Liver Neoplasms
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Pubmed
Journal: Journal of viral hepatitis
March/28/2016
Abstract

Hepatocyte clone size was measured in liver samples of 21 patients in various stages of chronic hepatitis B virus (HBV) infection and from 21 to 76 years of age. Hepatocyte clones containing unique virus-cell DNA junctions formed by the integration of HBV DNA were detected using inverse nested PCR. The maximum hepatocyte clone size tended to increase with age, although there was considerable patient-to-patient variation in each age group. There was an upward trend in maximum clone size with increasing fibrosis, inflammatory activity and with seroconversion from HBV e-antigen (HBeAg)-positive to HBeAg-negative, but these differences did not reach statistical significance. Maximum hepatocyte clone size did not differ between patients with and without a coexisting hepatocellular carcinoma. Thus, large hepatocyte clones containing integrated HBV DNA were detected during all stages of chronic HBV infection. Using laser microdissection, no significant difference in clone size was observed between foci of HBV surface antigen (HBsAg)-positive and HBsAg-negative hepatocytes, suggesting that expression of HBsAg is not a significant factor in clonal expansion. Laser microdissection also revealed that hepatocytes with normal-appearing histology make up a major fraction of the cells undergoing clonal expansion. Thus, preneoplasia does not appear to be a factor in the clonal expansion detected in our assays. Computer simulations suggest that the large hepatocyte clones are not produced by random hepatocyte turnover but have an as-yet-unknown selective advantage that drives increased clonal expansion in the HBV-infected liver.

Pubmed
Journal: Laboratory investigation; a journal of technical methods and pathology
August/9/1995
Abstract

BACKGROUND

Recent studies have demonstrated that the plant-derived alkaloid camptothecin (CPT) and its derivative, 9-nitro-CPT (9NC), are cytotoxic in tumorigenic cells but cytostatic in nontumorigenic cells in vitro and in vivo. Also, CPT induces differentiation of human leukemia cells in vitro along specific lineages. In this study, we have investigated the effects of 9NC on nontumorigenic HepG2 cells derived from human hepatoblastoma. A newly discovered senescent cell-derived inhibitor (SDI1) plays a critical role in the cell cycle, so we evaluated the effect of 9NC on the expression of the SDI1 gene.

METHODS

The effects of 9NC on HepG2 cells were evaluated by monitoring DNA synthesis, morphologic and ultrastructural changes of cells, and perturbation in the cell cycle and by assessing the levels of p53 protein and SDI1 mRNA.

RESULTS

Treatment of HepG2 cells with 9NC results in a dose-dependent inhibition of cell proliferation and DNA synthesis. Flow cytometric analysis of DNA content showed that 9NC-treated HepG2 cells are arrested in the G2-phase of the cell cycle. Light and electron microscopic examination revealed that 9NC at low concentrations induces morphologic and growth features that resemble properties highly differentiated or senescent cells, i.e., increased cell size and decreased nuclear/cytoplasmic ratio, as well as enlarged numbers of lysosomes, mitochondria, and lipid in the cytoplasm. No significant alteration in the p53 protein level was noted in 9NC-treated cells. In contrast to untreated, logarithmically grown HepG2 cells, 9NC-treated cells arrested at the G2-phase of the cell cycle and contained increased levels of SDI1 mRNA. Kinetic studies revealed gradual increases in SDI1 mRNA synthesis.

CONCLUSIONS

Induction of SDI1 mRNA by 9NC represents the first documentation that the SDI1 gene can be overexpressed in the G2-phase of the cell cycle and provides a valuable cell culture system to dissect the events controlling the G2 checkpoint. In addition, this finding corroborates the hypothesis that genes up-regulated in senescent cells can also be induced in tumor-derived immortalized cells.

Pubmed
Journal: Critical reviews in immunology
September/5/2013
Abstract

Scavenger receptors comprise a large family of structurally diverse proteins that are involved in many homeostatic functions. They recognize a wide range of ligands, from pathogen-associated molecular patterns (PAMPs) to endogenous, as well as modified host-derived molecules (DAMPs). The liver deals with blood micro-organisms and DAMPs released from injured organs, thus performing vital metabolic and clearance functions that require the uptake of nutrients and toxins. Many liver cell types, including hepatocytes and Kupffer cells, express scavenger receptors that play key roles in hepatitis C virus entry, lipid uptake, and macrophage activation, among others. Chronic liver disease causes high morbidity and mortality worldwide. Hepatitis virus infection, alcohol abuse, and non-alcoholic fatty liver are the main etiologies associated with this disease. In this context, continuous inflammation as a result of liver damage leads to hepatic fibrosis, which frequently brings about cirrhosis and ultimately hepatocellular carcinoma. In this review, we will summarize the role of scavenger receptors in the pathophysiology of chronic liver diseases. We will also emphasize their potential as biomarkers of advanced liver disease, including cirrhosis and cancer.

Pubmed
Journal: Magnetic resonance imaging
April/9/2008
Abstract

OBJECTIVE

The purpose of this study was to evaluate differences in the degrees of contrast enhancement effects of small hepatocellular carcinomas (HCCs) in patients with cirrhosis between helical computed tomography (CT) and magnetic resonance (MR) imaging during multiphasic contrast-enhanced dynamic imaging and to determine the diagnostic value of MR imaging especially in assessing hypovascular HCCs detected as hypoattenuating nodules on late-phase CT.

METHODS

This study included 64 small HCCs (<3 cm in diameter) in 40 patients with chronic hepatitis or cirrhosis who underwent multiphasic (arterial, portal and late phases) contrast-enhanced dynamic helical CT and MR imaging. The contrast enhancement patterns of each lesion in the arterial and late phases were evaluated by two radiologists experienced in liver MR imaging and categorized as one of five grades (1=hypoattenuated/hypointense; 2=slightly hypoattenuated/hypointense; 3=isoattenuated/isointense; 4=slightly hyperattenuated/hyperintense; 5=hyperattenuated/hyperintense), compared with the surrounding liver parenchyma.

RESULTS

Forty-three (67%) of 64 lesions showed Grade 4 (n=24) or Grade 5 (n=19) enhancement on arterial-phase CT, while 51 (80%) of 64 lesions showed Grade 4 (n=20) or Grade 5 (n=31) enhancement on arterial-phase MR imaging, indicating hypervascular HCCs. The grading score of hypervascular HCCs on arterial-phase MR imaging (mean: 4.61) was significantly (P<.01) higher than that for hypervascular HCCs on arterial-phase CT (mean: 4.20), showing better detection of the hypervascularity (arterial enhancement) of the lesion on arterial-phase MR imaging. Regarding hypovascular HCCs, all (100%) of 21 hypovascular HCCs on CT showed Grade 1 (n=10) or Grade 2 (n=11) enhancement on late-phase CT, seen as hypoattenuation. In contrast, 8 (62%) of 13 hypovascular HCCs on MR imaging showed Grade 1 (n=1) or Grade 2 (n=7) enhancement on late-phase MR imaging, seen as hypointensity. Grading scores of hypovascular HCCs on late-phase images were significantly (P<.001) lower on CT than on MR imaging (mean score: 1.52 vs. 2.31), indicating better washout effects for hypovascular HCCs on late-phase CT.

CONCLUSIONS

The washout effects for small HCCs on late-phase MR imaging were inferior to those for small HCCs on late-phase CT. Especially, hypovascular HCCs demonstrated as hypoattenuating nodules on late-phase CT were often not seen on late-phase MR imaging, requiring careful evaluation of other sequences, including unenhanced T(1)-weighted and T(2)-weighted MR images.

Pubmed
Journal: Life sciences
June/4/2006
Abstract

Cell detachment from extracellular matrix is closely related to induction of apoptosis. Epigallocatechin gallate (EGCG) has been shown to have antioxidant effect and to protect hypoxia-induced damage. We investigated whether EGCG reduced hypoxia-induced apoptosis and cell detachment in HepG2 cells. EGCG prevented cell death by hypoxia (0.5% O2) in a dose-dependent manner (hypoxic cell viability, 54.67%). RT-PCR and caspase3 activity assay showed that the hypoxia-induced cell death was caused by apoptosis increasing mRNA level of BAX, CASP3, and caspase3 activity. EGCG reduced increase of these mRNA and caspase3 activity. Western blot analysis and immunocytochemistry showed that EGCG increased cell adhesion proteins including E-cadherin (CDH1), tumor-associated calcium signal transducer 1 (TACSTD1), and protein tyrosine kinase 2 (PTK2) decreased by hypoxia. Hypoxia-induced apoptosis in HepG2 cells, and EGCG contributed to the HepG2 cell survival by attenuating the apoptosis.

Pubmed
Journal: Molecular carcinogenesis
May/11/2005
Abstract

The utility of liver H-ras codon 61 CAA to AAA mutant fraction as a biomarker of liver tumor development was investigated using neonatal male mice treated with 4-aminobiphenyl (4-ABP). Treatment with 0.1, 0.3, or 1.0 mumol 4-ABP produced dose-dependent increases in liver DNA adducts in B6C3F(1) and C57BL/6N mice. Eight months after treatment with 0.3 mumol 4-ABP or the DMSO vehicle, H-ras codon 61 CAA to AAA mutant fraction was measured in liver DNA samples (n = 12) by allele-specific competitive blocker-polymerase chain reaction (ACB-PCR). A significant increase in average mutant fraction was found in DNA of 4-ABP-treated mice, with an increase from 1.3 x 10(-5) (control) to 44.9 x 10(-5) (treated) in B6C3F(1) mice and from 1.4 x 10(-5) to 7.0 x 10(-5) in C57BL/6N mice. Compared with C57BL/6N mutant fractions, B6C3F(1) mutant fractions were more variable and included some particularly high mutant fractions, consistent with the more rapid development of liver foci expected in B6C3F(1) mouse liver. Twelve months after treatment, liver tumors developed in 79.2% of 4-ABP-treated and 22.2% of control B6C3F(1) mice; thus measurement of H-ras mutant fraction correlated with subsequent tumor development. This study demonstrates that ACB-PCR can directly measure background levels of somatic oncogene mutation and detect a carcinogen-induced increase in such mutation.

Pubmed
Journal: Acta chirurgica Belgica
February/28/2000
Abstract

Primary neuroendocrine neoplasms of the liver are extremely rare: about 30 cases only have been described in the literature. We report the case of a 42-year-old woman with a ten-year evolution. According to the previously reported cases, primary neuroendocrine carcinoma of the liver is usually multicentric, often mimicking liver metastases. The demonstration of the hepatic origin of a neuroendocrine carcinoma is often arduous. A careful surgical exploration and a prolonged follow-up are mandatory. The treatment of choice is surgical resection when possible. For progressive and unresectable disease, hepatic arterial chemoembolization may be considered. However, the prognosis of liver neuroendocrine tumours is much more favorable than that of hepatocellular carcinoma and progression has to be demonstrated before instauration of potentially harmful therapies.

Pubmed
Journal: Human pathology
September/12/1995
Abstract

We examined 41 consecutive cirrhotic liver explants from French patients for the presence of nodules of adenomatous hyperplasia (AH) and then analyzed these lesions, together with underlying cirrhosis (C) and associated hepatocellular carcinoma (HCC), for various histological parameters, cellular density, and proliferative activity. Thirty-five AHs were identified in 10 livers (prevalence, 24%); seven of 10 were HCV positive. Hepatocellular carcinoma was more frequent in patients with AH than in patients without. The AHs consisted of 17 ordinary (OAH) and 18 atypical (AAH) adenomatous hyperplasia lesions. There was a malignant focus in five of the 18 AAHs. Wide areas of large liver cell dysplasia were frequent in OAH but never found in AAH. Obvious steatosis was frequent in HCC but exceptional in AAH and absent in OAH. There was a significant increase in cellular density in AAH and HCC as compared with C and OAH. Proliferative cell nuclear antigen immunostaining similarly showed an increase in proliferation from OAH or C to AAH and HCC. These data suggest that, in Europe as in Japan, one pathway of hepatocarcinogenesis is a multistep process in which AAH should be considered as a premalignant lesion very close to grade I HCC, while OAH seems to correspond to a regenerative nodule with limited proliferative ability.

Pubmed
Journal: Abdominal imaging
September/12/2005
Abstract

BACKGROUND

We investigated the effect of iodinated contrast medium concentration on increased neoplastic lesion enhancement and its direct relation to diagnostic efficacy in biphasic spiral computed tomography for detection of hepatocellular carcinoma.

METHODS

A pilot, single-center, randomized, double-blind, crossover, comparative study was performed and included 22 participants. Each patient underwent two separate biphasic contrast-enhanced spiral computed tomographic examinations. Scans were performed with iomeprol containing 400 (iomeprol 400) or 300 (iomeprol 300) mg of iodine per milliliter (Iomeron, Bracco Imaging SpA, Milan, Italy) with a 2- to 12-day window scan; patients were given an equal total dose of 45 g of iodine at a fixed injection rate of 4 mL/s. Comparison included assessment of quantitative and qualitative parameters.

RESULTS

Lesion density and lesion-to-liver contrast increased more markedly with the higher concentration of contrast medium during the arterial phase (p = 0.0016 and 0.0005, respectively). There was no significant difference in any parameter between the two concentrations during the portal phase. Number of lesions detected during the arterial phase increased from 37 with iomeprol 300 to 42 with iomeprol 400; in the portal phase, the respective numbers were 34 and 36.

CONCLUSIONS

Even though a small number of patients was examined, our study suggests that, in patients with cirrhosis, an increased concentration of iodine improves liver-to-lesion contrast and may improve the detection of hepatocellular carcinoma.

Pubmed
Journal: Journal of biomedical science
May/23/2005
Abstract

Chromosomal instability (CIN) refers to high rates of chromosomal gains and losses and is a major cause of genomic instability of cells. It is thought that CIN caused by loss of mitotic checkpoint contributes to carcinogenesis. In this study, we evaluated the competence of mitotic checkpoint in hepatoma cells and investigated the cause of mitotic checkpoint defects. We found that 6 (54.5%) of the 11 hepatoma cell lines were defective in mitotic checkpoint control as monitored by mitotic indices and flow-cytometric analysis after treatment with microtubule toxins. Interestingly, all 6 hepatoma cell lines with defective mitotic checkpoint showed significant underexpression of mitotic arrest deficient 2 (MAD2), a key mitotic checkpoint protein. The level of MAD2 underexpression was significantly associated with defective mitotic checkpoint response (p < 0.001). In addition, no mutations were found in the coding sequences of MAD2 in all 11 hepatoma cell lines. Our findings suggest that MAD2 deficiency may cause a mitotic checkpoint defect in hepatoma cells.

Pubmed
Journal: Annals of oncology : official journal of the European Society for Medical Oncology
July/11/2004
Abstract

BACKGROUND

To investigate the efficacy and toxicity of the combination of gemcitabine and oxaliplatin (GEMOX) in patients with relapsed or cisplatin-refractory non-seminomatous germ cell tumors (NSGCT).

METHODS

Twenty-nine patients with relapsed or cisplatin-refractory NSGCT were treated with gemcitabine 1000 mg/m2 on days 1 and 8 followed by oxaliplatin 130 mg/m2 on day 1 every 3 weeks for a maximum of six cycles. Twenty-four patients (83%) were considered refractory and five (17%) absolutely refractory to cisplatin.

RESULTS

Twenty-eight patients were assessable for response. Overall, nine patients (32%) achieved a favourable response (complete response, four; partial response, five). One of the complete responders relapsed after 7 months and went into disease-free status lasting for 11+ months after resection of lung metastases. The rest of the complete responders are continuously disease-free at 14+, 19+ and 28+ months with the study regimen plus or minus surgery. One of the complete responders had absolutely cisplatin-refractory disease and another one presented with a late relapse. Toxicity was primarily hematological and generally manageable: 62% of patients experienced grade 3/4 neutropenia, 10% neutropenic fever and 41% grade 3/4 thrombocytopenia. Non-hematological toxicity consisted mainly of nausea/vomiting. Three patients (10%) developed grade 3 neurotoxicity and discontinued treatment.

CONCLUSIONS

The combination of GEMOX is an active, moderately toxic and easily administered regimen in patients with relapsed or cisplatin-refractory NSGCT. The 14% long-term disease-free status accomplished in this heavily pretreated patient population is quite encouraging.

Pubmed
Journal: European journal of nuclear medicine and molecular imaging
December/29/2005
Abstract

Several techniques have been developed for radionuclide therapy of hepatocellular carcinoma (HCC). Medical literature databases (Pubmed, Medline) were screened for available literature and articles were critically analysed as to their scientific relevance. In a palliative setting, intra-arterial administration of 131I-Lipiodol yields responses in 17-92% of patients. According to a randomised study, 131I-Lipiodol was far better tolerated than classic chemo-embolisation. The additive value of a single 131I-Lipiodol administration following partial liver resection for HCC was evaluated and evidence is available that adjuvant radionuclide treatment reduces the recurrence rate. Data concerning the role of 131I-Lipiodol in bridging patient to liver transplantation are scarce but suggest a potential benefit in terms of reducing the drop-out rate while patients are listed for transplantation. 188Re- and 90Y-labelled conjugates are emerging and initial clinical data are promising. Treatment of HCC with 90Y-labelled microspheres is likely as efficacious as treatment with radiolabelled Lipiodol but pretreatment 99mTc-MAA scintigraphy is required in order to exclude patients with significant lung shunting. Several antibodies targeting antigens expressed on HCC have been radiolabelled, almost exclusively with 131I, and evaluated in a preclinical or clinical setting. The use of radiolabelled Lipiodol and microspheres allows for selective targeting of HCC with limited toxicity. Prospective, randomised controlled trials demonstrating that both treatment modalities may provide a survival benefit in a palliative setting are mandatory. In addition, future research should focus on the complementary role of radionuclide treatment in patients at risk for recurrent disease following partial liver resection or while awaiting liver transplantation.

Pubmed
Journal: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
July/21/2009
Abstract

BACKGROUND

Differences were compared between laparoscopic surgery with and without hand-assisted laparoscopic technique (HALS) in order to assess whether HALS is a safe and feasible alternative to laparotomy and to determine what factors contributed to successful laparoscopic liver surgery.

METHODS

From a total of 416 liver resections, 45 patients with 46 hepatic tumors were chosen for laparoscopic liver resection with or without a hand-assisted technique. For each patient, her/his surgical duration, intraoperative blood loss, tumor size and location, hospital stay after surgery, mortality, and morbidity were recorded for analysis.

RESULTS

The 45 surgical laparoscopic liver resections included 19 left lateral lobectomies, three hemihepatectomies, three segmentectomies, and 21 partial hepatectomies. A HALS was used more frequently in the right posterior group (14/16) than in the anterior group (6/29). There was no notable difference between these two groups in terms of tumor size, mean surgical time, blood loss during surgical procedure, hospital stay after surgery, and occurrence of complication.

CONCLUSIONS

Surgical results between HALS and non-HALS usage were similar except for higher blood loss with HALS, higher use of HALS when liver cirrhosis was present, and less likelihood of using HALS when there was a superficial location of the tumor or lesion.

Pubmed
Journal: Clinical immunology (Orlando, Fla.)
February/15/2006
Abstract

Vaccination of mice with dendritic cells loaded with Hepa1-6, well-differentiated hepatocellular carcinoma cell line (DC/Hepa1-6), induced cytotoxic T lymphocytes against Hepa1-6. Liver-specific inflammation was generated by vaccination of mice with DC/Hepa1-6 and subsequent administration of interleukin (IL)-12. Vaccination with DCs loaded with MC38 or B16 and administration of IL-12 did not generate significant liver-specific inflammation. Splenic T cells from DC/Hepa1-6-vaccinated mice showed proliferative response by stimulation with S-100 protein of the liver and showed cytotoxic activity to hepatocytes. Hepatic mononuclear cells from DC/Hepa1-6 + IL-12-treated mice also showed cytotoxic activity to hepatocytes. Adoptive transfer of splenocytes from DC/Hepa1-6-vaccinated mice produced hepatic inflammation in recipient mice that had been pretreated with IL-12. IL-12 upregulated the expression of adhesion molecules and chemokines in the liver. In conclusion, CTLs responsive to hepatocytes induced by DC/Hepa1-6 and enhanced expression of adhesion molecules and chemokines in the liver by IL-12 would produce autoimmune hepatic inflammation.

Pubmed
Journal: Journal of biomedical materials research. Part A
March/26/2006
Abstract

Recent studies show that after radiofrequency (RF) ablation, fibrosis occurs at the ablation boundary, hindering anticancer drug transport from a locally implanted polymer depot to the ablation margin, where tumors recur. The purpose of this study is to investigate strategies that can effectively deliver dexamethasone (DEX), an anti-inflammatory agent, to prevent fibrosis. Polymer millirods consisting of poly(D,L-lactide-co-glycolide) (PLGA) were loaded with either DEX complexed with hydroxypropyl beta-cyclodextrin (HPbeta-CD), or an NaCl and DEX mixture. In vitro release studies show that DEX complexed with HPbeta-CD released 95% of the drug after 4 days, compared to 14% from millirods containing NaCl and DEX. Rat livers underwent RF ablation and received either DEX-HPbeta-CD-loaded millirods, PLGA millirods with an intraperitoneal (i.p.) DEX injection, or control PLGA millirods alone. After 8 days in vivo, heightened inflammation and the appearance of a well-defined fibrous capsule can be observed in both the control experiments and those receiving a DEX injection (0.29 +/- 0.08 and 0.26 +/- 0.07 mm in thickness, respectively), with minimal inflammation and fibrosis present in livers receiving DEX millirods (0.04 +/- 0.01 mm). Results from this study show that local release of DEX prevents fibrosis more effectively than a systemic i.p. injection.

Pubmed
Journal: Oncology reports
August/10/2009
Abstract

Thrombin has been recently demonstrated to promote hepatocellular carcinoma (HCC) cell migration by activation of the proteinase-activated receptor (PAR) subtypes PAR1 and PAR4 suggesting a role of these proteinase-receptor systems in HCC progression. In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic compound of green tea on thrombin-PAR1/PAR4-mediated hepatocellular carcinoma cell invasion and p42/p44 MAPKinase activation. In this study we used the permanent liver carcinoma cell line HEP-3B and two primary cultures established from surgically resected HCCs. We found that stimulation of HCC cells with thrombin, the PAR1-selective activating peptide, TFLLRN-NH2, and the PAR4-selective activating peptide, AYPGKF-NH2, increased cell invasion across a Matrigel-coated membrane barrier and stimulated activation of p42/p44 MAPKinase phosphorylation. Both the effects on p42/p44 MAPKinases, and on cell invasiveness induced by thrombin and the PAR1/4 subtype-selective agonist peptides were effectively blocked by EGCG. The results clearly identify EGCG as a potent inhibitor of the thrombin-PAR1/PAR4-p42/p44 MAPKinase invasive signaling axis in hepatocellular carcinoma cells as a previously unrecognized mode of action for EGCG in cancer cells. Moreover, the results suggest that (-)-epigal-locatechin-3-gallate might have therapeutic potential for hepatocellular carcinoma.

Pubmed
Journal: Seminars in liver disease
July/21/2004
Abstract

Recent advances in liver imaging, surgery, and transplantation have drawn attention to a variety of lesions that are found in chronically diseased, usually cirrhotic, livers. Several studies have established the precancerous nature of dysplastic foci and dysplastic nodules and have delineated the morphological features of small hepatocellular carcinoma. Dysplastic foci represent incidental findings on microscopic examination of hepatic specimens, whereas dysplastic nodules are detected grossly, and often radiologically. Dysplastic foci commonly consist of proliferating hepatocytes with small cell change, which is cytologically reminiscent of well-differentiated hepatocellular carcinoma. Dysplastic nodules may show evidence of cytological or structural atypia, or both, that is insufficient for the diagnosis of hepatocellular carcinoma. The evolution of dysplastic nodules to hepatocellular carcinoma within several months to a few years of follow-up is well-documented. Small hepatocellular carcinoma with indistinct margins has been identified as an early, well-differentiated neoplasm that usually measures less than 15 mm in greatest dimension. As this lesion grows larger, it may transform into nodular hepatocellular carcinoma with distinct margins.

Pubmed
Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
May/27/2004
Abstract

OBJECTIVE

Retinoid analogues have been reported to inhibit the growth of hepatocellular carcinoma (HCC). However, the expression profile of retinoic acid receptors (RARs) in HCC has not been fully clarified. In this study, we investigated the expression of RAR mRNAs and proteins in resected HCC and nontumor liver tissue.

METHODS

Reverse transcription-PCR and Western blot analysis were applied to investigate the expression of RAR mRNAs and proteins in 32 resected samples of HCC and 14 samples of nontumor liver tissue. A HCC cell line and primary-cultured hepatocyte were treated with RAR-alpha-selective retinoids in vitro to estimate their antiproliferative activity.

RESULTS

The intensities of mRNA and protein for RAR-alpha in HCC tissue were significantly higher than those in nontumor liver tissue (P = 0.002 and P = 0.002, respectively). The intensity ratios of HCC versus nontumor liver for RAR-alpha mRNA and protein were significantly higher than those for RAR-beta and RAR-gamma (mRNA, P = 0.02 and P = 0.006; protein, P = 0.04 and P = 0.007, respectively). There was only one significant correlation between the higher intensity of RAR-beta protein and tumor stage (stage I/II versus stage III/IVA, P = 0.01) among clinicopathological variables in the HCC patients. However, in vitro experiments showed that the growth of a RAR-alpha-elevated HCC cell line was potently inhibited by treatment with retinoids at concentrations that did not affect the growth of primary-cultured hepatocytes.

CONCLUSIONS

These results imply that RAR-alpha is the dominant receptor in HCC, which suggests that RAR-alpha-selective retinoid analogues may be useful for chemotherapy.

Pubmed
Journal: The American journal of pathology
December/28/1998
Abstract

Several studies have shown that cultured rat liver epithelial cells transform spontaneously after chronic maintenance in a confluent state in vitro. In the present study, multiple independent lineages of low-passage WB-F344 rat liver epithelial stem-like cells were initiated and subjected in parallel to selection for spontaneous transformation to determine whether spontaneous acquisition of tumorigenicity was the result of events (genetic or epigenetic) that occurred independently and stochastically, or reflected the expression of a pre-existing alteration within the parental WB-F344 cell line. Temporal analysis of the spontaneous acquisition of tumorigenicity by WB-F344 cells demonstrated lineage-specific differences in the time of first expression of the tumorigenic phenotype, frequencies and latencies of tumor formation, and tumor differentiations. Although spontaneously transformed WB-F344 cells produced diverse tumor types (including hepatocellular carcinomas, cholangiocarcinomas, hepatoblastomas, and osteogenic sarcomas), individual lineages yielded tumors with consistent and specific patterns of differentiation. These results provide substantial evidence that the stochastic accumulation of independent transforming events during the selection regimen in vitro were responsible for spontaneous neoplastic transformation of WB-F344 cells. Furthermore, cell lineage commitment to a specific differentiation program was stable with time in culture and with site of transplantation. This is the first report of a cohort of related, but independent, rat liver epithelial cell lines that collectively produce a spectrum of tumor types but individually reproduce a specific tumor type. These cell lines will provide valuable reagents for investigation of the molecular mechanisms involved in the differentiation of hepatic stem-like cells and for examination of potential causal relationships in spontaneously transformed rat liver epithelial cell lines between molecular/cellular alterations and the ability to produce tumors in syngeneic animals.

Pubmed
Journal: Anticancer research
July/9/2003
Abstract

BACKGROUND

The number of cytostatic agents effective in patients with advanced soft tissue sarcoma is limited. Trofosfamide, an alkylating agent, has been shown to be effective in several solid and haematological tumors.

METHODS

Eighteen patients with a median age of 57 years (range, 27-78) were treated with oral trofosfamide 300 mg/d for 1 week followed by 150 mg/d given continuously to analyze the efficacy and toxicity of continuous low-dose oral trofosfamide. All had received at least one anthracycline-based chemotherapeutic regimen prior to trofosfamide.

RESULTS

Nine patients (50%) achieved stable disease lasting for a median of 5.5+ months (range, 1-9+). The median time to progression was 10+ weeks (range, 4-37+) and the median survival 7+ months (range, 2-13+). Toxicity was mild, grade III degree toxicity was seen in 5 patients (28%): 3/2 patients with anemia/neutropenia and 2 patients with fatigue syndrome.

CONCLUSIONS

No objective remission was observed with oral low-dose trofosfamide in heavily pretreated soft tissue sarcoma patients, but almost half of the patients achieved disease stabilisation for half a year. The moderate toxicity profile observed in this study allows the consideration of trofosfamide as a reasonable palliative treatment option for patients with soft tissue sarcoma.

Pubmed
Journal: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
June/24/2009
Abstract

Acute graft-versus-host disease following orthotopic liver transplantation is a rare but feared complication arising in 1% to 2% of cases with a dismal prognosis. It most often presents as fever, rash, and diarrhea with or without pancytopenia. Patients die from complications of marrow failure such as sepsis or bleeding. Because of its low incidence, there is no clear treatment protocol for this complication. Both increasing and withdrawing immunosuppression have been attempted with variable success. Although anti-tumor necrosis factor alpha therapy has been widely used for the treatment of steroid-resistant acute graft-versus-host disease in the hematopoietic stem cell transplant setting, there previously have been no reported cases of its use in liver transplantation. The aim of this report is to review a case of acute graft-versus-host disease and the use of etanercept to manage this complication. Etanercept has never previously been used in liver transplantation complicated by acute graft-versus-host disease. In the hematology literature, the success of its use is offset by significant rates of serious infectious (especially fungal) complications. However, preliminary results are encouraging and offer insight into its use as a potentially viable therapeutic option. We report the first successful use of etanercept in liver transplantation-associated graft-versus-host disease, albeit complicated by invasive aspergillosis, and recommend concurrent antifungal prophylaxis when the drug is used in this setting.

Pubmed
Journal: Journal of the American College of Surgeons
January/29/1997
Abstract

BACKGROUND

Resection of the caudate lobe of the liver to treat malignancies has recently received attention, but long-term results after such resection for hepatocellular carcinoma have not been reported for an acceptable number of patients. This study analyzed the short- and long-term results after resection of the caudate lobe for primary and recurrent hepatocellular carcinoma in 19 patients.

METHODS

Complete or partial resection of the caudate lobe was performed for the treatment of primary (n = 13) and recurrent (n = 6) hepatocellular carcinoma. Eleven patients had a solitary tumor only in the caudate lobe, but eight patients had tumors in other segments of the liver as well. There were 16 men and 3 women. Age ranged from 35 to 79 years, averaging 63 years. Clinicopathologic features of these cases were evaluated from various viewpoints.

RESULTS

The duration of the operation ranged from 80 to 250 minutes (mean plus or minus standard deviation; 149 +/- 47) and blood loss from 200 to 2,400 g (836 +/- 651). Four patients (21.8 percent) had postoperative complications and one (5.3 percent) died of postoperative variceal bleeding. Tumor size ranged from 1.0 to 6.0 cm, averaging 3.7 +/- 1.4. A capsule was seen around the tumor in 68.4 percent, daughter nodules in 5.3 percent, and vascular invasion in 31.2 percent. Hepatic cirrhosis was present in 15 patients and chronic hepatitis in four. The 5-year survival rate in all patients was 31.3 percent. The survival rate was significantly better in patients with primary hepatocellular carcinoma than in those with recurrent tumors (49.2 percent compared with none) because of frequent recurrence in the latter group.

CONCLUSIONS

Resection of the caudate lobe of the liver for hepatocellular carcinoma associated with chronic hepatic disease can be performed safely with a satisfactory long-term result, particularly in patients with primary tumors in this lobe.

Pubmed
Journal: Blood
October/16/2003
Abstract

Gene therapy for hemophilia A requires efficient delivery of the factor VIII gene and sustained protein expression at circulating levels of at least 1% to 2% of normal. Adeno-associated viral type 2 (AAV2) vectors have a number of advantages over other viral vectors, including an excellent safety profile and persistent gene expression. However, a major disadvantage is their small packaging capacity, which has hampered their use in treating diseases such as hemophilia A, cystic fibrosis, and muscular dystrophy, which are caused by mutations in large genes. Here we demonstrate that this can be overcome by using small regulatory elements to drive expression of a B-domain-deleted form of FVIII. The use of this vector for hepatic gene transfer in a canine model of hemophilia A resulted in the sustained (> 14 months) expression of biologically active FVIII. FVIII activity levels of 2% to 4% were achieved. These levels correlated with a partial correction in the whole-blood clotting time and cuticle bleeding time. In addition, immunoprecipitation analysis demonstrated the expression of canine FVIII of the predicted size in the plasma of injected animals. These data support the use of AAV2 vectors in human clinical trials to treat hemophilia A patients.

Pubmed
Journal: The Lancet. Oncology
November/1/2004
Abstract

Thermal ablation by use of radiofrequency energy can be used to achieve necrosis of liver tumours, and increased availability of this technique is leading to more widespread use. Much of the impetus for the use of radiofrequency ablation has come from cohort series that have provided an evidence base for this technique. Here, we give an overview of the current status of radiofrequency ablation for liver tumours, including its physical properties, to assess the characteristics that make this technique applicable in clinical practice. We review the technical development of probe design and summarise current indications and outcomes of reported clinical use. We also provide a profile of side-effects and information on the integration of this technique into the general management of patients with liver tumours. Current evidence suggests that radiofrequency ablation can be done with few side effects; however, although this technique seems to ablate tumours effectively, it should form part of multidisciplinary care for liver cancer. Crucially, the role of radiofrequency ablation in lengthening the survival of patients with liver tumours remains to be assessed.

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