CYTOPATHOLOGY, Issue 3 2002
GORDON H. YU
The distinction of hepatocellular carcinoma (HCC) from benign lesions of the liver in fine needle aspiration (FNA) specimens can be problematic. In an attempt to separate well-differentiated HCC from benign hepatocellular lesions, the presence of tissue fragments displaying peripheral endothelial cells (PE) has been proposed in a previous study as a useful feature in favour of malignancy. In this study, we evaluated slides from 59 cases of liver masses undergoing FNA (19 HCC, 40 benign) and evaluated them for the presence of tissue fragments containing PE. We found that 90% of cases of HCC contained tissue fragments in which PE were either focally present or abundant. However, 68% of cases containing only benign hepatocytes also contained tissue fragments in which PE were at least focally present. In addition, it appears that within the group of benign lesions, the presence of PE was related to the overall cellularity of the specimen rather than the specific nature of the lesion. Thus, the presence of PE in tissue fragments does not, in isolation, appear to be a useful morphological feature for the separation of benign and malignant hepatocellular lesions in FNA material. [source]

Cutaneous Seeding of Hepatocellular Carcinoma Due to Percutaneous Ethanol Injection and Masquerading as a Pyogenic Granuloma

DERMATOLOGIC SURGERY, Issue 3 2004
Mei-Ching Lee MD
Background. This investigation reports a 68-year-old man with a history of hepatocellular carcinoma (HCC) diagnosed 2 years previously who developed a single, easy-bleeding, pyogenic granuloma (PG)-like lesion on his right upper abdomen, located in the area of previous therapeutic percutaneous ethanol injection (PEI) for HCC treatment. The lesion developed 3 months after the injection. The tumor was found to be identical to his previous HCC. Objective. To describe a case of cutaneous seeding of HCC during PEI presented as a PG-like lesion. To our knowledge, this is the first such case reported in the literature. Methods. This is a case report and review the literature. Results. Immunostainings for ,-fetoprotein and hepatocyte monoclonal antibody confirmed the diagnosis. Besides, the patient had no other metastatic lesion. Conclusion. This tumor is believed to be caused by cutaneous seeding of HCC during PEI and is simulated clinically as a PG. [source]

Metastatic hepatocellular carcinoma presenting as a pancreatic mass by computed tomography scan and mimicking a primary neuroendocrine tumor: A potential pitfall in aspiration cytology

DIAGNOSTIC CYTOPATHOLOGY, Issue 12 2009
Valerie A. Fitzhugh M.D.
Abstract Hepatocellular carcinoma (HCC) is a highly malignant neoplasm, often presenting at late stage and portending a poor prognosis for the patient. The peripancreatic fat is a rare site of extrahepatic metastasis, and metastatic HCC can mimic primary pancreatic neoplasms, even in this location. It is crucial to be aware of this pitfall in the evaluation of aspiration cytology of pancreatic neoplasms and to develop a strategy to reach the correct diagnosis. We present an endoscopic ultrasound fine-needle aspiration diagnosis of metastatic HCC presenting as a pancreatic mass radiologically that had neuroendocrine features on various cytological and histological preparations. The metastatic lesions were located surgically in the peripancreatic adipose tissue with involvement of one peripancreatic lymph node. This case illustrates the utility of FNA for diagnosing uncommon presentations of HCC and the importance of clinical history, cell block, and an immunocytochemical panel in determining the origin of the tumor. Diagn. Cytopathol. 2009. © 2009 Wiley-Liss, Inc. [source]

Fine-needle aspiration cytology of Hürthle cell carcinoma of the thyroid

DIAGNOSTIC CYTOPATHOLOGY, Issue 3 2008
Howard Her-Juing Wu M.D.
Abstract Specific criteria for the diagnosis of fine-needle aspiration (FNA) of Hürthle Cell Carcinoma (HCC) have rarely been discussed in the literature. A retrospective review of 35 FNA cases with the diagnosis of Hürthle cell lesion or Hürthle cell neoplasm was performed. In each case, there was a subsequent surgical excision. The FNA specimens were divided according to histologic diagnoses as HCC (12 cases), Hürthle cell adenoma (HCA) (14 cases), and benign nonneoplastic Hürthle cell lesions (BNHCL) (9 cases). Each case was examined using a semiquantitative scoring system for the following 11 features: presence or absence of colloid, lymphocytes, and transgressed blood vessels (each scored 0 or 1); the percentage of nuclear enlargement, small cell dysplasia, large cell dysplasia, nuclear crowding, and cellular dyshesion (each scored 0,3); and age, gender, and size of lesion. When diagnosed by FNA as either Hürthle cell neoplasm or Hürthle cell lesion, males were much more likely to have malignant tumors than females. Statistically significant cytologic features that favored malignant (HCC) over benign lesions (HCA and BNHCL) included small cell dysplasia, large cell dysplasia, nuclear crowding, and cellular dyshesion. The presence of colloid and lymphocytes favored a benign lesion. Nuclear enlargement and large tumor size are significantly more common in neoplasms than BNHCL. Diagn. Cytopathol. 2008;36:149,154. © 2008 Wiley-Liss, Inc. [source]

Laparoscopic findings in non-alcoholic steatohepatitis

DIGESTIVE ENDOSCOPY, Issue 4 2003
Shuichi Seki
Background:, Non-alcoholic steatohepatitis (NASH) is prevalent worldwide, but little attention has been paid to the gross visual appearance of NASH. The present study was performed to address the laparoscopic features of NASH and the relationship between laparoscopic and histologicalal findings. Methods:, Eleven patients were examined by laparoscopy with liver biopsy. Histological findings were examined according to the criteria of Brunt et al. with minor modification. Mallory bodies were immunohistochemically detected by an antibody to ubiquitin in addition to hematoxylin eosin staining. Results:, Laparoscopic features of NASH were swelling of the liver, formation of many depressions, and dull edges of the liver. When steatosis was present in more than one-third of lobules, yellowish markings appeared on the liver surface. NASH progressed from a smooth liver surface with or without yellowish markings, to formation of depressions on the liver surface, to cirrhosis with or without hepatocellular carcinoma (HCC). Conclusion:, Laparoscopy may provide useful information in the diagnosis and progression of NASH. [source]

Proteomic analysis of liver cancer cells treated with 5-Aza-2,-deoxycytidine (AZA),

DRUG DEVELOPMENT RESEARCH, Issue 1 2009
Shujun Bai
Abstract 5-Aza-2,-deoxycytidine (AZA) is a potent inhibitor of DNA methylation that exhibits anti-tumor activity in a variety of tumor cells via reactivation of tumor suppressor genes. However, few studies have been done on the biological and clinical significance of AZA in human hepatocellular carcinoma. To identify potential genes that may be aberrantly methylated and confer growth advantage to neoplastic cells and to better understand the molecular mechanism(s) underlying AZA anti-tumor activity, a proteomics approach was used to annotate global gene expression changes of HepG2 cell line pre- and post-treatment with AZA. A total of 56 differentially expressed proteins were identified by 2D gel analysis, 48 of which were up-regulated while the remaining 8 were down regulated. Among the identified proteins, eight of these showed marked changed proteins, including seven up-regulated proteins: glutathione S-transferase P, protein DJ-1, peroxiredoxin-2, UMP-CMP kinase, cytochrome c-type heme lyase, enhancer of rudimentary homolog, profilin-1, and one down-regulated protein, heat-shock protein ,,1. The possible implication of these proteins in hepatocarcinogenesis is discussed. We tested two up-regulated proteins, glutathione S-transferase P and peroxiredoxin-2, using RT-PCR and their expression was consistent with the results obtained in the protein level. Both of these genes were methylated when methylation-specific PCR was used against their promoter regions. Following treatment with AZA, the gene promoter regions were found to be unmethylated, concomitant with overexpression of the proteins compared to HepG2 cells without treatment. These data provide useful information in evaluating the therapeutic potential of AZA for the treatment of HCC. Drug Dev Res 69, 2009. © 2009 Wiley-Liss, Inc. [source]

Proteome analysis of human liver tumor tissue by two-dimensional gel electrophoresis and matrixassisted laser desorption/ionization-mass spectrometry for identification of disease-related proteins

ELECTROPHORESIS, Issue 24 2002
Jina Kim
Abstract Hepatocellular carcinoma (HCC) is a common malignancy worldwide and is a leading cause of death. To contribute to the development and improvement of molecular markers for diagnostics and prognostics and of therapeutic targets for the disease, we have largely expanded the currently available human liver tissue maps and studied the differential expression of proteins in normal and cancer tissues. Reference two-dimensional electrophoresis (2-DE) maps of human liver tumor tissue include labeled 2-DE images for total homogenate and soluble fraction separated on pH 3,10 gels, and also images for soluble fraction separated on pH 4,7 and pH 6,9 gels for a more detailed map. Proteins were separated in the first dimension by isoelectric focusing on immobilized pH gradient (IPG) strips, and by 7.5,17.5% gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels in the second dimension. Protein identification was done by peptide mass fingerprinting with delayed extraction-matrix assisted laser desorption/ionization-time of flight-mass spectrometry (DE-MALDI-TOF-MS). In total, 212 protein spots (117 spots in pH 4,7 map and 95 spots in pH 6,9) corresponding to 127 different polypeptide chains were identified. In the next step, we analyzed the differential protein expression of liver tumor samples, to find out candidates for liver cancer-associated proteins. Matched pairs of tissues from 11 liver cancer patients were analyzed for their 2-DE profiles. Protein expression was comparatively analyzed by use of image analysis software. Proteins whose expression levels were different by more than three-fold in at least 30% (four) of the patients were further analyzed. Numbers of protein spots overexpressed or underexpressed in tumor tissues as compared with nontumorous regions were 9 and 28, respectively. Among these 37 spots, 1 overexpressed and 15 underexpressed spots, corresponding to 11 proteins, were identified. The physiological significance of the differential expressions is discussed. [source]

A randomized controlled trial of transcatheter arterial chemoembolization with lipiodol, doxorubicin and cisplatin versus intravenous doxorubicin for patients with unresectable hepatocellular carcinoma

EUROPEAN JOURNAL OF CANCER CARE, Issue 5 2009
M. MABED md, professor
Hepatocellular carcinoma (HCC) is a major and often therapeutically frustrating oncological problem. A total of 100 patients with unresectable HCC were recruited and randomized to be treated with either transcatheter arterial chemoembolization (TACE) or systemic chemotherapy. Fifty patients were treated with TACE using lipiodol, doxorubicin and cisplatin, while 50 patients were treated with systemic doxorubicin alone. Patients treated with TACE achieved a significantly higher response rate, with partial response achieved in 16 patients (32%) versus five patients (10%) in the chemotherapy arm (P = 0.007). A significantly more favourable tumour response to chemoembolization was found in patients with single lesions (P = 0.02), Child class A (P = 0.007), Okuda stage 1 (P = 0.005) and ,-feto protein less than 400 ng/mL (P < 0.001). The probability of tumour progression was significantly lower in cases treated with TACE where the median progression free survival was 32 weeks (range, 16,70 weeks) versus 26 weeks (range, 14,54 weeks) for patients treated with systemic chemotherapy (P = 0.03). However, the median overall survival did not differ significantly in cases treated with TACE (38 weeks) compared with those treated with chemotherapy (32 weeks) (P = 0.08), except for patients with serum albumin >3.3 g/dL (60 vs. 36 weeks; P = 0.003). Multivariate Cox regression analysis showed that a rise of serum albumin by 1 g/dL is associated with a decrease in the risk of death by 33% (95% confidence interval: 0.12,0.94, P = 0.038). Mortality in the chemoembolization arm was due to tumour progression in 18 patients (53%), liver failure in 11 patients (32%) and gastro intestinal tract (GIT) bleeding in 5 patients (15%). Mortality in the chemotherapy arm was due to tumour progression in 23 patients (64%), liver failure in 9 patients (25%) and GIT bleeding in 4 patients (11%). Treatment-related mortality was 4% in the TACE arm versus 0% in the chemotherapy arm. In conclusion, the overall survival benefits of TACE and systemic doxorubicin are similar for patients with unresectable HCC amenable to either treatment. It is crucial to optimize the benefit,risk ratio of TACE. In this setting, serum albumin level is a candidate marker for selection of cases who may benefit from this procedure. [source]

Bradycardia and sinus arrest during percutaneous ethanol injection therapy for hepatocellular carcinoma

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2004
A. Ferlitsch
Abstract Background, Percutaneous ethanol injection (PEI) is an established method in the treatment of hepatocellular carcinoma (HCC) and considered a safe procedure, with severe complications occurring rarely. Cardiac arrhythmias have not been reported to date. Aim of the study was to investigate the occurrence of dysrhythmias during PEI. Patients and methods, Twenty-six consecutive patients with inoperable HCC were included. During ultrasound-guided PEI with 95% ethanol, electrocardiogram (ECG) monitoring was performed before starting and continuously during PEI. Results, During PEI a significant reduction in mean heart rate (> 20%) was seen in 15 of 26 (58%) patients. In 11 of 26 patients (42%) occurrence of sinuatrial block (SAB) or atrioventricular block (AVB) was observed after a median time of 9 s (range 4,50) from the start of PEI with a median length of 24 s (range 12,480). Clinical symptoms were seen in two patients, including episodes of unconsciousness, seizure-like symptoms in both and a respiratory arrest during PEI in one patient, requiring mechanical ventilation. In four of 12 patients with repeat interventions, dysrhythmias were reproducible during monthly performed procedures. There was a significant association between the occurrence of SAB or AVB and the amount of instilled alcohol (P = 0·03) and post-PEI serum ethanol levels (P = 0·03). Conclusions, Bradycardia and block formation occur frequently during PEI. These symptoms could be explained by a vasovagal reaction and/or the direct effect of ethanol on the sinus node or the right atrial conduction system. Ethanol dose is an important factor for the occurrence of SAB/AVB. ECG-monitoring seems mandatory during PEI. Prophylactic use of intravenously administered Atropine might be useful. [source]

DNAX accessory molecule-1 (CD226) promotes human hepatocellular carcinoma cell lysis by V,9V,2 T cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2009
Olivier Toutirais
Abstract Human V,9V,2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway-derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate. They display a strong cytotoxic activity against several tumor types, including hepatocellular carcinoma (HCC). Little is known about the mechanisms underlying V,9V,2 T-cell recognition of tumor cells, but there is strong evidence that activating NK receptors play a role in ,, T-cell cytotoxicity. In this study, we showed that the two NK receptors DNAX accessory molecule-1 (DNAM-1) and CD96 were expressed by V,9V,2 T cells. The ligands Nectin-like-5 specific of both DNAM-1 and CD96, and also Nectin-2, an additional ligand of DNAM-1, were present on all HCC cell lines analyzed. Furthermore, we demonstrated by mAb-mediated masking experiments that cytotoxicity against HCC cells as well as IFN-, production in ,, T cells were dependent on DNAM-1. Our experiments indicated that Nectin-like-5 but not Nectin-2 was involved in DNAM-1-dependent ,, T-cell functions. We did not reveal a role for CD96 in the killing of HCC cells. Finally, we showed by combined mAb-mediated blockade that DNAM-1 and NKG2D could cooperate in the cell lysis of HCC. [source]

An emerging role for interferon in haemophiliacs with chronic hepatitis C?

HAEMOPHILIA, Issue 1 2001
C. Aguilar
The combination of interferon (IFN) and ribavirin is the current gold standard for treatment of chronic hepatitis C virus (HCV) infection with sustained remission rates of 35,40% being achieved in haemophilic patients. A similar beneficial effect of this combined therapy has been suggested even for patients with compensated liver cirrhosis and some authors have reported a possible role for IFN and ribavirin in the prevention or delay in the development of hepatocellular carcinoma (HCC), a well known complication of HCV infection in haemophiliacs. The absence, due to design difficulties, of definite randomized controlled clinical trials remains a handicap for the routine use of specific therapy of HCV infected patients with the aim of preventing HCC. A discussion of these important issues has been performed in this paper. [source]

The value of frozen section in intraoperative surgical management of thyroid follicular carcinoma,

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 7 2003
Danijel Do, en MD
Abstract Background. Preoperative and intraoperative diagnosis of follicular carcinoma (FC), resulting in one-stage surgical treatment of follicular thyroid tumors, is an important issue in thyroid surgery. Methods. In the 10-year period there were 4158 operations performed on thyroid gland. There were 1559 patients with follicular tumors, 70 (4.4%) of them having FC. We analyzed the groups of patients with FC determined on frozen section (FS) and permanent section (PS) according to duration of clinical symptoms, ultrasound (US) examination, tumor size, patient gender and age, intensity of invasion, localization, and multiple or solitary occurrence of tumor. Results. FC was diagnosed in 39 (55.7%) patients on frozen section (FS). Among the encapsulated (minimal invasion) carcinomas, the FS was accurate in 19 of 33 (57.6%) FC and in 5 of 15 (27.8%) Hürthle cell carcinomas (HCC); among extensively invasive carcinoma in 11 of 14 (78.6%) FC and in 4 of 5 (80.0%) HCC. FC was significantly more common in men (p < .001) and in the right lobe (p < .05). We did not find statistically significant differences concerning duration of symptoms, US examination, tumor size, patient age, and multiple or solitary occurrence of the tumor between the patients with FC diagnosed on FS and the patients with FC diagnosed on PS. Conclusions. The intraoperative diagnosis of FC is difficult. Although the percentage of false-negative results was relatively high (44.3%), there were no false-positive results. This means that the second operation was avoided in 55.7% of the patients, and no unnecessary thyroidectomies were performed. FS biopsy is an important method in surgery of follicular tumors. Improved technical support and the ability to analyze a greater number of slides will increase the accuracy of the method. © 2003 Wiley Periodicals, Inc. Head Neck 25: 521,528, 2003 [source]

Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4,AKT,ATP-binding cassette G2 pathway,

HEPATOLOGY, Issue 2 2010
Xiao Qi Wang
Chemoresistance presents a major obstacle to the efficacy of chemotherapeutic treatment of cancers. Using chemotherapeutic drugs to select drug-resistant cancer cells in hepatocellular carcinoma (HCC) and several other cancer cell lines, we demonstrate that chemoresistant cells displayed cancer stem cell features, such as increased self-renewal ability, cell motility, multiple drug resistance, and tumorigenicity. Octamer 4 (Oct4) messenger RNA (mRNA) levels were dramatically increased in chemoresistant cancer cells due to DNA demethylation regulation of Oct4. By functional study, Oct4 overexpression enhanced whereas Oct4 knockdown reduced liver cancer cell resistance to chemotherapeutic drugs in vitro and in xenograft tumors. It is known that the Oct4-TCL1-AKT pathway acts on embryonic stem cells and cancer stem cells in cell proliferation through inhibition of apoptosis. We further demonstrate that Oct4 overexpression induced activation of TCL1, AKT, and ABCG2 to mediate chemoresistance, which can be overcome by addition of the PI3K/AKT inhibitor; therefore, a direct pathway of Oct4-TCL1-AKT-ABCG2 or a combination of Oct4-TCL1-AKT with the AKT-ABCG2 pathway could be a potential new mechanism involved in liver cancer cell chemoresistance. Moreover, the clinical significance of the Oct4-AKT-ABCG2 pathway can be demonstrated in HCC patients, with a strong correlation of expression patterns in human HCC tumors. The role of the Oct4-AKT-ABCG2 axis in cancer cell chemoresistant machinery suggests that AKT pathway inhibition (PI3K inhibitors) not only inhibits cancer cell proliferation, but may also enhance chemosensitivity by target potential chemoresistant cells. Conclusion: Oct4, a transcriptional factor of pluripotent cells, can mediate chemoresistance through a potential Oct4-AKT-ABCG2 pathway. (HEPATOLOGY 2010;) [source]

Loco-regional treatment of hepatocellular carcinoma,

HEPATOLOGY, Issue 2 2010
Riccardo Lencioni
Loco-regional treatments play a key role in the management of hepatocellular carcinoma (HCC). Image-guided tumor ablation is recommended in patients with early-stage HCC when surgical options are precluded. Radiofrequency ablation has shown superior anticancer effects and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials, and is currently established as the standard method for local tumor treatment. Novel thermal and nonthermal techniques for tumor ablation,including microwave ablation, irreversible electroporation, and light-activated drug therapy,seem to have potential to overcome the limitations of radiofrequency ablation and warrant further clinical investigation. Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with asymptomatic, noninvasive multinodular tumors at the intermediate stage. The recent introduction of embolic microspheres that have the ability to release the drug in a controlled and sustained fashion has been shown to significantly increase safety and efficacy of TACE with respect to conventional, lipiodol-based regimens. The available data for radioembolization with yttrium-90 suggests that this is a potential new option for patients with HCC, which should be investigated in the setting of randomized controlled trials. Despite the advances and refinements in loco-regional approaches, the long-term survival outcomes of patients managed with interventional techniques are not fully satisfactory, mainly because of the high rates of tumor recurrence. The recent addition of molecular targeted drugs with antiangiogenic and antiproliferative properties to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between loco-regional and systemic treatments. The outcomes of these trials are eagerly awaited, because they have the potential to revolutionize the treatment of HCC. (HEPATOLOGY 2010;) [source]

Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States,

HEPATOLOGY, Issue 1 2010
Jessica A. Davila
Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended but may not be performed. The extent and determinants of HCC surveillance are unknown. We conducted a population-based United States cohort study of patients over 65 years of age to examine use and determinants of prediagnosis surveillance in patients with HCC who were previously diagnosed with cirrhosis. Patients diagnosed with HCC during 1994-2002 were identified from the linked Surveillance, Epidemiology, and End-Results registry,Medicare databases. We identified alpha-fetoprotein (AFP) and ultrasound tests performed for HCC surveillance, and examined factors associated with surveillance. We identified 1,873 HCC patients with a prior diagnosis of cirrhosis. In the 3 years before HCC, 17% received regular surveillance and 38% received inconsistent surveillance. In a subset of 541 patients in whom cirrhosis was recorded for 3 or more years prior to HCC, only 29% received routine surveillance and 33% received inconsistent surveillance. Among all patients who received regular surveillance, approximately 52% received both AFP and ultrasound, 46% received AFP only, and 2% received ultrasound only. Patients receiving regular surveillance were more likely to have lived in urban areas and had higher incomes than those who did not receive surveillance. Before diagnosis, approximately 48% of patients were seen by a gastroenterologist/hepatologist or by a physician with an academic affiliation; they were approximately 4.5-fold and 2.8-fold, respectively, more likely to receive regular surveillance than those seen by a primary care physician only. Geographic variation in surveillance was observed and explained by patient and physician factors. Conclusion: Less than 20% of patients with cirrhosis who developed HCC received regular surveillance. Gastroenterologists/hepatologists or physicians with an academic affiliation are more likely to perform surveillance. HEPATOLOGY 2010 [source]

Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma by reducing Notch1 cleavage,

HEPATOLOGY, Issue 1 2010
Jiejie Xu
One of the serious sequelae of chronic hepatitis B virus (HBV) infection is hepatocellular carcinoma (HCC). Among all the proteins encoded by the HBV genome, hepatitis B virus X protein (HBx) is highly associated with the development of HCC. Although Notch1 signaling has been found to exert a tumor-suppressive function during HCC development, the mechanism of interaction between HBx expression and Notch1 signaling needs to be explored. In this study, we report that HBx expression in hepatic and hepatoma cells resulted in decreased endogenous protein levels of Notch1 intracellular domain (ICN1) and messenger RNA levels of its downstream target genes. These effects were due to a reduction of Notch1 cleavage by HBx through the suppression of presenilin1 (Psen1) transcription rather than inhibition of Notch1 transcription or its ligands' expression. Through transient HBx expression, decreased ICN1 resulted in enhanced cell proliferation, induced G1-S cell cycle progression, and blunted cellular senescence in vitro. Furthermore, the effect of blunted senescence-like growth arrest by stable HBx expression through suppression of ICN1 was shown in a nude mouse xenograft transplantation model. The correlation of inhibited Psen1-dependent Notch1 signaling and blunted senescence-like growth arrest was also observed in HBV-associated HCC patient tumor samples. Conclusion: Our results reveal a novel function of HBx in blunting senescence-like growth arrest by decreasing Notch1 signaling, which could be a putative molecular mechanism mediating HBV-associated hepatocarcinogenesis. (HEPATOLOGY 2010;) [source]

Sorafenib: Where do we go from here?,

HEPATOLOGY, Issue 1 2010
Abby B. Siegel
The approval of sorafenib as the first effective drug for the treatment of hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. A better understanding of HCC pathogenesis has led to the development of several novel targeted treatments. HCC is treated in a uniquely multidisciplinary way requiring surgeons, hepatologists, interventional radiologists, and oncologists. This review describes the molecular pathogenesis of HCC, explores current and future treatments based on these pathways, and describes how these new therapies may augment existing approaches to HCC treatment.(HHEPATOLOGY 2010;) [source]

S -adenosylmethionine regulates dual-specificity mitogen-activated protein kinase phosphatase expression in mouse and human hepatocytes,

HEPATOLOGY, Issue 6 2010
Maria Lauda Tomasi
Increased mitogen-activated protein kinase (MAPK) activity correlates with a more malignant hepatocellular carcinoma (HCC) phenotype. There is a reciprocal regulation between p44/42 MAPK (extracellular signal-regulated kinase [ERK]1/2) and the dual-specificity MAPK phosphatase MKP-1/DUSP1. ERK phosphorylates DUSP1, facilitating its proteasomal degradation, whereas DUSP1 inhibits ERK activity. Methionine adenosyltransferase 1a (Mat1a) knockout (KO) mice express hepatic S -adenosylmethionine (SAM) deficiency and increased ERK activity and develop HCC. The aim of this study was to examine whether DUSP1 expression is regulated by SAM and if so, elucidate the molecular mechanisms. Studies were conducted using Mat1a KO mice livers, cultured mouse and human hepatocytes, and 20S and 26S proteasomes. DUSP1 messenger RNA (mRNA) and protein levels were reduced markedly in livers of Mat1a KO mice and in cultured mouse and human hepatocytes with protein falling to lower levels than mRNA. SAM treatment protected against the fall in DUSP1 mRNA and protein levels in mouse and human hepatocytes. SAM increased DUSP1 transcription, p53 binding to DUSP1 promoter, and stability of its mRNA and protein. Proteasomal chymotrypsin-like and caspase-like activities were increased in Mat1a KO livers and cultured hepatocytes, which was blocked by SAM treatment. SAM inhibited chymotrypsin-like and caspase-like activities by 40% and 70%, respectively, in 20S proteasomes and caused rapid degradation of some of the 26S proteasomal subunits, which was blocked by the proteasome inhibitor MG132. SAM treatment in Mat1a KO mice for 7 days raised SAM, DUSP1, mRNA and protein levels and lowered proteosomal and ERK activities. Conclusion: DUSP1 mRNA and protein levels are lower in Mat1a KO livers and fall rapidly in cultured hepatocytes. SAM treatment increases DUSP1 expression through multiple mechanisms, and this may suppress ERK activity and malignant degeneration. HEPATOLOGY 2010 [source]

Inhibition of poly adenosine diphosphate-ribose polymerase decreases hepatocellular carcinoma growth by modulation of tumor-related gene expression,

HEPATOLOGY, Issue 1 2010
Rosa Quiles-Perez
Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to a lack of effective treatment options. In HCC a significant role is played by DNA damage and the inflammatory response. Poly (ADP-ribose) polymerase-1 (PARP-1) is an important protein that regulates both these mechanisms. The objective of this study was to examine the effect of pharmacology PARP-1 inhibition on the reduction of tumor volume of HCC xenograft and on the hepatocarcinogenesis induced by diethyl-nitrosamine (DEN). Pharmacologic PARP-1 inhibition with DPQ greatly reduces tumor xenograft volume with regard to a nontreated xenograft (394 mm3 versus 2,942 mm3, P < 0.05). This observation was paralleled by reductions in xenograft mitosis (P = 0.02) and tumor vasculogenesis (P = 0.007, confirmed by in vitro angiogenesis study), as well as by an increase in the number of apoptotic cells in DPQ-treated mice (P = 0.04). A substantial difference in key tumor-related gene expression (transformed 3T3 cell double minute 2 [MDM2], FLT1 [vascular endothelial growth factor receptor-1, VEGFR1], epidermal growth factor receptor [EPAS1]/hypoxia-inducible factor 2 [HIF2A], EGLN1 [PHD2], epidermal growth factor receptor [EGFR], MYC, JUND, SPP1 [OPN], hepatocyte growth factor [HGF]) was found between the control tumor xenografts and the PARP inhibitor-treated xenografts (data confirmed in HCC cell lines using PARP inhibitors and PARP-1 small interfering RNA [siRNA]). Furthermore, the results obtained in mice treated with DEN to induce hepatocarcinogenesis showed, after treatment with a PARP inhibitor (DPQ), a significant reduction both in preneoplastic foci and in the expression of preneoplastic markers and proinflammatory genes (Gstm3, Vegf, Spp1 [Opn], IL6, IL1b, and Tnf), bromodeoxyuridine incorporation, and NF-,B activation in the initial steps of carcinogenesis (P < 0.05). Conclusion: This study shows that PARP inhibition is capable of controlling HCC growth and preventing tumor vasculogenesis by regulating the activation of different genes involved in tumor progression. (HEPATOLOGY 2010;51:255,266.) [source]

Incidence, risk factors, and survival of hepatocellular carcinoma in primary biliary cirrhosis: Comparative analysis from two centers,

HEPATOLOGY, Issue 4 2009
Anna Cavazza
The limited information and divergent results on the prevalence, incidence, and risk factors for hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) may be due to the low prevalence of the disease and geographical and environmental differences. Therefore, we analyzed the incidence, prevalence, survival, and risk factors for HCC in patients with PBC from two European centers (389 from Barcelona, Spain, and 327 from Padova, Italy) followed up for 9.3 ± 6.5 years. Gender, age, smoking habit, alcohol consumption, presence of hepatitis B surface antigen (HBsAg) or hepatitis C virus antibodies (anti-HCV), and advanced histological stage (III-IV) were evaluated as risk factors for tumor development. Twenty-four patients (13 from Barcelona and 11 from Padova) developed HCC. The prevalence of HCC was similar in Barcelona (3.34%) and Padova (3.36%). The incidence was 0.35 and 0.37 per 100 patient-years, respectively. Male gender, age >52 years, smoking habit, alcohol >40 g/day, HBsAg, and anti-HCV were not associated with HCC. Advanced histological stage was the only factor associated with the development of HCC (odds ratio [OR]: 5.80, 95% confidence interval [CI]: 2.34-14.38, P < 0.001). When analyzing the two series separately, male gender was associated with higher likelihood of HCC in Padova (OR: 8.09, 95% CI: 1.93-33.8, P < 0.01). The median survival after the diagnosis of HCC was 36 months. Conclusion: The prevalence and incidence of HCC is similar in Spain and Italy and the advanced histological stage is the only risk factor associated with the development of HCC in PBC. The slight disparities observed between the two series might be explained by patient features on diagnosis of liver disease. (HEPATOLOGY 2009.) [source]

MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells,

HEPATOLOGY, Issue 1 2009
Teng Xu
Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Down-regulation of miR-195 has been observed in various types of cancers. However, the biological function of miR-195 is still largely unknown. In this study we aimed to elucidate the pathophysiologic role of miR-195. Our results showed that miR-195 expression was significantly reduced in as high as 85.7% of hepatocellular carcinoma (HCC) tissues and in all of the five HCC cell lines examined. Moreover, introduction of miR-195 dramatically suppressed the ability of HCC and colorectal carcinoma cells to form colonies in vitro and to develop tumors in nude mice. Furthermore, ectopic expression of miR-195 blocked G1/S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G1/S transition-related molecules, including cyclin D1, CDK6, and E2F3, as direct targets of miR-195. Silencing of cyclin D1, CDK6, or E2F3 phenocopied the effect of miR-195, whereas overexpression of these proteins attenuated miR-195-induced G1 arrest. In addition, miR-195 significantly repressed the phosphorylation of Rb as well as the transactivation of downstream target genes of E2F. These results imply that miR-195 may block the G1/S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3. Conclusion: Our data highlight an important role of miR-195 in cell cycle control and in the molecular etiology of HCC, and implicate the potential application of miR-195 in cancer therapy. (HEPATOLOGY 2009.) [source]

Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography,

HEPATOLOGY, Issue 6 2009
Ryota Masuzaki
Liver stiffness, noninvasively measured by transient elastography, correlates well with liver fibrosis stage. The aim of this prospective study was to evaluate the liver stiffness measurement (LSM) as a predictor of hepatocellular carcinoma (HCC) development among patients with chronic hepatitis C. Between December 2004 and June 2005, a total of 984 HCV-RNA positive patients, without HCC or a past history of it, visited the University of Tokyo Hospital. LSM was performed successfully in 866 patients, who gave informed consent. During the follow-up period (mean, 3.0 years), HCC developed in 77 patients (2.9% per 1 person-year). The cumulative incidence rates of HCC at 1, 2, and 3 years were 2.4%, 6.0%, and 8.9%, respectively. Adjusting for other significant factors for HCC development, patients with higher LSM were revealed to be at a significantly higher risk, with a hazard ratio, as compared to LSM ,10 kPa, of 16.7 (95% confidence interval [CI], 3.71-75.2; P < 0.001) when LSM 10.1-15 kPa, 20.9 (95% CI, 4.43-98.8; P < 0.001) when LSM 15.1-20 kPa, 25.6 (95%CI, 5.21-126.1; P < 0.001) when LSM 20.1-25 kPa, and 45.5 (95% CI, 9.75-212.3; P < 0.001) when LSM >25 kPa. Conclusions: This prospective study has shown the association between LSM and the risk of HCC development in patients with hepatitis C. The utility of LSM is not limited to a surrogate for liver biopsy but can be applied as an indicator of the wide range of the risk of HCC development. (HEPATOLOGY 2009.) [source]

Enhanced expression of vascular endothelial growth factor-A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis,

HEPATOLOGY, Issue 6 2009
Jui-Chu Yang
Ground glass hepatocytes (GGH) in chronic hepatitis B virus (HBV) infection harbor HBV pre-S deletion mutants in endoplasmic reticulum (ER) and exhibit complex biologic features such as ER stress, DNA damage, and growth advantage. The presence of pre-S mutants in serum has been shown to predict the development of hepatocellular carcinoma (HCC) in HBV carriers. GGHs hence represent a potentially preneoplastic lesion. Whether a specific growth factor is overexpressed and activated in GGHs remains to be clarified. In this study, growth factor(s) up-regulated by pre-S mutants was identified using a growth factor array in HuH-7 cells. Immunohistochemistry, reverse-transcriptase polymerase chain reaction, and Western blot analysis were performed to study the participation of these genes and their signal pathways in HuH-7 cells and liver tissues. We demonstrate that vascular endothelial growth factor-A (VEGF-A) was up-regulated by pre-S mutants in HuH-7 cells and further confirmed in GGHs by immunostaining. The VEGF-A up-regulation by pre-S mutants could be suppressed by vomitoxin, an ER stress inhibitor. Furthermore, pre-S mutants-expressed HuH-7 cells exhibited activation of Akt/mTOR (mammalian target of rapamycin) signaling and increased growth advantage, which could be inhibited by VEGF-A neutralization. Consistent with this notion, enhanced expression of VEGF-A and activation of Akt/mTOR signaling, comparable to the levels of paired HCC tissues, were also detected in HBV-related nontumorous livers. Conclusion: The enhanced expression of VEGF-A in GGHs provides potential mechanism to explain the progression from preneoplastic GGHs to HCC in chronic HBV infection. (HEPATOLOGY 2009;49:1962,1971.) [source]

Human inhibitor of growth 1 inhibits hepatoma cell growth and influences p53 stability in a variant-dependent manner,

HEPATOLOGY, Issue 2 2009
Zhi Zhu
Inhibitor of growth 1 (ING1) is a type II tumor suppressor that affects cell function by altering chromatin structure and regulating transcription. Recently, three ING1 splice variants have been cloned, but their roles in apoptosis and p53 regulation in human hepatocellular carcinoma (HCC) have not been fully elucidated. The present study found that ING1, in a variant-dependent manner, inhibited hepatoma cell proliferation and colony formation, induced apoptosis and cell cycle arrest at G0/G1 phase, and postponed tumor formation in nude mice. Expression of p33ING1b and p24ING1c variants, but not p47ING1a, was markedly reduced in HCC samples. Reverse transcription polymerase chain reaction and western blotting analysis revealed that ectopic overexpression of p33ING1b or p24ING1c variant increased the expression of p53 downstream genes such as p21waf1 and bax, and repressed bcl-2 expression (P < 0.01), whereas p47ING1a inactivated p21waf1 promoter (P < 0.01). Furthermore, we found that p33ING1b and p24ING1c repressed Mdm2 expression (P < 0.01) and competed with Mdm2 for binding to p53. Interestingly, p33ING1band p24ING1c did not directly bind to Mdm2 protein but strongly increased p14arf expression (P < 0.01) and interacted with p14arf protein to stimulate p53. Moreover, we found that ectopic overexpression of p33ING1b or p24ING1c significantly induced p53 protein acetylation at Lys-373/Lys-382 residue, but did not alter the phosphorylation status of p53. Conclusion: ING1 variants p33ING1b and p24ING1c may modulate p53 activity and subsequently inhibit hepatoma cell growth by at least two possible mechanisms: interacting with Mdm2 and p14arf to stabilize and activate p53, or increasing p53 acetylation. (HEPATOLOGY 2009.) [source]

Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis,,

HEPATOLOGY, Issue 2 2009
Yutaka Midorikawa
Early hepatocellular carcinoma (eHCC) originates from the hepatocytes of chronic liver disease and develops into classical hepatocellular carcinoma (HCC). To identify sequential genetic changes in multistep hepatocarcinogenesis, we analyzed molecular karyotypes using oligonucleotide genotyping 50K arrays. First, 1q21.3-44 gain and loss of heterozygosity (LOH) on 1p36.21-36.32 and 17p13.1-13.3 were frequently observed in eHCC, but not in chronic liver diseases, suggesting that such chromosomal aberrations are early, possibly causative events in liver cancer. Next, we detected 25 chromosomal loci associated with liver cancer progression in five HCCs with nodule-in-nodule appearance, in which the inner nodule develops within eHCC lesion. Using these chromosomal regions as independent variables, decision tree analysis was applied on 14 early and 25 overt HCCs, and extracted combination of chromosomal gains on 5q11.1-35.3 and 8q11.1-24.3 and LOH on 4q11-34.3 and 8p11.21-23.3 as distinctive attributes, which can classify early and overt HCCs recursively. In these four altered regions identified as late events of hepatocarcinogenesis, two tumors in 32 overt HCCs analyzed in the present study and one in a set of independent samples of 36 overt HCCs in our previous study harbored a homozygous deletion near the CSMD1 locus on 8p23.2. CSMD1 messenger RNA expression was decreased in HCC without 8p23.2 deletion, possibly due to hypermethylation of the CpG islands in its promoter region. Conclusion: 1q gain and 1p and 17p LOH are early molecular events, whereas gains in 5q and 8q and LOH on 4q and 8p only occur in advanced HCC, and inactivation of the putative suppressor gene, CSMD1, may be the key event in progression of liver cancer. (HEPATOLOGY 2009.) [source]

Liver stem cells and hepatocellular carcinoma,

HEPATOLOGY, Issue 1 2009
Lopa Mishra
Although the existence of cancer stem cells (CSCs) was first proposed over 40 years ago, only in the past decade have these cells been identified in hematological malignancies, and more recently in solid tumors that include liver, breast, prostate, brain, and colon. Constant proliferation of stem cells is a vital component in liver tissues. In these renewing tissues, mutations will most likely result in expansion of the altered stem cells, perpetuating and increasing the chances of additional mutations and tumor progression. However, many details about hepatocellular cancer stem cells that are important for early detection remain poorly understood, including the precise cell(s) of origin, molecular genetics, and the mechanisms responsible for the highly aggressive clinical picture of hepatocellular carcinoma (HCC). Exploration of the difference between CSCs from normal stem cells is crucial not only for the understanding of tumor biology but also for the development of specific therapies that effectively target these cells in patients. These ideas have drawn attention to control of stem cell proliferation by the transforming growth factor beta (TGF-,), Notch, Wnt, and Hedgehog pathways. Recent evidence also suggests a key role for the TGF-, signaling pathway in both hepatocellular cancer suppression and endoderm formation, suggesting a dual role for this pathway in tumor suppression as well as progression of differentiation from a stem or progenitor stage. This review provides a rationale for detecting and analyzing tumor stem cells as one of the most effective ways to treat cancers such as HCC. (HEPATOLOGY 2009;49:318,329.) [source]

Proteomic profiling reveals the prognostic value of adenomatous polyposis coli,end-binding protein 1 in hepatocellular carcinoma,

HEPATOLOGY, Issue 6 2008
Tatsuya Orimo
Histological differentiation is a major pathological parameter associated with poor prognosis in patients with hepatocellular carcinoma (HCC) and the molecular signature underlying HCC differentiation may involve key proteins potentially affecting the malignant characters of HCC. To develop prognostic biomarkers for HCC, we examined the global protein expression profiles of 45 surgically resected tissues, including 27 HCCs with different degree of histological differentiation, 11 adjacent nontumor tissues, and seven normal liver tissues. Unsupervised classification grouped the 45 samples according to their histological classification based on the protein expression profiles created by laser microdissection and two-dimensional difference gel electrophoresis (2D-DIGE). Statistical analysis and mass spectrometry identified 26 proteins with differential expression, of which 14 were functionally linked to c-Myc, AP-1, HIF1A, hepatocyte nuclear factor 4 alpha, or the Ras superfamily (RhoA, CDC42, and Rac1). Among the proteins identified, we focused on APC-binding protein EB1 (EB1) because it was dominantly expressed in poorly differentiated HCCs, which generally correlate with the poor prognosis in patients with HCC. In addition, EB1 is controlled by c-Myc, RhoA, and CDC42, which have all been linked to HCC malignancy. Immunohistochemistry in a further 145 HCC cases revealed that EB1 significantly correlated with the degree of histological differentiation (P < 0.001), and univariate and multivariate analyses indicated that EB1 is an independent prognostic factor for recurrence (hazard ratio, 2.740; 95% confidence interval, 1.771,4.239; P < 0.001) and survival (hazard ratio, 2.256; 95% confidence interval, 1.337,3.807; P = 0.002) of patients with HCC after curative surgery. Conclusion: Proteomic profiling revealed the molecular signature behind the progression of HCC, and the prognostic value of EB1 in HCC. (HEPATOLOGY 2008;48:1851-1863.) [source]

Molecular mechanisms of hepatocellular carcinoma,

HEPATOLOGY, Issue 6 2008
Rajagopal N. Aravalli
Hepatocellular carcinoma (HCC) typically has poor prognosis, because it is often diagnosed at an advanced stage. Heterogeneous phenotypic and genetic traits of affected individuals and a wide range of risk factors have classified it a complex disease. HCC is not amenable to standard chemotherapy and is resistant to radiotherapy. In most cases, surgical resection and liver transplantation remain the only curative treatment options. Therefore, development of novel, effective therapies is of prime importance. Extensive research over the past decade has identified a number of molecular biomarkers as well as cellular networks and signaling pathways affected in liver cancer. Recent studies using a combination of "omics" technologies, microRNA studies, combinatorial chemistry, and bioinformatics are providing new insights into the gene expression and protein profiles during various stages of the disease. In this review, we discuss the contribution of these newer approaches toward an understanding of molecular mechanisms of HCC and for the development of novel cancer therapeutics. (HEPATOLOGY 2008;48:2047-2063.) [source]

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1,

HEPATOLOGY, Issue 5 2008
Silvia Martin-Lluesma
Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), but its role in the transformation process remains unclear. HBV encodes a small protein, known as HBx, which is required for infection and has been implicated in hepatocarcinogenesis. Here we show that HBx induces lagging chromosomes during mitosis, which in turn leads to formation of aberrant mitotic spindles and multinucleated cells. These effects require the binding of HBx to UV-damaged DNA binding protein 1 (DDB1), a protein involved in DNA repair and cell cycle regulation, and are unexpectedly attributable to HBx interfering with S-phase progression and not directly with mitotic events. HBx also affects S-phase and induces lagging chromosomes when expressed from its natural viral context and, consequently, exhibits deleterious activities in dividing, but not quiescent, hepatoma cells. Conclusion: In addition to its reported role in promoting HBV replication, the binding of HBx to DDB1 may induce genetic instability in regenerating hepatocytes and thereby contribute to HCC development, thus making this HBV,host protein interaction an attractive target for new therapeutic intervention. (HEPATOLOGY 2008.) [source]

The angiogenic makeup of human hepatocellular carcinoma does not favor vascular endothelial growth factor/angiopoietin-driven sprouting neovascularization,,

HEPATOLOGY, Issue 5 2008
Wenjiao Zeng
Quantitative data on the expression of multiple factors that control angiogenesis in hepatocellular carcinoma (HCC) are limited. A better understanding of the mechanisms underlying angiogenesis in HCC will improve the rational choice of anti-angiogenic treatment. We quantified gene and protein expression of members of the vascular endothelial growth factor (VEGF) and angiopoietin systems and studied localization of VEGF, its receptors VEGFR-1 and VEGFR-2, Angiopoietin (Ang)-1 and Ang-2, and their receptor, in HCC in noncirrhotic and cirrhotic livers. We employed real-time reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistology, and compared the outcome with highly angiogenic human renal cell carcinoma (RCC). HCC in noncirrhotic and cirrhotic livers expressed VEGF and its receptors to a similar extent as normal liver, although in cirrhotic background, VEGFR-2 levels in both tumor and adjacent tissue were decreased. Ang-1 expression was slightly increased compared with normal liver, whereas Tie-2 was strongly down-regulated in the tumor vasculature. Ang-2 messenger RNA (mRNA) levels were also low in HCCs of both noncirrhotic and cirrhotic livers, implying that VEGF-driven angiogenic sprouting accompanied by angiopoietin-driven vascular destabilization is not pronounced. In RCC, VEGF-A levels were one order of magnitude higher. At the same time, endothelially expressed Ang-2 was over 30-fold increased compared with expression in normal kidney, whereas Ang-1 expression was decreased. Conclusion: In hepatocellular carcinoma, tumor vascularization is not per se VEGF/angiopoietin driven. However, increased CD31 expression and morphological changes representative of sinusoidal capillarization in tumor vasculature indicate that vascular remodeling is taking place. This portends that therapeutic intervention of HCC at the level of the vasculature is optional, and that further studies into the molecular control thereof are warranted. (HEPATOLOGY 2008.) [source]