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Liver Cancer

Primary liver cancer is a disease in which the cells of liver become cancerous (malignant). Primary liver cancer is different from cancer that has spread from another place in the body to the liver. The liver is found in the upper right side of the abdomen. It is an an important organ which is involved in digesting food and converting it to energy and it also filters and stores blood. Liver cancer is relatively rare, known risk factors for liver cancer are prior hepatitis B or C infections or cirrhosis of the liver. There are two main types of liver cancer in adults: hepatocellular carcinoma and cholangiocarcinoma. Hepatoblastoma is another type of liver cancer which mostly occurs in children. Some types of liver cancer produce abnormaly high levels of alpha-fetoprotein (AFP) which can aid diagnosis.

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Childhood Liver Cancer

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    MeSH term: Liver Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Chou ST, Hsiang CY, Lo HY, et al.
Exploration of anti-cancer effects and mechanisms of Zuo-Jin-Wan and its alkaloid components in vitro and in orthotopic HepG2 xenograft immunocompetent mice.
BMC Complement Altern Med. 2017; 17(1):121 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Zuo-Jin-Wan (ZJW), a two-herb formula consisting of Coptis chinensis (CC) and Evodia rutaecarpa (ER), is commonly used in traditional Chinese medicine for the treatment of cancers. However, the efficacies and mechanisms of ZJW and its alkaloid components on cancers are still unclear.
METHODS: Here we investigated the anti-cancer effects and mechanisms of ZJW, CC, ER, berberine, and evodiamine in cells and in intrahepatic xenograft mice.
RESULTS: Treatment of HepG2 cells with ZJW, CC, ER, berberine, and evodiamine significantly displayed cytotoxic effects in a dose- and time-dependent manner. Hierarchical cluster analysis of gene expression profiles showed that CC and ZJW shared a similar mechanism for the cytotoxic effects, suggesting that CC was the active ingredient of ZJW for anti-cancer activity. Network analysis further showed that c-myc was the likely key molecule involved in the regulation of ZJW-affected gene expression. A human hepatoma xenograft model was established by intrahepatic injection of HepG2 cells containing nuclear factor-κB-driven luciferase genes in immunocompetent mice. In vivo bioluminescence imaging showed that cells had been successfully transplanted in mouse liver. Oral administration of ZJW for 28 consecutive days led to a significant decrease in the accumulation of ascites, the ratio of tumor-to-liver, and the number of transplanted cells in livers.
CONCLUSIONS: In conclusion, our findings suggested for the first time that ZJW significantly suppressed human cancer cell growth in orthotopic HepG2 xenograft-bearing immunocompetent mice. Moreover, c-myc might play a potent role in the cytotoxic mechanisms of ZJW, CC, ER, berberine, and evodiamine.

Ting CT, Kuo CJ, Hu HY, et al.
Prescription frequency and patterns of Chinese herbal medicine for liver cancer patients in Taiwan: a cross-sectional analysis of the National Health Insurance Research Database.
BMC Complement Altern Med. 2017; 17(1):118 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Chinese herbal medicine (CHM) is frequently provided to HCC patients. The aim of this study was to understand the prescription frequency and patterns of CHM for HCC patients by analyzing the claims data from the National Health Insurance (NHI) in Taiwan.
METHODS: We identified 73918 newly diagnosed HCC subjects from the database of Registry for Catastrophic Illness during 2002 to 2009 and to analyze the frequency and pattern of corresponding CHM prescriptions for HCC patients.
RESULTS: There were a total of 685,079 single Chinese herbal prescriptions and 553,952 Chinese herbal formula prescriptions used for 17,373 HCC subjects before 2 years of HCC diagnosis. Among the 13,093 HCC subjects who used CHMs after HCC diagnosis, there were 462,786 single Chinese herbal prescriptions and 300,153 Chinese herbal formula prescriptions were counted. By adjusting with person-year and ratio of standardized incidence rate, the top ten prescribed single herbal drugs and Chinese herbal formulas for HCC patients were described in our study. Among them, we concluded that, Oldenlandia diffusa (Chinese herbal name: Bai-Hua-She-She-Cao), Radix et Rhizoma Rhei (Da Huang) and the herbal preparation of Xiao-Chai-Hu-Tang and Gan-Lu-Yin, were the most obviously increased and important CHMs been used for HCC patients.
CONCLUSION: We established an accurate and validated method for the actual frequency and patterns of CHM use in treating HCC in Taiwan. We propose that these breakthrough findings may have important implications for HCC therapy, clinical trials and modernization of CHM.

Huang C, Li NM, Gao P, et al.
In vitro and in vivo evaluation of macromolecular prodrug GC-FUA based nanoparticle for hepatocellular carcinoma chemotherapy.
Drug Deliv. 2017; 24(1):459-466 [PubMed] Related Publications
A novel type of macromolecular prodrug delivery system is reported in this research. The N-galactosylated-chitosan-5-fluorouracil acetic acid conjugate (GC-FUA) based nanoparticle delivery system was evaluated in vitro and in vivo. Biocompatibility of GC-FUA-NPs was screened by BSA adsorption test and hemolysis activity examination in vitro. Cytotoxicity and cellular uptake study in HepG2 and A549 cells demonstrated that compared to free 5-Fu, the GC-FUA-NPs play great function in killing cancer cells for the cell endocytosis mediated by asialoglycoprotein receptor (ASGPR), which overexpresses on the cell surface. Pharmacokinetics study further illustrated that the drug-loaded nanoparticles has a much longer half-time than free 5-Fu in blood circulation in Sprague-Dawley (SD) rats. Tissue distribution was investigated in Kunming mice, and the result showed that the GC-FUA-NPs have a long circulation effect. The obtained data suggested that GC-FUA-NP is a very promising drug delivery system for efficient treatment of hepatocellular carcinoma.

Baker E, Jacobs C, Martinie J, et al.
Mixed Hepatocellular Carcinoma, Neuroendocrine Carcinoma of the Liver.
Am Surg. 2016; 82(11):1121-1125 [PubMed] Related Publications
We present the case of a 76-year-old male found to have a large tumor involving the left lateral lobe of the liver, presumed to be hepatocellular carcinoma (HCC). After resection, pathologic features demonstrated both high-grade HCC and high-grade neuroendocrine carcinoma (NEC). Areas of NEC stained strongly for synaptophysin, which was not present in HCC component. The HCC component stained strongly for Hep-Par 1, which was not present in the NEC component. The patient underwent genetic analysis for biomarkers common to both tumor cell types. Both tumor components contained gene mutations in CTNNB1 gene (S33F located in exon 3). They also shared mutations in PD-1, PGP, and SMO. Mixed HCC/NEC tumors have been rarely reported in the literature with generally poor outcomes. This patient has been referred for adjuvant platinum-based chemotherapy; genetic biomarker analysis may provide some insight to guide targeted chemotherapy.

Rosales A, Que FG
Spontaneous Hepatic Hemorrhage: A Single Institution's 16-Year Experience.
Am Surg. 2016; 82(11):1117-1120 [PubMed] Related Publications
Spontaneous hemorrhage from hepatic tumors is an uncommon but serious complication. Recently, interventional radiologic (IR) techniques are being used increasingly in the management of these patients. We report our 16-year experience in managing spontaneous hemorrhage from liver tumors. Twenty-six consecutive patients were diagnosed with spontaneous liver hemorrhage between 1995 and 2011. Initial management was operative in eight, IR in six, and supportive in 12 patients. Of those managed operatively, five were segmentectomies; one hemihepatectomy; one wedge resection; and one packing who later died from coagulopathy. In the IR patients, seven had an angiographic embolization; two required reembolization; one underwent resection of a hepatic adenoma 21 days after angiographic embolization. The malignant lesions included hepatocellular carcinoma (n = 6), angiosarcoma (n = 1), metastatic squamous cell carcinoma (n = 1), metastatic leiomyosarcoma (n = 1), nonsquamous cell carcinoma (n = 1), or metastatic angiosarcoma (n = 1). Benign diseases included hepatic adenoma (n = 5), end-stage liver disease (n = 1), and polycystic liver (n = 1). Spontaneous hemorrhage from the liver occurs evenly from benign or malignant causes, one-third of which are primary liver disease. If the patients presents emergently, angiographic embolization may control the bleeding and allow for elective resection once the sequelae of bleeding have resolved.

Atkin C, Earwaker P, Pallan A, et al.
Exceptional serological and radiological response to sorafenib in 2 patients with advanced hepatocellular carcinoma and chronic hepatitis C viral infection: case report and review of the literature.
BMC Gastroenterol. 2017; 17(1):30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In patients with advanced hepatocellular carcinoma (HCC), the multikinase inhibitor sorafenib is the only systemic treatment that has been shown to increase overall survival. However, similar to other tyrosine kinase inhibitors, most patients achieve disease stabilisation radiologically, and only 2-3% of patients achieve a partial response. Recent exploratory subgroup analyses of the large phase 3 trials have demonstrated that patients with chronic hepatitis C virus (HCV) infection associated HCC survive longer than those who are negative for HCV. The mechanism underlying this currently remains unknown. A small number of cases of complete response to sorafenib treatment have now been reported worldwide, however a prolonged response has only been reported in 2 cases, both of whom had HCV-related HCC.
CASE PRESENTATION: A 55 year old gentleman was diagnosed with hepatocellular carcinoma and concomitant chronic hepatitis C viral infection. He progressed following transarterial chemoemoblisation treatment and was commenced on sorafenib treatment. His serum alphafetoprotein level normalised within 2 months of treatment and he achieved an almost complete radiological response. This response was maintained for 20 months before the patient progressed. A 75 year old lady was diagnosed with advanced hepatocellular carcinoma and concomitant chronic hepatitis C viral infection. She was commenced on sorafenib treatment but required early dose reductions due to palmar plantar erythrodysesthesia, and liver decompensation. Despite this she achieved an excellent serological and radiological response that was maintained for 24 months.
CONCLUSIONS: Our two cases show that patients with HCV-associated HCC can attain excellent responses to sorafenib treatment that is durable. Furthermore, such exceptional responses can be achieved even with dose reductions and treatment breaks.

Shen L, Zhang G, Lou Z, et al.
Cryptotanshinone enhances the effect of Arsenic trioxide in treating liver cancer cell by inducing apoptosis through downregulating phosphorylated- STAT3 in vitro and in vivo.
BMC Complement Altern Med. 2017; 17(1):106 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Arsenic trioxide (ATO) is approved for treating terminal-stage liver cancer in China. Cryptotanshinone (CT), a STAT3 inhibitor, has exhibited certain anti-tumor potency; however, the use of CT enhanced ATO for treating liver cancer has not been reported. Here we try to elucidate how CT could enhance the efficacy of ATO for treating liver cancer and its correlation to STAT3 in vitro and in vivo.
METHODS: Cell viability of ATO combined with CT was assessed by (1)MTT assay. Cell apoptosis induced by ATO combined with CT was detected by Annexin V/PI staining and apoptosis-related proteins were detected by western blotting. STAT3-related proteins were analysis by western blotting analysis and Immunofluorescence assays. Efficacy evaluation of ATO combined with CT on xenograft was carried in nude mice and related proteins were analysis by Immunohistochemistry assays.
RESULTS: First we evaluated cell vitality, and our data indicated that the ATO combined with CT showed obvious growth inhibition of Bel-7404 cells compared to ATO or CT alone. Next we found that ATO combined with CT induced cell apoptosis in Bel-7404 cells and upregulated the activation of apoptosis-related proteins cleaved-caspase-3, cleaved-caspase-9, and cleaved-poly(ADP-ribose) polymerase in a time-dependent manner. Next, we found that ATO combined with CT not only inhibited the constitutive levels of phosphorylated-JAK2 and phosphorylated-STAT3(Tyr705) but did so in a time-dependent manner. We also found that ATO combined with CT reversed the upregulated expression of phosphorylated-STAT3(Tyr705) stimulated by interleukin-6 and downregulated STAT3 direct target genes and the anti-apoptotic proteins Bcl-2, XIAP, and survivin but obviously upregulated the promoting apoptosis proteins Bak,.In vivo studies showed that ATO combined with CT decreased tumor growth. Tumors from ATO combined with CT-treated mice showed decreased levels of phosphorylated-STAT3(Tyr705) and the anti-apoptotic protein Bcl-2 but an increased level of pro-apoptotic protein Bax.
CONCLUSIONS: Our study provides strong evidence that CT could enhance the efficacy of ATO in treating liver cancer both in vitro and in vivo. Downregulation of phosphorylated-STAT3 expression may play an important role in inducing apoptosis of Bel-7404 cells.

Zhou YM, Sui CJ, Zhang XF, et al.
Influence of cirrhosis on long-term prognosis after surgery in patients with combined hepatocellular-cholangiocarcinoma.
BMC Gastroenterol. 2017; 17(1):25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Little is known about the prognostic impact of cirrhosis on long-term survival of patients with combined hepatocellular-cholangiocarcinoma (cHCC-CC) after hepatic resection. The aim of this study was to elucidate the long-term outcome of hepatectomy in cHCC-CC patients with cirrhosis.
METHODS: A total of 144 patients who underwent curative hepatectomy for cHCC-CC were divided into two groups: cirrhotic group (n = 91) and noncirrhotic group (n = 53). Long-term postoperative outcomes were compared between the two groups.
RESULTS: Patients with cirrhosis had worse preoperative liver function, higher frequency of HBV infection, and smaller tumor size in comparison to those without cirrhosis. The 5-year overall survival rate in cirrhotic group was significantly lower than that in non-cirrhotic group (34.5% versus 54.1%, P = 0.032). The cancer recurrence-related death rate was similar between the two groups (46.2% versus 39.6%, P = 0.446), while the hepatic insufficiency-related death rate was higher in cirrhotic group (12.1% versus 1.9%, P = 0.033). Multivariate analysis indicated that cirrhosis was an independent prognostic factor of poor overall survival (hazard ratio 2.072, 95% confidence interval 1.041-4.123; P = 0.038).
CONCLUSIONS: The presence of cirrhosis is significantly associated with poor prognosis in cHCC-CC patietns after surgical resection, possibly due to decreased liver function.

Clark I, Torbenson MS
Immunohistochemistry and Special Stains in Medical Liver Pathology.
Adv Anat Pathol. 2017; 24(2):99-109 [PubMed] Related Publications
Histochemical and immunostains are routinely used to evaluate medical liver biopsy specimens. The use of these special stains allows the identification of more clinically important information than is available on hematoxylin and eosin stains alone. These special stains are important for evaluating active and chronic injury and for establishing a specific diagnosis. The skillful use of these stains greatly improves patient care. Information on the use of special stains can be scattered in different sources, making the information hard to access. In this article, the use of special stains in medical liver biopsies is concisely reviewed.

Ikegami T, Yoshizumi T, Kawasaki J, et al.
Surgical Resection for Lymph Node Metastasis After Liver Transplantation for Hepatocellular Carcinoma.
Anticancer Res. 2017; 37(2):891-895 [PubMed] Related Publications
BACKGROUND: Treatment strategies for lymph node (LN) metastasis after liver transplantation (LT) for hepatocellular carcinoma (HCC) have not been studied.
PATIENTS AND METHODS: The treatment modes and outcomes in patients with LN metastasis after LT (n=6) for HCC were reviewed.
RESULTS: The mean time from LT to LN recurrence was 2.0±1.3 years, and the locations of the LNs recurrences included the phrenic (n=2), common hepatic artery (n=2), inferior vena cava (n=1) and gastric (n=1) regions. Treatments included surgery alone (n=3), surgery followed by chemoradiation (n=1), radiation followed by chemotherapy (n=1), and chemotherapy, radiation and sorafenib (n=1). Although the patients receiving non-surgical treatments (n=3) died within 1.2 years, those who underwent surgical removal of the metastatic LNs survived 11.2 years, 4.5 years and 0.8 years, respectively, without any signs of re-recurrence.
CONCLUSION: Surgical resection is the only feasible and potentially curative treatment for LN metastasis after LT for HCC.

Friedman P, Lai JP
Liver Metastasis of Urothelial Carcinoma with Hepatoid Features: An Unusual Morphological Finding.
Anticancer Res. 2017; 37(2):801-804 [PubMed] Related Publications
Bladder cancer comprises of many well-known variants and divergent histologies, both of urothelial and adenocarcinomatous type. Extrahepatic tumors with features that resemble hepatocellular carcinoma, often referred to as hepatoid adenocarcinomas, have been described in many different organs, and are aggressive and prognostically unfavorable. Hepatoid features of bladder cancer are unusual and rarely reported. We report a unique case of a metastatic lesion to the liver consisting of a urothelial carcinoma with hepatoid features, a tumor that likely falls within the hepatoid adenocarcinoma spectrum. It is an unusual morphological finding in urothelial carcinoma and is important to recognize due to its potential for aggressive behavior, particularly when it involves a liver lesion in which hepatocellular carcinoma may be suspected.

Chen YL, Huang WC, Yao HL, et al.
Down-regulation of RASA1 Is Associated with Poor Prognosis in Human Hepatocellular Carcinoma.
Anticancer Res. 2017; 37(2):781-785 [PubMed] Related Publications
BACKGROUND/AIM: RASA1 (p120RasGAP), encodes Ras GTPase-activating protein 1 and, is a potent tumor suppressor gene that is frequently inactivated in several human cancer types. However, its precise role in hepatocellular carcinoma (HCC) has been blurred.
MATERIALS AND METHODS: We hypothesized that RASA1 plays a crucial role in tumor pathogenesis and progression of HCC. RASA1 expression levels were analyzed in 226 cases of HCC by immunohistochemistry.
RESULTS: It was found that 38.68% (41/106) of the high-grade HCC samples and 54.17% (65/120) of the low-grade HCC samples expressed RASA1 protein. The difference between RASA1 expression in high-grade and low-grade HCC was statistically significant (p=0.02). Additionally, RASA1 high expression was inversely associated with larger tumor size (p<0.001). Although RASA1 is known as a tumor suppressor, its role in overall survival (OS) in HCC is unclear. Kaplan-Meier survival analysis showed that patients with low level of RASA1 expression correlated with a significantly poorer survival compared to those with high level of RASA1 expression.
CONCLUSION: These data support that RASA1 could serve as an independent prognostic marker for HCC patients.

Zeng H, Wu HC, Wang Q, et al.
Telomere Length and Risk of Hepatocellular Carcinoma: A Nested Case-control Study in Taiwan Cancer Screening Program Cohort.
Anticancer Res. 2017; 37(2):637-644 [PubMed] Related Publications
BACKGROUND: Telomere length (TL) measured in peripheral blood leucocytes (PBL) might be a useful biomarker to identify elevated cancer risk.
PATIENTS AND METHODS: A case-control study which included 268 newly-diagnosed HCC cases and 536 matched controls, was conducted. Absolute TL in PBL was analyzed by quantitative real-time PCR.
RESULTS: The overall median length of TL was not statistically shorter in HCC cases compared to healthy controls. However, we found a significant synergistic effect of longer TL and HCV infection to increase HCC risk with a relative excess risk of 6.86 (95% CI: 2.14-11.58). Among HCC cases, significant shorter TLs were observed for <5 years (OR=3.93, 95% CI: 2.00-7.72); 5-10 years (OR=2.16, 95% CI: 1.10-4.24) compared to >10 years prior to diagnosis.
CONCLUSION: Shorter PBL TL alone was not significantly associated with increased HCC risk. Among HCC cases, significant shorter TLs were observed for <5 years prior to diagnosis.

Ryu SH, Heo SH, Park EY, et al.
Selumetinib Inhibits Melanoma Metastasis to Mouse Liver via Suppression of EMT-targeted Genes.
Anticancer Res. 2017; 37(2):607-614 [PubMed] Related Publications
AIM: We investigated the therapeutic effects of a mitogen-activated protein (MEK) inhibitor, selumetinib, in a hepatic melanoma metastasis model and studied its possible mechanism of action.
MATERIALS AND METHODS: Melanoma cell lines were exposed to selumetinib under different experimental conditions. We established a mouse model of liver metastasis and treated mice orally with vehicle or selumetinib and then evaluated metastasis progress.
RESULTS: Growth inhibition was observed in melanoma cells as a consequence of G1-phase cell-cycle arrest and the subsequent induction of apoptosis in a dose- and time-dependent manner. Mice with established liver metastases that were treated with selumetinib exhibited significantly less tumor progression than vehicle-treated mice. c-Myc expression in metastasized liver tissues were suppressed by selumetinib. Moreover, oral treatment with selumetinib modulated expression of epithelial-to-mesenchymal transition- and metastasis-related genes, including integrin alpha-5 (ITGA5), jagged 1 (JAG1), zinc finger E-box-binding homeobox 1 (ZEB1), NOTCH, and serpin peptidase inhibitor clade E (SERPINE1).
CONCLUSION: We established a mouse model of hepatic metastasis using a human melanoma cell line, such models are essential in elucidating the therapeutic effects of anti-metastatic drugs. Our data suggest the possibility that selumetinib presents a new strategy to treat liver metastasis in patients with melanoma by suppressing epithelial-to-mesenchymal transition-related genes.

Zhang S, Tang D, Zang W, et al.
Synergistic Inhibitory Effect of Traditional Chinese Medicine Astragaloside IV and Curcumin on Tumor Growth and Angiogenesis in an Orthotopic Nude-Mouse Model of Human Hepatocellular Carcinoma.
Anticancer Res. 2017; 37(2):465-473 [PubMed] Related Publications
AIM: The aim of the present study was to investigate the efficacy of the traditional Chinese medicine (TCM), astragaloside IV (AS-IV) and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma (HCC). We have previously shown the usefulness of orthotopic models of human cancer for evaluation of the efficacy of TCM.
MATERIALS AND METHODS: Nude mice with orthotopic HepG2 HCC were treated with vehicle control (0.01 ml/g normal saline), cisplatinum (2 mg/kg), AS-IV (20 mg/kg), curcumin (100 mg/kg) or AS-IV plus curcumin (20 mg/kg + 100 mg/kg). Tumor inhibition in each group was evaluated by tumor weight at autopsy. The effect of AS-IV and curcumin on tumor angiogenesis was assessed by CD34 staining and expression of fibroblast growth factor-2 (FGF2), matrix metalloproteinase 2 (MMP2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), thrombosis-related factor tissue factor (TF) and coagulation factor VII (FVII), as well as microRNAs miR-122 and miR-221.
RESULTS: AS-IV and curcumin alone and in combination significantly reduced mean tumor weight compared to vehicle control (p<0.05). Tumor microvessel count was reduced by AS-IV and curcumin alone. Expression of FGF2, MMP2, VEGF, HGF, TF and FVII was reduced by AS-IV and curcumin alone. AS-IV and curcumin alone up-regulated expression of miR-122 and down-regulated that of miR-221. The combination of AS-IV and curcumin demonstrated significant synergistic effects on microvessel count as well as on expression of angiogenic and thrombosis-related factors and microRNAs.
CONCLUSION: The present study indicates future clinical potential of combination therapy with AS-IV and curcumin for HCC.

Magistri P, Tarantino G, Ballarin R, et al.
The Evolving Role of Local Treatments for HCC in the Third Millennium.
Anticancer Res. 2017; 37(2):389-401 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) represents the fifth most common malignancy and the third cancer-related cause of death worldwide. The aim of this review was to clarify the role of local treatments for HCC, analyzing the indications and defining future perspectives.
MATERIALS AND METHODS: A systematic literature search was performed independently by two of the authors according to the PRISMA statement guidelines. The search was limited to studies reported in English between January 2005 and June 2016.
RESULTS: The literature search yielded 238 articles; after duplicates were removed, 179 titles and abstracts were reviewed. Most relevant data and articles about radiofrequency ablation, transarterial chemoembolization, percutaneous ethanol injection, microwave ablation and radioembolization are reported and discussed.
CONCLUSION: Data in the literature are confusing and difficult to compare due to the lack of prospective studies. Multidisciplinary and tailored approaches for each patient are key features, considering both guideline indications and patient-specific characteristics, and enhance hospital-specific best practice.

Glazer ES, Zager JS
Chemosaturation With Percutaneous Hepatic Perfusion in Unresectable Hepatic Metastases.
Cancer Control. 2017; 24(1):96-101 [PubMed] Related Publications
BACKGROUND: In patients with hepatic metastases from solid-organ malignancies, surgical resection may be a potentially curative option, but it is not possible in most cases. Chemosaturation with percutaneous hepatic perfusion was developed for the management of unresectable metastases to the liver.
METHODS: Relevant medical literature was summarized with regard to the outcomes and limitations of chemosaturation with percutaneous hepatic perfusion.
RESULTS: Six articles were identified that contained data on 91 individuals who received chemosaturation with percutaneous hepatic perfusion. More than 60% of these study patients were diagnosed with ocular melanoma. The overall response rate was 48% and the rate of disease control was 90%. Chemosaturation with percutaneous hepatic perfusion improved the rates of overall and hepatic progression-free survival (PFS). The data are limited but suggest that the rate of PFS was improved in study patients with isolated melanoma hepatic metastases who received chemosaturation with percutaneous hepatic perfusion compared with those assigned to standard care.
CONCLUSIONS: Our results suggest that chemosaturation with percutaneous hepatic perfusion produces favorable tumor response rates in select individuals with unresectable hepatic metastases from multiple primary cancers, particularly ocular and cutaneous melanomas. Data from a single randomized clinical trial have also shown that chemosaturation with percutaneous hepatic perfusion can affect hepatic PFS in certain patients.

Nanjappa S, Pla-Fernandez CA, Apuri S, et al.
Liver-Directed Embolization for the Long-Term Control of Hypercalcemia of Malignancy in Metastatic Breast Cancer.
Cancer Control. 2017; 24(1):57-59 [PubMed] Related Publications
Hypercalcemia of malignancy is a common complication of certain types of cancers. No standard therapies exist for the treatment of hypercalcemia secondary to paraneoplastic syndromes that result in the long-term control of serum calcium levels. We report a case of metastatic breast cancer with parathyroid hormone-related protein associated with hypercalcemia of malignancy that was treated with transarterial embolization of the hepatic metastatic lesions.

Luz JH, Luz PM, Martin HS, et al.
DEB TACE for Intermediate and advanced HCC - Initial Experience in a Brazilian Cancer Center.
Cancer Imaging. 2017; 17(1):5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: According to Barcelona Clinic Liver Cancer classification transarterial chemoembolization is indicated in patients with Hepatocellular Carcinoma in the intermediate stage. Drug-eluting microspheres can absorb and release the chemotherapeutic agent slowly for 14 days after its intra-arterial administration. This type of transarterial chemoembolization approach appears to provide at least equivalent effectiveness with less toxicity.
METHODS: This is a prospective, single-center study, which evaluated 21 patients with intermediate and advanced hepatocellular carcinoma who underwent transarterial chemoembolization with drug-eluting microspheres. The follow up period was 2 years. Inclusion criteria was Child-Pugh A or B liver disease patients, intermediate or advanced hepatocellular carcinoma and performance status equal or below 2. Transarterial chemoembolization with drug-eluting microspheres was performed at 2-month intervals during the first two sessions. The third and subsequent sessions were performed according to the image findings on follow-up, on a "demand schedule". Tumor response and time to progression were evaluated along the two-year follow up period.
RESULTS: Of the 21 patients 90% presented with liver cirrhosis, 62% had Barcelona Clinic Liver Cancer stage B and 38% had Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma. Average tumor size was 6.9 cm. The average number of Transarterial chemoembolization with drug-eluting microspheres procedures was 3 with a total of 64 sessions. The predominant toxicity was mild. Liver function was not significantly affected in most patients. Two deaths occurred within 90 days after Transarterial chemoembolization with drug-eluting microspheres (ischemic hepatitis and hydropic decompensation). Technical success was achieved in 63 of 64 procedures. The mean hospital stay was 1.5 days. The progression free and overall survival at 1 and 2 years were 73.0% and 37.1%, 73.7% and 41.6%, respectively.
CONCLUSION: Transarterial chemoembolization with drug-eluting microspheres is able to deliver significant tumor response and progression free survival rate with acceptable toxicity. Larger studies are needed to identify exactly which subset of advanced hepatocellular patients may benefit from this treatment.
TRIAL REGISTRATION: study ID ISRCTN16295622. Registered October 14th 2016. Retrospectively registered. Website registration: http://www.isrctn.com/ISRCTN16295622.

Nagata K, Tajiri K, Shimada S, et al.
Rectal Neuroendocrine Tumor G1 with a Solitary Hepatic Metastatic Lesion.
Intern Med. 2017; 56(3):289-293 [PubMed] Related Publications
Rectal neuroendocrine tumor (NET) is a relatively rare tumor. NET is classified as G1, G2, or G3 according to the degree of mitosis or Ki-67 proliferation index, which reflect the malignant potential of the tumor, such as metastasis. Advanced cases with metastasis are indicated for chemotherapy treatment. However, the efficacy of chemotherapy is limited. Therefore, resection is considered, even in metastatic cases, if complete resection is possible. We herein report a case of small rectal NET discovered with hepatic metastasis classified as G1. The patient showed good progress with no recurrence after undergoing hepatectomy and endoscopic resection of rectal NET.

Shimomura Y, Takaki A, Wada N, et al.
The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma.
Intern Med. 2017; 56(3):243-251 [PubMed] Related Publications
Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

Lee HW, Park TI, Jang SY, et al.
Clinicopathological characteristics of TERT promoter mutation and telomere length in hepatocellular carcinoma.
Medicine (Baltimore). 2017; 96(5):e5766 [PubMed] Free Access to Full Article Related Publications
Promoter mutations in telomerase reverse transcriptase (TERT) and telomere length have been studied in various tumors. In the present study, the frequency and clinical characteristics of TERT promoter mutation and telomere length were studied in hepatocellular carcinoma (HCC). TERT promoter mutation and telomere length were analyzed in 162 tumor samples of the patients with HCC by sequencing and real-time PCR, respectively. The TERT promoter mutation rate was 28.8% (46/160) in HCC and was associated with males (P = 0.027). The telomere length was not significantly different in the presence of a TERT promoter mutation but was shorter in high-grade tumor stages (P = 0.048). Survival analyses showed that poor overall survival was associated with longer telomere length (P = 0.013). However, the TERT promoter mutation did not have a prognostic value for HCC. Multivariate survival analyses demonstrated that the telomere length was an independent prognostic marker for poor overall survival (hazard ratio = 1.75, 95% confidence interval: 1.046-2.913, P = 0.033). These data demonstrated that TERT promoter mutation is a frequent event in HCC; however, telomere length, but not the presence of a TERT promoter mutation, might have potential value as a prognostic indicator of HCC.

Kudo M
Immune Checkpoint Inhibition in Hepatocellular Carcinoma: Basics and Ongoing Clinical Trials.
Oncology. 2017; 92 Suppl 1:50-62 [PubMed] Related Publications
Clinical trials of antibodies targeting the immune checkpoint inhibitors programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for the treatment of advanced hepatocellular carcinoma (HCC) are ongoing. Expansion cohorts of a phase I/II trial of the anti-PD-1 antibody nivolumab in advanced HCC showed favorable results. Two phase III studies are currently ongoing: a comparison of nivolumab and sorafenib in the first-line setting for advanced HCC, and a comparison of the anti-PD-1 antibody pembrolizumab and a placebo in the second-line setting for patients with advanced HCC who progressed on sorafenib therapy. The combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies is being evaluated in other phase I/II trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. Immune checkpoint inhibitors may therefore open new doors to the treatment of HCC.

Mukherjee A, Subramanian S, Ambade R, et al.
Development of Semiautomated Module for Preparation of (131)I Labeled Lipiodol for Liver Cancer Therapy.
Cancer Biother Radiopharm. 2017; 32(1):33-37 [PubMed] Related Publications
Intra-arterial injection of (131)I Lipiodol is an effective treatment option for primary hepatocellular carcinoma as it delivers high radiation dose to liver tumor tissue with minimal accumulation in adjacent normal tissue. The present article demonstrates design, fabrication, and utilization of a semiautomated radiosynthesis module for preparation of (131)I labeled Lipiodol. The radiolabeling method was standardized for preparation of patient dose of (131)I labeled Lipiodol radiochemical yield (RCY); radiochemical purity (RCP) and pharmaceutical purity of the product were determined using optimized procedures. Sterile and apyrogenic (131)I labeled Lipiodol in >60% RCY could be prepared with >95% RCP. Preclinical evaluation in animals indicated retention of more than 90% of activity at 24 hours postportal vein injection. This is the first report demonstrating potential application of simple user friendly and safe semiautomated system for routine production of (131)I labeled Lipiodol, which is adaptable at centralized hospital radiopharmacies. The described prototype module can be modified as per demand for preparation of other therapeutic radiopharmaceuticals.

Kim WJ, Kim KH, Shin MH, et al.
Totally laparoscopic anatomical liver resection for centrally located tumors: A single center experience.
Medicine (Baltimore). 2017; 96(4):e5560 [PubMed] Free Access to Full Article Related Publications
Laparoscopic major hepatectomy is a common procedure that has been reported frequently; however, laparoscopic resection of centrally located tumors involving segments 4, 5, and 8 remains a technically difficult procedure because it requires 2 transection planes and dissection of numerous branches of the hepatic vein and glissonean capsule compared to hemi-hepatectomy. Here, we present 7 cases of totally laparoscopic right anterior sectionectomy (Lap-RAS) and 3 cases of totally laparoscopic central bisectionectomy (Lap-CBS).Between May 2013 and January 2015, 10 totally laparoscopic anatomical resections of centrally located tumors were performed in our institution. The median age of the patients was 54.2 (38-72) years and the median ICG-R15 was 10.4 (3.9-17.4). There were 8 patients with hepatocellular carcinoma (HCC) and 2 with metastatic colorectal cancer. All the HCC patients has the liver function impairment on the degree of Child-Pugh score A.The mean operation time was 330 ± 92.7 minutes with an estimated blood loss of 325 ± 234.5 mL. Only 1 patient required transfusion during surgery. Mean postoperative hospital stay was 9.5 ± 3.4 day and postop complication was reported only 1 case that has the fluid collection at the resection margin of the liver. Mean resection margin was 8.5 ± 6.1 mm and tumor size was 2.9 ± 1.9 cm.Totally lap-RAS and lap-CBS are feasible operative procedures in patients with centrally located tumor of the liver and particularly in patients with limited liver function such as those with cirrhosis.

Chen S, Yan W, Lang W, et al.
SESN2 correlates with advantageous prognosis in hepatocellular carcinoma.
Diagn Pathol. 2017; 12(1):13 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: SESN2 plays important roles in the regulation of cell survival, cell protection, and tumor suppression. However, the relationship between SESN2 expression and the clinicopathological attributes of hepatocellular carcinoma (HCC) is barely investigated.
METHODS: One-step quantitative reverse transcription PCR, Western blotting analysis in 15 fresh HCC tissues, and immunohistochemistry (IHC) analysis in a tissue microarray (TMA) containing 100 HCC cases were performed to examine SESN2 expression. Survival analyses by Cox regression method and Kaplan-Meier curve were performed to describe the overall survival of 100 HCC patients.
RESULTS: The SESN2 expression in HCC tissues declined dramatically compared with the corresponding noncancerous tissues, and SESN2 expression was remarkably associated with HBV infection (p = 0.019), HCV infection (p = 0.001), and lymph node metastasis (p = 0.033). Survival analysis further demonstrated that SESN2 expression could serve as an independent prognostic biomarker for overall survival in univariate (p = 0.001) and multivariate analyses (p = 0.003).
CONCLUSION: The data are the first to indicate that SESN2 might be a novel prognostic marker for HCC and that elevated SESN2 expression predicts advantageous outcomes in HCC patients.

Kumar Mongre R, Sharma N, Singh Sodhi S, et al.
Novel phyto-derivative BRM270 inhibits hepatocellular carcinoma cells proliferation by inducing G2/M phase cell cycle arrest and apoptosis in xenograft mice model.
Biomed Pharmacother. 2017; 87:741-754 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a major threat to human health worldwide and development of novel antineoplastic drug is demanding task. BRM270 is a proprietary combination of traditional medicinal herbs, has been shown to be effective against a wide range of stem-like cancer initiating cells (SLCICs). However, the underlying mechanism and antitumor efficacy of BRM270 in human hepatocellular carcinoma (HCC) cells have not been well elucidated till date. Here we studied the tumoricidal effect of BRM270 on human-CD133(+) expressing stem-like HepG-2 and SNU-398 cells. Gene expression profiling by qPCR and specific cellular protein expressions was measured using immunocytochemistry/western blot analysis. In vivo efficacy of BRM270 has been elucidated in the SLCICs induced xenograft model. In addition, 2DG-(2-Deoxy-d-Glucose) optical-probe guided tumor monitoring was performed to delineate the size and extent of metastasized tumor. Significant (P<0.05) induction of Annexin-V positive cell population and dose-dependent upregulation of caspase-3 confirmed apoptotic cell death by pre/late apoptosis. In addition, bright field and fluorescence microscopy of treated cells revealed apoptotic morphology and DNA fragmentation in Hoechst33342 staining. Levels of c-Myc, Bcl-2 and c-Jun as invasive potential apoptotic marker were detected using qPCR/Western blot. Moreover, BRM270 significantly (P<0.05) increased survival rate that observed by Kaplan-Meier log rank test. In conclusion, these results indicate that BRM270 can effectively inhibit proliferation and induce apoptosis in hepatoma cells by down-regulating CyclinD1/Bcl2 mediated c-Jun apoptotic pathway.

Lan J, Wang N, Huang L, et al.
Design and synthesis of novel tetrandrine derivatives as potential anti-tumor agents against human hepatocellular carcinoma.
Eur J Med Chem. 2017; 127:554-566 [PubMed] Related Publications
Tetrandrine, a lead anti-tumor compound with a bis-benzyltetrahydroisoquinoline skeleton isolated from medicinal plant Stephania tetrandra. In order to obtain active anti-tumor agents and evaluate their structure-activity relationships, a series of novel tetrandrine derivatives were designed and synthesized in this study. Their anti-tumor activities against human hepatocellular carcinoma cell lines (HMCC97L and PLC/PRF/5) were also evaluated. The bioassay results showed that the derivatives exhibited moderate to strong inhibition against the two cell lines. Among them, compound 31 showed prominent cytotoxicity with IC50 = 1.06 μM (15.8 folds than that of tetrandrine, and 30.3 folds than that of Sorafenib). Further studies on the mechanisms demonstrated that the in vitro anti-tumor activity of compound 31 was predominantly due to the inducement of apoptosis of HCC cells. Compound 31 was capable of initiating endoplasmic reticulum stress-associated apoptotic cell death, and the activation of JNK as well as caspase pathways were probably involved. Our results suggest that compound 31, a new 14-position substituted amide tetrandrine derivative, might be a potential candidate for developing novel anti-HCC drugs in the coming future.

Kgatle MM, Setshedi M, Hairwadzi HN
Hepatoepigenetic Alterations in Viral and Nonviral-Induced Hepatocellular Carcinoma.
Biomed Res Int. 2016; 2016:3956485 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is a major public health concern and one of the leading causes of tumour-related deaths worldwide. Extensive evidence endorses that HCC is a multifactorial disease characterised by hepatic cirrhosis mostly associated with chronic inflammation and hepatitis B/C viral infections. Interaction of viral products with the host cell machinery may lead to increased frequency of genetic and epigenetic aberrations that cause harmful alterations in gene transcription. This may provide a progressive selective advantage for neoplastic transformation of hepatocytes associated with phenotypic heterogeneity of intratumour HCC cells, thus posing even more challenges in HCC treatment development. Epigenetic aberrations involving DNA methylation, histone modifications, and noncoding miRNA dysregulation have been shown to be intimately linked with and play a critical role in tumour initiation, progression, and metastases. The current review focuses on the aberrant hepatoepigenetics events that play important roles in hepatocarcinogenesis and their utilities in the development of HCC therapy.

Chung TW, Lin SC, Su JH, et al.
Sinularin induces DNA damage, G2/M phase arrest, and apoptosis in human hepatocellular carcinoma cells.
BMC Complement Altern Med. 2017; 17(1):62 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Sinularin isolated from the cultured soft coral Sinularia flexibilis has been reported to exert potent cytotoxic effects against particular types of cancer. This study was carried out to investigate the cytotoxic effects in sinularin-treated human hepatocellular carcinoma cells, HepG2, and to subsequently explore the underlying molecular mechanisms.
METHODS: TheMTT (3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyl- tetrazolium bromide) method was used to evaluate the cytotoxicity of sinularin on HepG2 and Hep3B cell lines. Furthermore, the cell cycle distribution assay, apoptosis assay, and western blot analysis in vitro were used to explore the possible mechanisms of action.
RESULTS: From the results of our study, cell viability was obviously inhibited by sinularin in a dose-dependent manner. In addition, our results suggested that sinularin triggered DNA damage and subsequently induced cell cycle G2/M arrest associated with up-regulation of p-ATM (Ser(1981)), p-Chk2 (Tyr(68)), p-cdc2 (Tyr(15)), and p53 coupled with increased expression of downstream proteins p21 and down-regulation of p-cdc25 (Ser(216)). Moreover, the results of the apoptosis assay and western blot analysis indicated that the cytotoxic activity could be related to mitochondrial apoptosis, characterized by decrease of Bcl-2 expression, disruption of mitochondrial membrane potential, and sequential activation of caspases and Poly (ADP-ribose) polymerase (PARP).
CONCLUSIONS: This study reveals for the first time the anti-HCC activities of sinularin, the active compound isolated from the cultured soft coral Sinularia flexibilis. We believe that our results warrant further evaluation of sinularin as a new anti-HCC chemotherapeutic agent.

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