently resistant to conventional chemotherapy and radiotherapy. Targeted therapy which specifically inhibits molecular abnormalities has emerged as a novel approach for the innovative and effective medical treatment of malignancies. In order to fulfill this promise there is an urgent need to identify the optimal targets for the treatment of HCC. A multi-kinase angiogenesis inhibitor, sorafenib, has been revealed as the first agent to show favorable overall survival in patients with advanced HCC. A new era of HCC treatment has arrived, but there has been limited improvement in survival benefits with the status quo. This review summarizes molecular targeted therapy for HCC, with a focus on angiogenesis, growth signaling, and mitosis, as well as a promising concept, ??cancer stemness?? for the current and potential next strategies of HCC treatment.     

Emerging role of ~(18)F-fluorodeoxyglucose positron emission tomography for guiding management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of major causes of cancer mortality worldwide. For decades, ~(18)F-fluorodeoxyglucose(FDG) positron emission tomography(PET) has been widely used for staging, predicting prognosis, and detecting cancer recurrence in various types of malignant diseases. Due to low sensitivity of FDG PET for detecting intrahepatic HCC lesions, the clinical value of FDG PET in HCC patients has been limited. However, recent studies with diverse analytic methods have shown that FDG PET has promising role in aiding management of HCC patients. In this review, we will discuss the clinical role of FDG PET for staging, predicting prognosis, and evaluating treatment response in HCC. Further, we will focus on recent clinical studies regarding implication of volumetric FDG PET parameters, the significance of FDG uptake in HCC for selecting treatment and predicting treatment response, and the use of radiomics of FDG PET in HCC.     

Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe?

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it has diverse etiologies with multiple mechanisms. The diagnosis of HCC typically occurs at advanced stages when there are limited therapeutic options. Hepatocarcinogenesis is considered a multistep process, and hepatic macrophages play a critical role in the inflammatory process leading to HCC. Emerging evidence has shown that tumor-associated macrophages (TAMs) are crucial components defining the HCC immune microenvironment and represent an appealing option for disrupting the formation and development of HCC. In this review, we summarize the current knowledge of the polarization and function of TAMs in the pathogenesis of HCC, as well as the mechanisms underlying TAM-related anti-HCC therapies. Eventually, novel insights into these important aspects of TAMs and their roles in the HCC microenvironment might lead to promising TAM-focused therapeutic strategies for HCC.     

Progress of targeted and immunotherapy for hepatocellular carcinoma and the application of next-generation sequencing

Hepatocellular carcinoma (HCC), leading cancer worldwide, has a high degree of genetic heterogeneity; next-generation sequencing (NGS) technology has contributed significantly to the discovery of driving genes as well as high-frequency mutations in HCC. The detection of gene alterations may allow us to predict prognosis and adverse drug reactions for individuals, paving the way for personalized medicine in HCC patients. In this review, we summarized the common systemic therapy regimens for HCC and the predictive efficacy of genetic biomarkers on the prognosis of patients under these treatments. Finally, we put forward a future perspective on the potential of NGS technology for the guidance of targeted therapy and immunotherapy in HCC.     

The Wnt/β-catenin pathway as a therapeutic target in human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. However, targeted therapies are still at their beginning for the treatment of this poor-prognosis tumor. Among the signaling cascades deregulated in HCC, the Wnt/β-catenin signaling pathway plays a key role in hepatic oncogenesis. Although it has been shown, using HCC cell lines, that inhibition of the β-catenin signaling has anti-tumoral effect, no molecules targeting the Wnt pathway are currently tested in clinical trials for the treatment of HCC. Here we review our current knowledge about the role of the Wnt/β-catenin pathway in hepatocellular carcinoma pathogenesis and the benefits and limits of targeting this pathway in HCC.     

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma and future treatments for the poor responders

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The most common problem associated with HCC is a high risk of intrahepatic recurrence despite radical treatment, and in many patients, this recurrence has fatal consequences. For patients with advanced-stage HCC according to the Barcelona Clinic Liver Cancer staging system, the multikinase inhibitor sorafenib is the current standard of care. In contrast, hepatic arterial infusion chemotherapy (HAIC) is the recommended treatment in Japan for patients with intermediate-stage or advanced-stage HCC. In this review, we describe the use of HAIC for advanced HCC. Furthermore, we demonstrate an alternative therapy for HCC, the iron chelator deferoxamine, and discuss future therapeutic possibilities.     

Mouse models for investigating the underlying mechanisms of nonalcoholic steatohepatitis-derived hepatocellular carcinoma

As the incidence of hepatocellular carcinoma(HCC) caused by infection with the hepatotropic viruses hepatitis B and hepatitis C decreases, greater attention has become focused on HCC caused by nonalcoholic steatohepatitis(NASH), an advanced form of nonalcoholic fatty liver disease which has shown increasing prevalence in correspondence with the overall increase in metabolic syndrome over the recent decades. Several clinical population studies have shown a positive relationship between NASH and HCC, while also providing initial insights into the underlying mechanisms of HCC development from NASH. Research into the pathological progression of NASH to HCC has advanced by use of several beneficial rodent models. In this review, we summarize the established mouse models for preclinical research of NASH-associated HCC and discuss the underlying hepatic mechanisms of NASH-related tumorigenesis identified to date that could lead to new targets for treatment and prevention.     

Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma

BACKGROUND/AIMS: Alcohol has been shown to be an important risk factor for hepatocellular carcinoma (HCC). The role of tobacco as a risk factor for HCC is controversial. Recently, obesity has been reported to be a risk factor for HCC. We investigated whether these factors increase the risk of HCC in American patients. METHODS: Consecutive patients with HCC, cirrhosis without HCC and, control patients without liver disease were enrolled and exposure to risk factors was assessed. RESULTS: When HCC cases were compared to cirrhotic controls, the risk of HCC increased 6-fold for alcohol (OR 5.7; 95% CI: 2.4-13.7), 5-fold for tobacco (OR 4.9; 95% CI: 2.2-10.6), and 4-fold with obesity (OR 4.3; 95% CI: 2.1-8.4). Using spline regression, a dose-dependent relationship between alcohol and tobacco exposure with risk of HCC was noted. There was significant interaction between alcohol, tobacco and obesity, with synergistic indices greater than 1. CONCLUSIONS: Alcohol, tobacco and obesity are independent risk factors for HCC in our patient population, and they interact synergistically to increase the risk of HCC. Data from this study may allow us to stratify cirrhotics into low- and high-risk groups for the development of HCC surveillance strategies.     

Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus (HCV), and non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products (AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs (TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs (RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC.