Showing papers in "Liver cancer in 2015"

Surveillance, diagnosis, treatment, and outcome of liver cancer in Japan.

Abstract: Background: Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the third leading cause of cancer-related death worldwide. HCC is most common in Asia, but its prevalence is rapidly increasing in Western countries; consequently, HCC is a global medical issue that urgently needs to be addressed. Japan is the only developed country that has experienced both hepatitis B-related and hepatitis C-related HCC and has a long history of innovation when it comes to new diagnostic and therapeutic modalities, such as computed tomography angiography, anatomical resection, ablation, and transarterial chemoembolization. Among these innovations, a nationwide surveillance program was well established by the 1980s, and such a long-term national program does not exist anywhere else in the world. Summary: More than 60% of the initially detected HCCs in Japan are Barcelona Clinic Liver Cancer stage 0 or A, which can undergo curative therapies such as resection, ablation, or transplantation. The recent 5-year survival rate of HCC patients in Japan was 43% and the median survival time was 50 months. In addition, both incidence and mortality rates are drastically declining as a result of the successful surveillance program, careful diagnostic flow, and extensive repeated treatments. Key Message: Japan’s successful model in the surveillance, diagnosis, and treatment of HCC should be adopted as widely as possible to improve the survival of HCC patients worldwide.

Effectiveness of Sorafenib in Patients with Transcatheter Arterial Chemoembolization (TACE) Refractory and Intermediate-Stage Hepatocellular Carcinoma

Abstract: Background and Aims: Patients with intermediate-stage hepatocellular carcinoma (HCC) refractory to transcatheter arterial chemoembolization (TACE) are considered to be candidates for sorafenib. The aim of this study was to evaluate the superiority of conversion of treatment to sorafenib on overall survival (OS) for cases refractory to TACE. Methods: This was a retrospective cohort study carried out on 497 patients with HCC who were treated with TACE therapy at our hospital between January 2008 and December 2013. Fifty-six patients were diagnosed as refractory to TACE during their clinical course and they were divided into two cohorts, (1) those who switched from TACE to sorafenib and (2) those who continued TACE. The overall survival (OS) after the time of being refractory to TACE was evaluated between the two groups. Results: After refractoriness to TACE therapy was confirmed, 24 patients continued with TACE (TACE-group) and 32 patients underwent treatment conversion to sorafenib (sorafenib-group). The median OS was 24.7 months in the sorafenib-group and 13.6 months in the TACE-group (p=0.002). Conclusions: Conversion to sorafenib significantly improves the OS in patients refractory to TACE therapy with intermediate-stage HCC. Administration of sorafenib is therefore recommended in such circumstances of TACE treatment failure.

Surgical and Locoregional Therapy of HCC: TACE.

Abstract: Transcatheter arterial chemoembolization (TACE) is performed worldwide for patients with intermediate-stage hepatocellular carcinoma (HCC). TACE has produced survival advantages in two randomized controlled trials and a meta-analysis, and is currently the mainstay of treatment for this stage of HCC. However, there are currently no global guidelines regarding the dose, choice or combination of cytotoxic agents for TACE; therefore, it is difficult to compare data from different TACE studies. In Japan, most of the TACE procedures have been based on iodized oil as conventional TACE, utilizing the microembolic and drug-carrying characteristic of iodized oil. Superselective TACE with lipiodol is the primary TACE procedure that has reported satisfactory levels of local control associated with a lower risk of complications. Conversely, TACE performed using drug-eluting beads has been widely used in western countries, and this has shown similar tumor response and median survival compared to conventional TACE. Moreover, the combination of TACE and molecular targeted agents is now ongoing to evaluate the synergistic effect. In this review, the indication, technical issues, and complications of TACE are reviewed.

Tumor Markers for Hepatocellular Carcinoma: Simple and Significant Predictors of Outcome in Patients with HCC.

Abstract: Background: The effectiveness of tumor markers in evaluating outcomes of patients with hepatocellular carcinoma (HCC) remains to be clarified. Summary: The usefulness of the HCC tumor markers, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3), and des-gamma-carboxy prothrombin (DCP) was reviewed. Elevations in these tumor markers at the time of HCC diagnosis correlate with disease progression as assessed by both imaging studies and pathologic examinations. The combination of these three tumor markers results in good predictive ability for patient survival after diagnosis. In addition, combination at the time of HCC diagnosis of these three tumor markers (as a measure of tumor progression) and serum albumin and bilirubin levels (as indicators of remnant liver function) can be used for HCC staging and further predicts prognosis in patients with HCC. Key Message: The prognosis of patients with HCC can be well discriminated based solely on serum markers. Staging of HCC with serum markers is objective; if stored serum samples are available, HCC stages can be standardized across different countries and time periods.

Recent Advances in Tumor Ablation for Hepatocellular Carcinoma

Abstract: Image-guided tumor ablation for early stage hepatocellular carcinoma (HCC) is an accepted non-surgical treatment that provides excellent local tumor control and favorable survival benefit. This review summarizes the recent advances in tumor ablation for HCC. Diagnostic imaging and molecular biology of HCC has recently undergone marked improvements. Second-generation ultrasonography (US) contrast agents, new computed tomography (CT) techniques, and liver-specific contrast agents for magnetic resonance imaging (MRI) have enabled the early detection of smaller and inconspicuous HCC lesions. Various imaging-guidance tools that incorporate imaging-fusion between real-time US and CT/MRI, that are now common for percutaneous tumor ablation, have increased operator confidence in the accurate targeting of technically difficult tumors. In addition to radiofrequency ablation (RFA), various therapeutic modalities including microwave ablation, irreversible electroporation, and high-intensity focused ultrasound ablation have attracted attention as alternative energy sources for effective locoregional treatment of HCC. In addition, combined treatment with RFA and chemoembolization or molecular agents may be able to overcome the limitation of advanced or large tumors. Finally, understanding of the biological mechanisms and advances in therapy associated with tumor ablation will be important for successful tumor control. All these advances in tumor ablation for HCC will result in significant improvement in the prognosis of HCC patients. In this review, we primarily focus on recent advances in molecular tumor biology, diagnosis, imaging-guidance tools, and therapeutic modalities, and refer to the current status and future perspectives for tumor ablation for HCC.

Image-Guided Ablation of Malignant Liver Tumors: Recommendations for Clinical Validation of Novel Thermal and Non-Thermal Technologies - A Western Perspective.

Abstract: Background: Image-guided ablation is used to treat patients with unresectable malignant hepatic tumors that are limited in number and size, especially hepatocellu

Clinical Practice Guidelines for Hepatocellular Carcinoma Differ between Japan, United States, and Europe

Abstract: Hepatocellular carcinoma (HCC) is a malignant tumor that is the fifth most common type of cancer and the third leading cause of cancer-related death globally. Although HCC was once thought to be a special type of cancer prevalent only in Southeast Asia and Africa, it has rapidly become more common in other regions, particularly Europe and the United States, which has led to greater interest in the diagnosis and treatment of HCC worldwide. Consequently, the American Association for the Study of Liver Diseases (AASLD) [1] and the European Association for the Study of the Liver and the European Organisation for Research and Treatment of Cancer (EASL-EORTC) [2] have published clinical practice guidelines for liver cancer. In Japan, the first edition of evidence-based clinical practice guidelines was published in 2005 [3, 4], followed by a revised edition in 2009 and a third revision in 2013 [5, 6]. In addition, 1 or 2 years after the publication of each revised edition of the evidence-based treatment guidelines, The Japan Society of Hepatology (JSH) has also published consensusbased clinical practice manuals for HCC. The first edition was published in 2007 and the second edition in 2010 [7, 8]. A third edition will be published in 2015. In this article, differences between the aforementioned European and American clinical practice guidelines and Japanese clinical practice guidelines will be discussed. Specifically, as these guidelines primarily consist of both a surveillance and diagnostic algorithm and a treatment algorithm, each component of the algorithms will be explained in detail.

Current Status of Hepatic Arterial Infusion Chemotherapy

Abstract: Background: Hepatic arterial infusion chemotherapy (HAIC) is frequently used to treat advanced hepatocellular carcinoma (HCC) in Asian countries. However, there is a lack of evidence supporting the use of HAIC. Summary: Many studies report high response rates in patients with advanced HCC receiving HAIC, and clinical responses translate to survival benefits. Therefore, prediction of an antitumor response is important in selecting appropriate treatments. There are no proven post-sorafenib therapeutic measures or procedures for HCC patients with poor liver function, and HAIC is one of the few options for patients in these situations. Despite studies showing its effectiveness, the use of HAIC for treatment of advanced HCC is unclear because convincing data from large-scale randomized clinical trials are lacking. For HAIC to become a standard treatment for HCC, such trials must establish its efficacy compared with other HCC therapies; prediction of antitumor response in HAIC may aid trial design, and a multi-center, open-labelled, randomized clinical trial of HAIC in advanced HCC is currently in progress. Optimization of HCC treatment protocols and regimens is also required. Key message: We think that both HAIC and sorafenib are effective treatments for advanced HCC, and this review presents evidence supporting this contention.

Insufficient ablative margin determined by early computed tomography may predict the recurrence of hepatocellular carcinoma after radiofrequency ablation.

Abstract: Tumor recurrence in hepatocellular carcinoma (HCC) patients after radiofrequency ablation (RFA) remains common; some studies have reported that insufficient ablative margin after RFA might contribute to HCC recurrence. The aim of this study was to investigate whether insufficient ablative safety margins determined by early computed tomography (CT) predicts HCC recurrence after RFA. This retrospective study recruited patients with a single HCC lesion after RFA in our department between May 2013 and March 2014. Early follow-up CT was performed within 7 days after RFA. An adequate ablative margin assessed by follow-up CT was defined as (maximum post-RFA CT radius)3/(maximum pre-RFA CT radius + 5 mm)3> 1. All patients in whom complete ablation was achieved underwent a CT scan every 3 months for early detection of HCC recurrence. In total, 72 patients (48 male, mean age 69.4 years) were analyzed. Of these, eight patients had local tumor progression, four had intra-hepatic distant recurrence, and two had extra-hepatic metastasis. Insufficient ablative margin, defined as an ablative volume with a safety margin of less than 5 mm, was an important predictor of local tumor progression (LTP) (p = 0.015) and overall recurrence (p = 0.012). The sensitivity, specificity, and positive and negative predictive values of an insufficient ablative margin for predicting LTP and overall recurrence were 36.4%, 97.2%, 50.0%, and 87.9%, and 46.2%, 89.7%, 42.9%, and 87.9%, respectively. An ablative volume with an ablative margin of less than 5 mm is associated with higher rates of both LTP and overall recurrence in HCC after RFA.

Contrast-Enhanced Ultrasound for the Characterization of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

Abstract: Purpose and methods: The ability of contrast-enhanced ultrasound (CEUS) to differentiate between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is still controversial. We reviewed the CEUS imaging of 819 patients (HCC=546, ICC=273) with an established pathological diagnosis. The enhancement patterns of lesions and the diagnostic performance of CEUS were analyzed. Results: Arterial hyperenhancement followed by washout was observed in 92.3% (504/546) of the HCC lesions and 85.7% (234/273) of the ICC lesions on CEUS (pConclusions: Although ICC may show the typical enhancement pattern of HCC on CEUS, peripheral rim-like enhancement and quick contrast washout show high efficiency in the differentiation of HCC from ICC.

Recent Advances in the Imaging Diagnosis of Hepatocellular Carcinoma: Value of Gadoxetic Acid-Enhanced MRI

Abstract: Magnetic resonance imaging (MRI) using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DPTA), or gadoxetic acid for short, is a hepatocyte-specific contrast agent which is now increasingly used for the detection and characterization of focal hepatic lesions, particularly in patients at high-risk of developing hepatocellular carcinomas (HCC). In fact, several recent guidelines now recognize gadoxetic acid-enhanced MRI (Gd-EOB-MRI) as the primary diagnostic imaging modality for the noninvasive diagnosis of HCC, although it must be noted that several major guidelines still include only extracellular contrast media-enhanced computed tomography and MRI. The primary merits of Gd-EOB-MRI lie in the fact that it can provide not only dynamic imaging, but also hepatobiliary phase (HBP) imaging which can lead to high lesion-to-liver contrast and give additional information regarding hepatocyte uptake via organic anion transporting polypeptides. This, in turn, allows higher sensitivity in detecting small HCCs and helps provide additional information regarding the multistep process of hepatocarcinogenesis. Indeed, many recent studies have investigated the diagnostic value of Gd-EOB-MRI for early HCCs as well as its role as a potential imaging biomarker in predicting outcome. We herein review the recent advances in the imaging diagnosis of HCCs focusing on the applications of Gd-EOB-MRI and the challenging issues that remain.

Locoregional Therapy for Hepatocellular Carcinoma.

Abstract: Transplantation, resection, and ablation are recommended for the treatment of very early (single <2 cm diameter) and early (single or <3 nodules <3 cm diameter) stage hepatocellular carcinomas (HCCs) as determined using the Barcelona Clinic Liver Cancer (BCLC) staging system [1]. In addition, transarterial chemoembolization (TACE) is recommended for intermediate-stage multinodular HCCs, systemic therapy with sorafenib for advancedstage HCCs, and best supportive care for end-stage HCCs, respectively. In this issue, we review current locoregional therapeutic modalities including local ablation, TACE and arterial infusion chemotherapy. Although radiofrequency ablation (RFA) [2, 3] is the best current method for ablation, many differences exist between the techniques used in Japan and those used in other countries such as the United States and in Europe. In Japan, computed tomography is used to assess the outcome of RFA immediately after the procedure, and the technique is repeated until a sufficient ablative margin is obtained, which has been found to produce nearly a 100% tumor necrosis rate. In other words, the RFA is repeated to achieve a complete response (CR) in most cases, and this is markedly different from the RFA treatment performed in the United States and Europe, in which the outcome is usually assessed at one month after a single ablation. Consequently, necrosis rates of HCC following RFA are different between Japan and the other aforementioned countries, which is described in detail in the review articles by Drs. Kang and Rhim [4]. Furthermore, TACE, which is the representative regional therapy, has conventionally been performed by first infusing doxorubicin or epirubicin suspended in Lipiodol, followed by embolization with a gelatin sponge (conventional Lipiodol-TACE). Conversely, in the United States and Europe, drug-eluting beads TACE (DEB-TACE) with microspheres (DC beads) is frequently performed as the standard method. In addition, radioembolization with yttrium-90 for internal irradiation has also been performed proactively in recent years. We are proud of TACE, which was first developed in Japan and that has evolved markedly over the years, because the complete cure of HCC is now possible with the use of superselective or subsegmental TACE. However, conventional TACE is often ineffective, or it may even adversely affect hepatic functional reserve when used in patients with huge and/ © 2015 S. Karger AG, Basel 2235-1795/15/0043-0163$39.50/0 www.karger.com/lic Liver Cancer 2015;4:163–164

Imaging Modalities for Assessment of Treatment Response to Nonsurgical Hepatocellular Carcinoma Therapy: Contrast-Enhanced US, CT, and MRI

Abstract: Tumor response and time to progression have been considered pivotal for surrogate assessment of treatment efficacy for patients with hepatocellular carcinoma (HCC) Recent advancements in imaging modalities such as contrast-enhanced ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) are playing an important role in assessing the therapeutic effects of HCC treatments According to some HCC clinical guidelines, post-therapeutic evaluation of HCC patients is based exclusively on contrast-enhanced dynamic imaging criteria The recommended techniques are contrast-enhanced CT or contrast-enhanced MRI Contrast-enhanced US is employed more in the positive diagnosis of HCC than in post-therapeutic monitoring Although contrast enhancement is an important finding on imaging, enhancement does not necessarily depict the same phenomenon across modalities We need to become well acquainted with the characteristics of each modality, including not only contrast-enhanced CT and MRI but also contrast-enhanced US Many nonsurgical treatment options are now available for unresectable HCC, and accurate assessment of tumor response is essential to achieve favorable outcomes For the assessment of successful radiofrequency ablation (RFA), the achievement of a sufficient ablation margin as well the absence of tumor vascular enhancement is essential To evaluate the response to transcatheter arterial chemoembolization (TACE), enhanced tumor shrinkage is relied on as a measure of antitumor activity Here, we give an overview of the current status of imaging assessment of HCC response to nonsurgical treatments including RFA and TACE

Immune Checkpoint Blockade in Hepatocellular Carcinoma

Abstract: Extremely encouraging results from the interim analysis of the phase I/II nivolumab trial (CA209-040 trial) evaluating the efficacy of nivolumab in patients with hepatocellular carcinoma (HCC) were reported at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago from May 29 to June 2, 2015 [1]. According to the report, a dose escalation study showed the safety and efficacy of 0.1–10 ml/kg of nivolumab, a monoclonal antibody against programmed cell death 1 (PD-1), in patients with HCC due to hepatitis C virus (HCV), hepatitis B virus (HBV), or without infection. Of the 47 patients with HCC, 33 (70%) had extrahepatic metastasis and six (13%) had vascular invasion. Thirty-two (68%) patients had previously been treated with sorafenib, indicating that these patients had relatively advanced liver cancers. The results of an interim analysis performed on March 12, 2015, after the treatment with the anti-PD-1 antibody, showed that 17 patients remained on the study treatment, while 30 patients terminated or discontinued the treatment because of disease progression (n=26), complete response (CR) (n=2), or adverse events (AE) (n=2, for elevated bilirubin or events unrelated to the study drug). According to the Common Terminology Criteria for Adverse Events (CTCAE) grading, the only grade 4 AE was an elevated lipase level, whereas grade 3 AEs included elevated liver enzymes [aspartate aminotransferase (AST) (11%, n=5) and alanine aminotransferase (ALT) (9%, n=4)]. None of the patients developed serious liver dysfunction or autoimmune disease. The overall objective response rate was 19% (n=8), including the two patients who achieved CR (5%). Disease control rates were 67% (n=28) for stable disease (SD) or better and 33% (n=14) for progressive disease (PD), indicating an extremely favorable study outcome (table 1). Waterfall plots revealed tumor size stabilization or reduction in 67% of the patient cohorts with HBV, HCV and those without infection. Regarding the durability of treatment responses, the two patients with CR achieved this within three months of therapy and this was sustained for 12–18 months or longer. Another patient had SD until 11 months after the initiation of treatment and subsequently achieved a partial response (PR), to almost a CR, at approximately 13 months. Patients with PR and SD had sustained disease, and none of them had PD due to acquired tolerance. These outcomes show excellent durability of treatment using the anti-PD-1 antibody in HCC, as observed in other types of cancer. A durable response is © 2015 S. Karger AG, Basel 2235-1795/15/0044-0201$39.50/0 www.karger.com/lic Liver Cancer 2015;4:201–207

The Effectiveness of Multiple Electrode Radiofrequency Ablation in Patients with Hepatocellular Carcinoma with Lesions More than 3 cm in Size and Barcelona Clinic Liver Cancer Stage A to B2.

Abstract: Outcomes of hepatocellular carcinoma (HCC) lesions >3.0 cm in size including Barcelona Clinic Liver Cancer (BCLC) stage B after radiofrequency ablation (RFA) with a single electrode remain unsatisfactory. This study aimed to investigate the outcomes of RFA with multiple electrodes (ME-RFA) for HCC tumors 3.1-7.0 cm in size and BCLC stage B. This retrospective study included 70 consecutive patients with 58 medium- (3.1-5.0 cm) and 17 large- (5.1-7.0 cm) sized HCCs after ME-RFA using a controller. Outcomes in terms of complete response, primary technique effectiveness, local tumor progression, and overall survival were investigated. After 1-4 applications of ME-RFA, the rates of complete response and PTE in medium-sized tumors were 79.3% and 91.4%, respectively, and in large tumors were 76.5% and 94.1%, respectively. Overall, the major complication rate was 5.7%. After a median 21-month follow-up period, both two- and three-year estimated overall survival rates were above 80%. There were no significant differences in overall survival and local tumor progression rates between medium- and large-size tumors and among BCLC stages A, B1 and B2. A complete response to ME-RFA was the only significant factor associated with improved survival (p=0.008). In conclusion, ME-RFA can effectively treat 3.1-7.0-cm sized HCCs with a comparable outcome between medium- and large-size tumors and among BCLA stages A to B2.

Hong Kong Consensus Recommendations on the Management of Hepatocellular Carcinoma

Abstract: Background: Hepatocellular carcinoma (HCC) is particularly prevalent in Hong Kong because of the high prevalence of chronic hepatitis B (CHB) infection; HCC is the fourth commonest cancer in men and the seventh commonest in women, and it is the third leading cause of cancer death in Hong Kong. The full spectrum of treatment modalities for HCC is available locally; however, there is currently no local consensus document detailing how these modalities should be used. Summary: In a series of meetings held between May and October 2013, a multidisciplinary group of Hong Kong clinicians − liver surgeons, medical oncologists, clinical oncologists, hepatologists, and interventional radiologists − convened to formulate

Yttrium-90 microsphere radioembolization for hepatocellular carcinoma

Abstract: Yttrium-90 (Y90) radioembolization is an emerging strategy to treat liver malignancies, and clinical data supporting its use have accumulated in recent years. Y90-radioembolization has shown clinical effectiveness in intermediate and advanced hepatocellular carcinoma, with a favorable safety profile. Retrospective data show similar levels of effectiveness to transarterial chemoembolization in intermediate hepatocellular carcinoma, with some evidence of better tolerance. While phase 3 studies comparing Y90-radioembolization to chemoembolization in intermediate hepatocellular carcinoma would be difficult to conduct, studies comparing or combining Y90-radioembolization with sorafenib are under way. Questions also remain about the most suitable modalities for defining the dose to administer. Phase 3 studies are under way to clarify the place of Y90-radioembolization in the algorithm of HCC treatment.

Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Portal Vein Thrombosis: Impact of Early Response to 4 Weeks of Treatment.

Abstract: Aim: The aim of the study was to investigate the impact of early response (ER) to hepatic arterial infusion chemotherapy (HAIC) on outcomes of patients with advanced hepatocellular carcinoma (HCC) complicated with major portal vein tumor thrombosis (PVTT). Methods: Thirty-nine patients receiving HAIC with low-dose cisplatin, 5-fluorouracil (5FU), and leucovorin were enrolled. One course of HAIC consisted of 5 days of treatment and 2 days rest per week for 4 consecutive weeks. ER was categorized as complete response, partial response, or minor response and was determined by World Health Organization criteria with dynamic computed tomography findings performed within 1 week after the first course of HAIC. Results: Thirteen (33%) patients achieved an ER. Twelve (92.3%) of these 13 ER patients achieved a higher overall response than all but one (3.8%) of the 26 non-early responders (NERs) (pConclusions: HAIC can yield a satisfactory ER for advanced HCC with PVTT. Moreover, achievement of ER after HAIC in advanced HCC with PVTT is strongly associated with better overall survival and PFS.

Yttrium-90 microspheres: a review of its emerging clinical indications.

Abstract: Background: Many patients with liver malignancies are not candidates for resection, and systemic therapies are often not effective. Radioembolization (RE) is an alternative treatment for this group of patients. The safety and efficacy of RE with yttrium 90 (Y90) in patients with hepatocellular carcinoma (HCC) or metastatic colon cancer to the liver have been proven in several studies. However, fewer studies have focussed on the safety and efficacy of RE with Y90 in other extrahepatic primary and secondary liver cancers. The effect on outcomes of concomitant use of Y90 with a systemic therapy is still currently under investigation. Summary: A review of the published data on the use of RE as stand-alone, concomitant or sequential with other treatment modalities in HCC and other primary and secondary liver cancer is reported here. Key message: RE for the treatment of HCC and other extrahepatic, primary and secondary liver cancer has reasonable efficacy and acceptable toxicities. Definitive studies to establish the role of RE in the treatment of such malignancies are warranted.

Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil.

Abstract: We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m(2), on days 1 and 8) and 5-FU (170-330 mg/m(2), continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m(2) of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m(2) are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. A large prospective randomized multicenter study (ClinicalTrials.gov Identifier NCT01214343) is ongoing.

Treatment of hepatocellular carcinoma in the community: disparities in standard therapy.

Abstract: Background and Aims: Hepatocellular carcinoma (HCC) incidence is expected to rise dramatically over the next decades because of increasing hepatitis C infections and obesity-related comorbidities. However, little information exists regarding the treatment of patients with HCC in the community setting. The purpose of this article was to characterize patterns of diagnosis, treatment, and survival for HCC in the community. Methods: We identified 946 HCC patients in the 2007 National Cancer Institute's Patterns of Care study. Chi-square analyses and multivariable regression were used to examine patient and provider factors associated with treatment and survival by stage at diagnosis. Results: Our primary findings indicate that liver transplants, embolization, or radiofrequency ablation for Barcelona Clinic Liver Cancer stage A patients were performed significantly less often for non-Hispanic blacks, Hispanics, patients in the highest income quartile, and patients with Medicaid. Patients with stage D disease were less likely to receive cancer therapy if they had Medicaid insurance compared to private insurance (pConclusions: This is the first population-based study to evaluate therapy provided for HCC in the community. Current therapy depended on patients' HCC stage at diagnosis and other clinical and demographic factors. Overall, our study identifies those least likely to receive specific therapies in a variety of health care settings and can inform strategies for promoting appropriate therapy now and as new agents are developed.

Molecular Targeted Therapy for Hepatocellular Carcinoma: Where Are We Now?

Abstract: Seven years have passed since sorafenib was approved as a systemic chemotherapeutic agent that improves survival in patients with advanced hepatocellular carcinoma (HCC). Despite numerous studies over subsequent years aimed at developing novel molecular targeted agents, no new drugs have produced positive results to date. Because of the difficulties faced in developing novel agents, the patients selected for drug development trials have shifted from those with similar hepatic functions and tumor stages, as in conventional trials, to those with homogeneous biological characteristics based on biomarkers. In addition, a promising new strategy in the development of treatments for HCC is the emerging field of immuno-oncology. However, to reduce medical costs, it is necessary to take a broad perspective to drug development by, for example, incorporating new concepts such as a master protocol system.

Was Hypervascular Hepatocellular Carcinoma Visible on Previous Gadoxetic Acid-Enhanced Magnetic Resonance Images?

Abstract: Background: During the follow-up of patients with chronic liver disease, hypervascular hepatocellular carcinomas (HCCs) can develop either from pre-existing high-risk nodules or by de novo hepatocarcinogenesis. The purpose of this study was to evaluate, by retrospective analysis, the detectability and signal intensity on previous hepatocyte-phase gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) of hypervascular HCC initially detected on current EOB-MRIs. Methods: We examined 50 initially detected hypervascular HCCs that showed typical enhancement features on EOB-MRI in 39 patients whose previous EOB-MRI images obtained 6-19 months earlier were available. The detectability of each hypervascular HCC on the hepatocyte phase images of previous EOB-MRIs was assessed. The imaging features on hepatocyte-phase images of previous EOB-MRIs at the locations where hypervascular HCCs were found on the current EOB-MRI images were classified as detectable or undetectable. The signal intensities of detectable nodules (defined as group A) on hepatocyte-phase images of previous EOB-MRIs were classified as hypo-, iso-, or hyperintensity. Nodules undetectable on the hepatocyte-phase images of previous EOB-MRIs were assigned to group B. Results: Twenty-two (22/50, 44%) hypervascular HCCs were detectable on the earlier hepatocyte phase images (group A). In contrast, 28 (28/50, 56%) hypervascular HCCs were not detectable on the hepatocyte phase of earlier EOB-MRI images (group B). Conclusion: When the previous EOB-MRI images were used as the reference, more than half (28/50, 56%) of hypervascular HCCs initially appearing on the current EOB-MRI images were found not to have developed from nodules detectable on the previous MRIs through the traditionally accepted process of multistep carcinogenesis. Instead, they seemed to have developed via an “imaging-occult” process of carcinogenesis in patients with chronic liver diseases.

Consensus development from the 5th asia-pacific primary liver cancer expert meeting (APPLE 2014)

Abstract: A key mission of the Asia-Pacific Primary Liver Cancer Expert (APPLE) Association is to ensure a coherent view for management of hepatocellular carcinoma (HCC) and to advance new treatment for this difficult disease At the 5th APPLE meeting, held in July 2014 in Taipei, Taiwan, an APPLE consensus development program was established to facilitate discussion among experts in the Asia-Pacific region on pertinent issues for HCC management, including (1) surgery for intermediate/advanced-stage disease, (2) prevention of HCC recurrence after curative treatment, (3) optimizing imaging diagnosis, (4) radiotherapy: current practice and future clinical trials, and (5) the role of cytotoxic chemotherapy A pre-congress questionnaire was undertaken with the consensus development committee members to help understand the current practice patterns for HCC in the Asia-Pacific region and to identify issues relating to optimal patient care and further clinical trials for which consensus needs to be developed In this report, the results of the questionnaire are presented, and the pertinent issues identified by each consensus group for further discussion and consensus development are summarized

Imaging Diagnosis of Hepatocellular Carcinoma: Recent Advances of Contrast-Enhanced Ultrasonography with SonoVue®.

Abstract: Due to the ability to detect the typical contrast-imaging pattern for hepatocellular carcinoma (HCC), that is hyperenhancement in the arterial phase and hypoenhancement in the late phase on a cirrhotic background, contrast-enhanced ultrasonography (CEUS) was included in the American diagnostic algorithm for HCC in 2005. However, its role has been questioned because of the possibility of misdiagnosis of cholangiocarcinoma. The present review aims to describe the advantages and disadvantages of CEUS applications using Sonovue® for HCC. In particular there is focus on the accuracy of CEUS in detecting the typical HCC pattern, the CEUS patterns of intrahepatic cholangiocarcinoma (ICC), the risk of misdiagnosis with HCC, the diagnostic use of CEUS in cases of locoregional and systemic treatments, and the evaluation of response to antiangiogenic treatment using dedicated software.

Novel Imaging Diagnosis for Hepatocellular Carcinoma: Consensus from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014)

Abstract: Current novel imaging techniques in the diagnosis of hepatocellular carcinoma (HCC), with the latest evidence in this field, was discussed at the Asia-Pacific Primary Liver Cancer Expert (APPLE) meeting held in Taipei, Taiwan, in July 2014. Based on their expertise in a specific area of research, the novel imaging group comprised 12 participants from Japan, South Korea, Taiwan, and China and it included 10 abdominal radiologists, one hepatologist, and one pathologist. The expert participants discussed topics related to HCC imaging that were divided into four categories: (i) detection method, (ii) diagnostic method, (iii) evaluation method, and (iv) functional method. Consensus was reached on 10 statements; specific comments on each statement were provided to explain the rationale for the voting results and to suggest future research directions.

Phase I trial of sorafenib following liver transplantation in patients with high-risk hepatocellular carcinoma.

Abstract: Liver transplantation offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who fall within established criteria. For those outside such criteria, or with high-risk pathologic features in the explant, HCC recurrence rates are higher. We conducted a multicenter phase I trial of sorafenib in liver transplantation patients with high-risk HCC. Subjects had HCC outside the Milan criteria (pre- or post-transplant), poorly differentiated tumors, or vascular invasion. We used a standard 3+3 phase I design with a planned duration of treatment of 24 weeks. Correlative studies included the number of circulating endothelial cells (CECs), plasma biomarkers, and tumor expression of p-Erk, p-Akt, and c-Met in tissue micro-arrays. We enrolled 14 patients with a median age of 63 years. Of these, 93% were men and 71% had underlying hepatitis C virus (HCV) and 21% had HBV. The maximum tolerated dose of sorafenib was 200 mg BID. Grade 3-4 toxicities seen in >10% of subjects included leukopenia (21%), elevated gamma-glutamyl transferase (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, one patient died and four recurred. The mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean soluble vascular endothelial growth factor receptor-2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression to correlate with increased risk of recurrence. Post-transplant sorafenib was found to be feasible and tolerable at 200 mg PO BID. The effect of post-transplant sorafenib on recurrence-free survival is potentially promising but needs further validation in a larger study.

Clinical Characteristics of Patients with Cryptogenic Hepatocellular Carcinoma in a Hepatitis B Virus-Endemic Area.

Abstract: Objectives: Chronic hepatitis B virus (HBV) infection is the most common cause of hepatocellular carcinoma (HCC) in South Korea, but a high prevalence of metabolic diseases may result in increases in the incidence of cryptogenic HCC (cHCC). We studied characteristics of the cHCC in a single-center cohort. Methods: A cohort of 1,784 HCC patients newly diagnosed and treated at the National Cancer Center, Korea, between 2004 and 2009 was reviewed and analyzed. Results: The cause of HCC was categorized as cHCC, HBV, hepatitis C virus (HCV), or alcohol. Overall, 162 (9.1%) patients of the HCC cohort had cHCC, and their mean age was 61.9 years. The median survival of cHCC patients was 24.7 months, which was the second shortest among the four groups after HBV HCC. cHCC patients had the largest tumor size (mean 7.4 cm) and the second highest proportion of poor prognostic factors such as the proportion of poorly defined tumors and extrahepatic spread in imaging studies. cHCC patients had better survival than HBV HCC patients according to multivariate analysis. Among cHCC patients, 137 (84.6%) had anti-HBc IgG antibodies, but this sub-group had different clinical features to those of HBV HCC patients. The body mass index (BMI) and hyperglycemia and hypercholesterolemia levels in cHCC patients were similar to those in HCV and alcoholic HCC patients. Conclusions: Anti-HBc IgG antibodies were present in most cHCC patients, but cHCC patients had better survival than HBV HCC patients on multivariate analysis. However, cHCC patients had a larger mean tumor size and more aggressive tumor characteristics than HCV HCC or alcoholic HCC patients did. It is hoped that this study will contribute to a better understanding of cHCC in HBV-endemic areas.

Malignant Transformation of Hepatocellular Adenoma: How Frequently Does It Happen?

Abstract: Hepatocellular adenoma is a very rare disease in Japan, and institutions encounter only a limited number of cases. This is one of the reasons for the current skepticism in Japan over whether hepatocellular adenoma can truly undergo malignant transformation to hepatocellular carcinoma. However, hepatocellular adenoma is highly prevalent in Western countries, particularly in Europe, and textbooks from these countries have long noted that hepatocellular adenoma carries risks of bleeding and malignant transformation. Most of the cases of hepatocellular carcinoma routinely encountered in Japan occur as a result of chronic liver injury from viral disease, and it is extremely rare to encounter liver cancer that has developed from hepatocellular adenoma in healthy liver. It would be no exaggeration to say that this is almost never seen. Therefore, a survey and literature review was conducted to assess how many cases of hepatocellular adenoma actually undergo malignant transformation in Japan.

Potential Role of Phosphorylation as a Regulator of Aspartyl-(asparaginyl)-β-hydroxylase: Relevance to Infiltrative Spread of Human Hepatocellular Carcinoma

Abstract: Abundant expression of aspartyl-(asparaginyl)-β-hydroxylase (AAH) correlates with infiltrative growth of hepatocellular carcinoma (HCC). Herein, we examine the role of phosphorylation in relation to AAH's protein expression, hydroxylase activity, promotion of cell motility, and activation of Notch signaling in human Huh7 hepatoma cells. Predicted glycogen synthase kinase-3β (GSK-3β), protein kinase A (PKA), protein kinase C (PKC), and casein kinase 2 (CK2) phosphorylation sites encoded by human AAH cDNA were ablated by S/T→A site-directed mutagenesis using N-Myc-tagged constructs in which gene expression was controlled by a cytomegalovirus promoter. Functional consequences were assessed in transiently transfected Huh7 cells. Cells transfected with wildtype AAH had significantly increased AAH expression, catalytic activity, HES-1 expression, and directional motility relative to controls. Single phosphorylation site mutations in the C-terminus largely abrogated these effects and further inhibited catalytic activity relative to that in cells transfected with empty vector, whereas the effects of single point mutations within the N-terminus were more varied. In contrast, AAH cDNAs carrying multiple phosphorylation site mutations exhibited wildtype levels of AAH catalytic activity suggesting that the effects of AAH phosphorylation are complex and non-uniform. AAH expression and function can be modulated by direct phosphorylation of the protein. These findings suggest additional strategies for inhibiting infiltrative growth of HCC.