Purpose: To characterize tumor growth of NISI cells implanted into the liver of Sprague-Dawley rats to determine if this model could be used for survival studies. These results were compared with tumor growth after im...
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Purpose: To characterize tumor growth of NISI cells implanted into the liver of Sprague-Dawley rats to determine if this model could be used for survival studies. These results were compared with tumor growth after implantation with MeA-RH7777 cells. Materials and Methods: NISI or McA-RH7777 cells were implanted into the liver of Sprague-Dawley rats (n = 20 and n = 12, respectively) using ultrasound (US) guidance, and tumor growth was followed by using US. Serum profiles of 19 cytokines were compared in naive versus tumor-bearing rats. Results: Both types of tumors were visible on US 1 week after tumor implantation, but the mean tumor volume of NISI tumors was larger compared to MeA-RH7777 tumors (231 mm(3) vs 82.3 mm(3), respectively). Tumor volumes in both groups continued to increase, reaching means of 289 mm(3) and 160 mm(3) in NISI and McA-RH7777 groups, respectively, 2 weeks after tumor implantation. By week 3, tumor volumes had decreased considerably, and six tumors (50%) in the McA-RH7777 had spontaneously regressed, versus two (10%) in the NISI group. Tumor volumes continued to decrease over the following 3 weeks, and complete tumor regression of all tumors was seen 5 weeks and 6 weeks after tumor implantation in the MeA-RH7777 and NISI groups, respectively. In an N1S1-implanted rat, multiple cytokines that have been shown to correlate with the ability of the tumor to survive in a hostile environment were increased by as much as 50%, whereas the average increase in cytokine levels was 90%. These findings suggest that the net cytokine environment favors an antitumor immune response. A similar trend was observed in a rat with a McA-RH7777 tumor, and the increase in cytokine levels was considerably more pronounced, with an average increase of 320%. Conclusions: The model of NISI cell implantation in the liver of Sprague Dawley rats is not ideal for survival studies and should only be used with great caution in short-term studies that involve cancer therapies.
Dnmt1 is frequently overexpressed in cancers, which contributes significantly to cancer-associated epigenetic silencing of tumor suppressor genes. However, the mechanism of Dnmt1 overexpression remains elusive. Herein...
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Dnmt1 is frequently overexpressed in cancers, which contributes significantly to cancer-associated epigenetic silencing of tumor suppressor genes. However, the mechanism of Dnmt1 overexpression remains elusive. Herein, we elucidate a pathway through which nuclear receptor SHP inhibits zinc-dependent induction of Dnmt1 by antagonizing metal-responsive transcription factor-1 (MTF-1). Zinc treatment induces Dnmt1 transcription by increasing the occupancy of MTF-1 on the Dnmt1 promoter while decreasing SHP expression. SHP in turn represses MTF-1 expression and abolishes zinc-mediated changes in the chromatin configuration of the Dnmt1 promoter. Dnmt1 expression is increased in SHP-knockout (sko) mice but decreased in SHP-transgenic (stg) mice. In human hepatocellular carcinoma (HCC), increased DNMT1 expression is negatively correlated with SHP levels. Our study provides a molecular explanation for increased Dnmt1 expression in HCC and highlights SHP as a potential therapeutic target.
There is increasing evidence that a relevant number of patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria may benefit from liver transplantation (LT). We retrospectively analyzed the prognostic ...
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There is increasing evidence that a relevant number of patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria may benefit from liver transplantation (LT). We retrospectively analyzed the prognostic significance of [18F]fludeoxyglucose ([18F]FDG) positron emission tomography (PET) for identifying appropriate LT candidates with advanced HCC on clinical staging. Between 1995 and 2008, 111 patients with HCC were listed for LT. All underwent a pretransplant PET evaluation. LT was performed for 91 of these patients. The tumor recurrence rate after LT was 3.6% for patients with non[18F]FDG-avid (PET-) tumors, but it was 54.3% for patients with [18F]FDG-avid (PET+) tumors (P < 0.001). The 5-year recurrence-free survival rates were comparable for patients with tumors meeting the Milan criteria (86.2%) and patients with PET- HCC exceeding the Milan criteria (81%) at LT, but these rates were significantly higher than the rate for liver recipients with [18F]FDG-avid advanced HCC (21%, P = 0.002). In a multivariate analysis, negative PET findings (odds ratio = 21.6, P < 0.001), an alpha-fetoprotein level <400 IU/mL (odds ratio = 3.3, P = 0.013), and a total tumor diameter <10 cm (odds ratio = 3.0, P = 0.022) were identified as pretransplant prognostic variables for recurrence-free survival. A PET+ status was assessed as the only independent clinical predictor of tumor-related patient dropout from the waiting list (hazard ratio = 5.7, P = 0.01). Patients with non[18F]FDG-avid HCC beyond the Milan criteria according to clinical staging may achieve excellent long-term recurrence-free survival after LT. Liver Transpl 18:5361, 2012. (C) 2011 AASLD.
Because of the severe organ shortage, living donor liver transplantation (LDLT) offers a timely alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, the...
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Because of the severe organ shortage, living donor liver transplantation (LDLT) offers a timely alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, the higher recurrence rate of HCC after LDLT and the indication criteria remain controversial. By conducting a quantitative meta-analysis, we sought to compare the survival outcomes and recurrence rates with LDLT and DDLT for patients with HCC. Comparative studies of LDLT and DDLT for HCC, which were identified by a comprehensive literature search, were included in this study. The evaluated outcomes included patient survival, recurrence-free survival (RFS), and recurrence rates at defined time points. Seven studies with a total of 1310 participants were included in this study. For LDLT and DDLT recipients, we found comparable patient survival rates [1 year, odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.62-1.73;3 years, OR = 1.07, 95% CI = 0.77-1.48;and 5 years, OR = 0.64, 95% CI = 0.33-1.24] and RFS rates (1 year, OR = 0.86, 95% CI = 0.54-1.38;3 years, OR = 1.04, 95% CI = 0.69-1.58;and 5 years, OR = 1.11, 95% CI = 0.70-1.77). Moreover, we found no significant differences in the 1-, 3-, or 5-year recurrence rates between LDLT and DDLT recipients (1 year, OR = 1.55, 95% CI = 0.36-6.58;3 years, OR = 2.57, 95% CI = 0.53-12.41;and 5 years, OR = 1.21, 95% CI = 0.44-3.32). A subgroup analysis revealed similar outcomes for patients with HCC meeting the Milan criteria. These findings demonstrate that for HCC patients (especially those within the Milan criteria), LDLT represents an acceptable option that does not compromise patient survival or increase HCC recurrence in comparison with DDLT. Liver Transpl 18:1226-1236, 2012. (c) 2012 AASLD.
Background. Radiofrequency ablation (RFA) use among patients with hepatocellular carcinoma (HCC) has increased dramatically over the last decade, but assessments outside specialized centers are lacking. This populatio...
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Background. Radiofrequency ablation (RFA) use among patients with hepatocellular carcinoma (HCC) has increased dramatically over the last decade, but assessments outside specialized centers are lacking. This population-based study was intended to evaluate the safety and effectiveness of RFA when used to treat HCC. Methods. A cohort study of HCC patients (diagnosed 2002-2005) was performed using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Early (<= 90-day) mortality and readmission as well as survival among patients undergoing RFA, resection, or no treatment were compared using multivariate and propensity score adjusted Poisson and Cox regression models. Results. Of 2631 patients (mean age 76.1 +/- 6.1 years, 65.9% male), 16% underwent RFA (49.6%) or resection (50.4%). Early mortality (13.6 vs. 18.7%, P = .16) and readmission (34.5 vs. 32.1%, P = .60) rates were similar among RFA and resection patients. The 1-year survival after RFA and resection was similar (72.2 vs. 79.7%, P = .18), but beyond 3 years there was a survival benefit among patients undergoing resection (39.2 vs. 58.0%, P < .001). Patients treated with RFA as a sole therapeutic intervention in the 1st year had a similar hazard of death compared with untreated patients (hazard ratio [HR] 0.84, 95% confidence interval [95% CI] 0.54-1.33). Conclusions. In the general community, patients treated with RFA have a similar risk of early adverse events compared with those treated with resection with no clear survival benefit when used as a sole intervention. Although RFA has been described as a safe and effective treatment for HCC at specialized centers, this experience may not extrapolate to the general community and requires further evaluation.
Hepatic arterial infusion chemotherapy (HAIC) allows the long-term administration of cytotoxic drugs to the liver. In Japan, HAIC has traditionally been used to treat patients with advanced hepatocellular carcinoma (H...
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Hepatic arterial infusion chemotherapy (HAIC) allows the long-term administration of cytotoxic drugs to the liver. In Japan, HAIC has traditionally been used to treat patients with advanced hepatocellular carcinoma (HCC) with vascular invasion or multiple intrahepatic lesions, or both. The most common chemotherapy drugs used for HAIC in Japan are 5-fluorouracil and cisplatin. Although HAIC is associated with a high rate of response in some studies, it is not associated with a survival benefit. Furthermore, HAIC is associated with complications that are not observed with systemic chemotherapy, including peptic ulcer, arterial occlusion and port infection. A molecular targeted agent, sorafenib, recently became the standard therapy for advanced HCC on the basis of data from two randomized controlled trials. For this reason, the position of HAIC in the treatment of advanced HCC in Japan is under discussion. Clinical trials must be undertaken to establish standardized protocols and regimens for HAIC, and to determine the efficacy of HAIC in comparison with other therapies for HCC. Without evidence from such trials, HAIC may not find an established role in the treatment of HCC, and may even fall out of use. Recent evidence suggests that HAIC may be useful in combination with molecular targeted therapy;this is currently being investigated in a number of clinical trials.
We have previously found that expression of MARVELD1 was remarkably downregulated in multiple tumor tissues, but unclear in hepatocellular carcinoma (HCC) and its function has not been explored yet. In the present stu...
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We have previously found that expression of MARVELD1 was remarkably downregulated in multiple tumor tissues, but unclear in hepatocellular carcinoma (HCC) and its function has not been explored yet. In the present study, to uncover the underlying mechanism of MARVELD1 in the pathogenesis and development of HCC, we investigated the expression pattern of MARVELD1 and its effect on tumor proliferation in HCC. The results indicated the frequent downregulation of MARVELD1 in clinic samples and cell lines of HCC resulted from promoter methylation, as well as genetic deletion. Furthermore, treatment of MARVELD1 unexpressing Hep3B2.1-7 and PLC/PRF/5 cells with the demethylating agent 5-aza-2' deoxycytidine restored its expression. Overexpression of MARVELD1 suppressed the proliferation of HCC cells in vitro and in vivo, whereas downregulation of endogenous MARVELD1 by shRNAs significantly enhanced these characters. MARVELD1 overexpression could enhance chemosensitivity of HCC cells to epirubicin and 10-hydroxycamptothecin. Corresponding to these results, the expression of p-ERK1/2 and cyclin D1 were decreased, whereas p16 and p53 were increased in MARVELD1-transfected cells. We also demonstrated that knockdown of MARVELD1 resulted in upregulation of p-ERK1/2 and cyclin D1, and downregulation of p16 and p53. Moreover, the effect of the decreased cell growth rate was significantly reversed when MARVELD1-overexpressing cells were trasfected with p53 or p16 siRNA. Our findings suggest that MARVELD1 is a tumor suppressor by negatively regulating proliferation, tumor growth and chemosensitivity of HCC cells via increasing p53 and p16 in vitro and in vivo. MARVELD1 may be a potential target for HCC therapy. (Cancer Sci 2012;103: 716722)
Objectives: Surgical decision making for patients with early hepatocellular carcinoma (HCC) and well-compensated cirrhosis remains controversial. The aim of the current study was to conduct a meta-analysis of publishe...
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Objectives: Surgical decision making for patients with early hepatocellular carcinoma (HCC) and well-compensated cirrhosis remains controversial. The aim of the current study was to conduct a meta-analysis of published reports to compare survival outcomes after transplantation and resection, respectively, in patients with early HCC [i.e. HCC falling within the Milan Criteria (a solitary lesion measuring =5 cm or fewer than three lesions with a largest diameter of =3 cm, and absence of macroscopic vascular invasion or extrahepatic disease)] and well-compensated cirrhosis. Methods: A total of 990 abstracts were identified through a PubMed-based search. Ten articles comparing transplantation and resection in patients with early HCC were included in the meta-analysis. Meta-analysis was performed using stata 9.2 statistical software. Results: Outcomes were analysed for a total of 1763 patients with early HCC. The 5-year overall survival (OS) for all patients was 58% (transplantation: 63%;resection: 53%). Meta-analysis of all 10 studies revealed a survival advantage for transplantation [odds ratio (OR) 0.581, 95% confidence interval (CI) 0.3590.939;P= 0.027]. Analysis of only those reports that utilized an intention-to-treat strategy failed to demonstrate a survival advantage for either treatment approach (OR 0.600, 95% CI 0.2911.237;P= 0.166). Conclusions: The current study demonstrates a favourable outcome in patients with early HCC treated by either transplantation or resection. Although transplantation was noted to have a survival advantage in some settings, resection continues to be a viable treatment approach.
Background Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropri...
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Background Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropriate candidates is paramount in an era of graft shortage. Aim To review systematically the role of liver transplantation m t nn in the merit of HCC In current clinical practice. manage Methods An electronic literature search using PUBMED (1980-2010) was performed. Search terms included HCC, hepatoma, liver cancer, and liver transplantation. Results Liver transplantation is a highly successful treatment for HCC, in patients within Milan criteria (MC), defined as a solitary tumour < 50 mm in diameter or < 3 tumours < 30 mm in diameter in the absence of extra-hepatic or vascular spread. Other eligibility criteria for liver transplantation are also used in clinical practice, such as the University of California, San Francisco criteria, with outcomes comparable to MC. Loco-regional therapies have a role in the bridging treatment of HCC by minimising wait-list drop-out secondary to tumour progression. Beyond MC, encouraging results have been demonstrated for patients with down-staged tumours. Post-liver transplantation, there is no evidence to support a specific immunosuppressive regimen. In the context of an insufficient cadaveric donor pool to meet demand, the role of adult living donation may be increasingly important. Conclusions Liver transplantation offers a curative therapy for selected patients with HCC. The optimisation of eligibility criteria is paramount to ensure that maximum benefit is accrued. Although wait-list therapies have been incorporated into clinical practice, additional high quality data are required to support this strategy.
Cirrhotic livers are characterized by irreversible remodeling of architecture with bridging fibrosis, vascular reorganization and formation of hepatocellular nodules, which are classified histologically as either rege...
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Cirrhotic livers are characterized by irreversible remodeling of architecture with bridging fibrosis, vascular reorganization and formation of hepatocellular nodules, which are classified histologically as either regenerative or dysplastic lesions. The differentiation of these lesions is important because regenerative nodules (RNs) are benign, whereas dysplastic nodules (DNs) are premalig-nant. Pathologically, hepatocarcinoma (HCC) develops in a multistep fashion in the following sequence: from low-grade dysplastic nodule (LGDN) to high-grade dysplastic nodule (HGDN), small HCC and, finally, large HCC. Differentiation between DN and early HCC is the most important issue in the clinical *** article reviews the current concepts regarding the multistep process of hepatocarcinogenesis, along with the associated histologic and MRI manifestations.
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