Interaction of hepatitis B virus X protein with PARP1 results in inhibition of DNA repair in hepatocellular carcinoma.

Hepatitis B virus X protein (HBx) contributes to the development of hepatocellular carcinoma (HCC), probably by regulating activities of many host or viral proteins through protein-protein interactions. In this study, we identified poly(ADP-ribose) polymerase (PARP1), a crucial factor in DNA repair, as an HBx-interacting protein using a proteomics approach. Coimmunoprecipitation and proximity ligation assays confirmed the binding and colocalization of HBx and PARP1 in the nucleus. The carboxyl-terminus of HBx protein bound to the catalytic domain of PARP1, and this binding reduced the enzymatic activity of PARP1 in both in vitro and in vivo assays. HBx interrupted the binding of PARP1 to Sirt6, which catalyzes the mono-ADP-ribosylation required for DNA repair. Consistently, overexpression of HBx inhibited the clearance of γH2AX DNA repair foci generated under oxidative stress in Chang liver cells. Recruitment of the DNA repair complex to the site-specific double-strand breaks was inhibited in the presence of HBx, when measured by laser microirradiation assay and damage-specific chromatin immunoprecipitation assays. Consequently, HBx increased signs of DNA damage such as accumulation of 8-hydroxy-2'-deoxyguanosine and comet formation, which were reversed by overexpression of PARP1 and/or Sirt6. Finally, the interaction between PARP1 and Sirt6 was markedly lower in the livers of HBx-transgenic mice and specimens obtained from HCC patients to compare with the corresponding control. Our data suggest that the physical interaction of HBx and PARP1 accelerates DNA damage by inhibiting recruitment of the DNA repair complex to the damaged DNA sites, which may lead to the onset of hepatocarcinogenesis.

Characteristics of combined hepatocelluar-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma.

BACKGROUND: The 7th American Joint Committee on Cancer (AJCC) currently classifies combined hepatocellular-cholangiocarcinoma (cHCC-CC) and intrahepatic cholangiocarcinoma (ICC) into one category. Study outcomes comparing the two carcinomas have shown contrary results. This study was designed to compare the survival and prognostic factors of both carcinomas. METHODS: We retrospectively reviewed the medical records of 107 patients with cHCC-CC or ICC who underwent liver resection between January 2000 and December 2009. RESULTS: Thirty patients (28%) were diagnosed with cHCC-CC, and 77 patients (72%) had ICC. Disease-free survival (DFS) was poorer in the cHCC-CC patients (six months), and the overall survival (OS) durations were similar (p = 0.477) between cHCC-CC (58 months) and ICC (45 months) patients. A tumor size larger than 5 cm, vascular invasion and lymph node (LN) metastasis were prognostic factors in all patients. However, tumor size and LN metastasis in cHCC-CC patients and carbohydrate antigen 19-9, differentiation and LN metastasis in ICC patients were found to be independent prognostic factors. CONCLUSIONS: Patients with cHCC-CC showed poorer DFS and similar OS rates compared to those with ICC. Our study revealed different prognostic factors in cHCC-CC. To understand more accurately cHCC-CC's prognosis, difference of genetic characteristics and tumor biology should be further evaluated.

A survival benefit of major hepatectomy for hepatocellular carcinoma identified by preoperative [18F] fluorodeoxyglucose positron emission tomography in patients with well-preserved hepatic function.

AIMS: Hepatic resection can cure hepatocellular carcinoma (HCC). However, the optimal extent of resection remains controversial. Major hepatectomy could minimize a tumor recurrence, but it is harmful due to decreased hepatic functional reserve. [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) scans are known as their reflection tumor differentiation and biological activity in HCC. To evaluate a benefit of major hepatectomy for HCC, we performed this retrospective analysis in patients with well-preserved hepatic function, and further analyzed in the subset identified by preoperative FDG-PET. METHODS: We reviewed the medical records of 189 patients with HCC who underwent curative resection between August 2004 and December 2010 at two institutes. All patients underwent anatomical resection, either by major or minor hepatectomy. RESULTS: Median overall survival did not differ significantly between the major and minor hepatectomy groups (29.4 versus 26.3 months, p = 0.269). However, the major hepatectomy group had a better recurrence-free survival (24.5 versus 19.9 months, p = 0.004). On multivariate analysis, the presence of intrahepatic metastasis independently predicted overall survival (p = 0.009), but other examined variables did not. Overall survival and recurrence-free survival were significantly better following major hepatectomy rather than minor hepatectomy in patients whose preoperative FDG-PET indicated that the maximum standardized uptake value of the tumor (SUVtumor) was ≥4 and the tumor-to-nontumor SUV ratio (TNR) was ≥1.5. CONCLUSIONS: Our findings suggest that preoperative FDG-PET may be useful in identifying patients with favorable hepatic reserve who are most likely to benefit from major rather than minor hepatectomy.

The efficacy of portal vein embolization prior to right extended hemihepatectomy for hilar cholangiocellular carcinoma: a retrospective cohort study.

BACKGROUND/PURPOSE: Preoperative portal vein embolization was introduced to minimize complications after extended hepatectomy. This retrospective cohort study was conducted to compare outcomes with and without portal vein embolization before hepatectomy for hilar cholangiocellular carcinoma. METHODS: This study was conducted with 35 patients who underwent right extended hemihepatectomy for hilar cholangiocellular carcinoma from 2001 to 2008. Preoperative portal vein embolization was performed in 14 patients (embolization group) and not performed in 21 patients (non-embolization group). RESULTS: The groups did not differ in terms of sex, age, operative time, transfusion, postoperative serum bilirubin level, prothrombin time, and length of intensive care unit (ICU) stay. Although blood loss was higher in the embolization group than in the non-embolization group (P = .009), no major complications were observed between embolization and resection. At presentation, future liver remnant was smaller in the embolization group (19.8%, range 16-35%) than in non-embolization group (28.3%, 15-47%; P = .001). After embolization, the volume of the future liver remnant increased significantly to 27.2% (range, 23-42%; P = .001). Future liver remnants just before operation were similar in both groups (P > .99). There was no significant difference in terms of the rate of morbidity and in-hospital mortality. No statistically significant differences were observed in disease-free survival (P = .52) and overall survival (P = .30). CONCLUSIONS: Portal vein embolizations do not increase the rate of morbidity, in-hospital mortality, local recurrence and system metastasis. Therefore it can be considered safe and effective for patients with small future liver remnants. Embolization can lessen postoperative liver failure and widen the indication of the surgical resection, especially in patients with marginal future liver remnants.

Characteristic Dynamic Enhancement Pattern of MR Imaging for Malignant Thyroid Tumor. Preliminary Report.

The purpose of this study was to determine the characteristic dynamic enhancement pattern of MR imaging for malignant thyroid tumor. Eight patients were collected, who had pathology confirmed malignant thyroid tumor preoperatively. There were five papillary carcinomas, one medullary carcinoma, one follicular carcinoma and one FNAB proven atypical cell. All images were obtained with a 3.0-T MR imaging system with and without iv contrast administration. Pathologic report and US imaging finding were collected retrospectively. Based on preoperative MR imaging, we compared dynamic MR enhancement pattern relating to pathologic type. All biopsy proven malignant thyroid tumors show hypoechogenicity on previous US imaging, except one follicular carcinoma (isoechogenicity). On T1-weighted images, one papillary carcinoma showed high SI and one medullary carcinoma showed low SI. The other cases were not differentiated with normal parenchyma. On T2-weighted images, three papillary carcinomas and one follicular carcinoma showed high SI and one papillary carcinoma showed low SI. The other case was not differentiated with normal parenchyma. On contrast agent-enhanced dynamic T1WI, five papillary carcinomas and one medullary carcinoma showed delayed enhancement compared to normal parenchyma. One follicular carcinoma showed stronger enhancement than normal parenchyma, one papillary carcinoma showed persistently decreased enhancement than normal parenchyma. Although this study is limited by the small patient population, the data suggest that delayed enhancement on enhanced dynamic T1WI may be a characteristic MR finding of malignant thyroid tumor.

MRI findings of uncommon non-hepatocyte origin primary liver tumours with pathological correlation.

The objective of this article was to illustrate the MRI findings of uncommon non-hepatocyte origin primary liver tumours, correlate them with the pathological features and discuss differential diagnoses. In conclusion, the MRI findings of uncommon benign and malignant non-hepatocyte-origin primary liver tumours vary. Awareness of characteristic MRI features can aid differential diagnosis and prevent unnecessary surgery.

H-Ras is degraded by Wnt/beta-catenin signaling via beta-TrCP-mediated polyubiquitylation.

Ras is an important proto-protein that is regulated primarily by GDP/GTP exchange. Here, we report a novel regulatory mechanism whereby turnover of both endogenous and overexpressed H-Ras protein is controlled by beta-TrCP-mediated ubiquitylation, proteasomal degradation and the Wnt/beta-catenin signaling pathway. The interaction of H-Ras with the WD40 domain of beta-TrCP targeted H-Ras for polyubiquitylation and degradation. This process was stimulated by Axin or adenomatous polyposis coli (Apc), and was inhibited by Wnt3a. Ras-mediated cellular transformation was also inhibited by the expression of beta-TrCP and/or Axin. In vivo regulation of Ras stability by Wnt/beta-catenin signaling was determined via measurements of the status of Ras in the intestines of mice stimulated with recombinant Wnt3a by intravenous tail vein injection. The regulation of Ras stability by Wnt/beta-catenin signaling provides a mechanical basis for crosstalk between the Wnt/beta-catenin and the Ras-ERK pathways involved in transformation.

Clinical features and treatment outcomes of advanced stage primary hepatic angiosarcoma.

BACKGROUND: Primary hepatic angiosarcoma is a very rare malignancy with a poor prognosis. While surgical resection has been validated as curative choice, most cases are diagnosed too late for resection. Nonetheless, treatment protocols have not been established and also there are very few reports on the clinical features and treatment outcomes. PATIENTS AND METHODS: Among 11,939 patients diagnosed with primary hepatic tumors from January 1985 to December 2007 at two centers, five patients were diagnosed with primary hepatic angiosarcoma. We analyzed patients' demographics, tumor characteristics, treatment modality, and outcomes using imaging, serology, and pathology. RESULTS: All five patients were diagnosed at advanced stage with distant metastases. The most common symptom was abdominal pain. The levels of the tumor markers were within the normal range and serological tests were negative for hepatitis B and C viruses. Two of four patients who received chemotherapy died <3 months after diagnosis, but the other two patients survived >6 months. CONCLUSIONS: A combination of chemotherapy resulted in an improved outcome for two of four patients, suggesting the potential usefulness of palliative chemotherapy to improve survival. This case study may aid in planning chemotherapy for patients with advanced hepatic angiosarcoma.

Mangafodipir trisodium-enhanced MRI of hepatocellular carcinoma: correlation with histological characteristics.

AIM: To define histopathological factors related to the degree of mangafodipir trisodium (MnDPDP) uptake in hepatocellular carcinomas (HCCs) on magnetic resonance imaging (MRI). MATERIALS AND METHODS: In-phase and opposed-phase gradient-echo MRI images were obtained preoperatively in 37 patients with 38 HCCs before and 15-30 min after intravenous injection of MnDPDP. Subjective ratings of the enhancement degree, the signal-to-noise ratio (SNR) of the lesion and the liver, and the contrast enhancement ratios (CER) were compared with histopathological factors. RESULTS: The mean SNR of HCCs increased from 59.6 to 95.0 (CER=59.5%), whereas that of the liver increased from 75.1 to 108.7 (CER=45.2%). Eight HCCs showed mild enhancement, 11 moderate enhancement, and 15 strong enhancement. There was no visually perceptible enhancement in four HCCs (10.3%). The degree of MnDPDP enhancement was significantly related with the cell density ratio (p<.05) and monoclonal hepatocyte antibody positivity (p<0.005), but not with size, growth type, cell type, histological type, cytokeratin 7, or cytokeratin 19. Well-differentiated HCC showed higher MnDPDP enhancement compared with higher grade HCCs, but the differences were not statistically significant. CONCLUSION: The uptake of MnDPDP by HCC was correlated with hepatocyte antibody expression and the cellular density ratio. Well-differentiated HCC tended to show higher MnDPDP enhancement.

High prevalence of significant histology in asymptomatic chronic hepatitis B patients with genotype C and high serum HBV DNA levels.

Current treatment guidelines suggest that antiviral therapy be considered for chronic hepatitis B (CHB) patients with high viral load if a biopsy shows significant liver disease despite alanine aminotransferase (ALT) levels two times or less than the upper limit of normal (ULN). We evaluated the histological findings in CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels. Between January 2003 and June 2006, 105 consecutive treatment-naive patients with CHB who underwent ultrasonography-guided percutaneous liver biopsy, had detectable serum HBV DNA (>10(5) copies/mL) in a direct hybridization assay and normal or slightly elevated serum ALT levels (≤2 × ULN) for at least 12 months were included in a prospective study. Histological assessment was based on the METAVIR scoring system. Significant histology was defined as fibrosis stage ≥F2 or necroinflammation grade ≥A2. Among the 105 CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels for at least 12 months, significant fibrosis (F2-F4 fibrosis) was observed in 63 patients (60.0%) and the actual significant histology was found in 65 patients (61.9%). On multivariate analysis, serum ALT levels and age at which they entered the study were independent factors associated with significant histology. Odds ratios for significant histology increased progressively according to serum ALT levels and age. In conclusion, a large proportion of CHB patients with genotype C, high viral load and ALT ≤2 × ULN had significant liver disease on liver biopsy and should be considered for antiviral therapy.

Ectopic Cushing's syndrome due to concurrent corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secreted by malignant gastrinoma.

Ectopic Cushing's syndrome due to various malignancies is not uncommon. However, a few cases of ectopic Cushing's syndrome caused by corticotropin-releasing hormone (CRH), or CRH with adrenocorticotropic hormone (ACTH) have been reported. A 28-year-old woman presented with acute upper gastrointestinal bleeding caused by an active ulcer, located atypically in the 2nd portion of duodenum. Further work-up revealed high gastrin levels and abdominal computed tomography (CT) scans showed a large pancreatic head mass with multiple liver metastases. The serum cortisol and ACTH levels were checked due to hypokalemia with metabolic alkalosis and recent amenorrhea. Cortisol and ACTH were both highly elevated with pituitary hyperplasia and elevated CRH. The existence of ectopic ACTH and CRH in the liver biopsy was also demonstrated immunohistochemically. Since an operation was not feasible, chemotherapy was conducted using paclitaxel and etoposide. These two drugs were chosen according to the IN VITRO chemotherapy response assay to maximize the treatment. This report demonstrates concurrent ACTH- and CRH-related ectopic Cushing's syndrome caused by malignant gastrinoma with multiple liver metastases that was treated with marginal success using a multidisciplinary medical approach.

The white-phase-specific gene WH11 is not required for white-opaque switching in Candida albicans.

Phenotypic switching between white and opaque cells is important for adaptation to different host environments and for mating in the opportunistic fungal pathogen Candida albicans. Genes that are specifically activated in one of the two cell types are likely to be important for their phenotypic characteristics. The WH11 gene is a white-phase-specific gene that has been suggested to be involved in the maintenance of the white-phase phenotype. To elucidate the role of WH11 in white-opaque switching, we constructed mutants of the C. albicans strain WO-1 in which the WH11 gene was deleted. The Delta wh11 mutants were still able to form both white and opaque cells whose cellular and colony phenotypes were indistinguishable from those of the wild type. Deletion of WH11 also did not affect the activation and deactivation of the white-phase-specific WH11 promoter and the opaque-phase-specific OP4 and SAP1 promoters in the appropriate cell type. Finally, switching from the white to the opaque phase and vice versa occurred with the same frequency in wild-type and Delta wh11 mutants. Therefore, the WH11 gene is not required for phenotypic switching, and its protein product seems to have other roles in white cells, which are dispensable after the switch to the opaque phase.

Apoptosis and proliferation in hepatocarcinogenesis related to cirrhosis.

BACKGROUND: Dysplastic nodules (DNs) recently have been identified as preneoplastic lesions of hepatocellular carcinoma (HCC). To test an alternative hypothesis regarding DN development, in which we have suggested that DNs develop as an infiltrating clonal expansion in advance of, or parallel to cirrhosis, the authors investigated the rates of apoptosis and proliferation in human hepatocarcinogenesis. METHODS: The authors performed terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and proliferation cell nuclear antigen (PCNA) staining in 11 low-grade DNs, 8 high-grade DNs including 3 cases with HCC subnodules, 10 small HCCs, and 29 cases of surrounding cirrhotic nodules. Hepatocellular carcinoma subnodules were present in three cases of high DNs. They determined TUNEL-labeling indices (LIs) and PCNA-LIs as the percentage of positive hepatocyte nuclei per 500 randomly counted cells. RESULTS: TUNEL-LIs (mean +/- standard deviation) were 0.8 +/- 0.82 in cirrhotic nodules, 1.0 +/- 0.98 in low-grade DNs, 3.0 +/- 4.33 in high-grade DNs, 8.7 +/- 7.71 in HCC subnodules of high-grade DNs, and 3.2 +/- 3.58 in small HCCs. The peak values of apoptotic activity were higher in high-grade DNs and HCCs than in low-grade DNs and cirrhotic nodules. Each case of low-grade DN showed a low to medium level of apoptotic activity when compared with those of the four surrounding cirrhotic nodules. The PCNA-LIs were 2.6 +/- 1.35 in cirrhotic nodules, 4.5 +/- 2.31 in low-grade DNs, 15.3 +/- 10.50 in high-grade DNs, 25.4 +/- 5.25 in HCC subnodules of high-grade DNs, and 34.9 +/- 15.70 in small HCCs. The peak values gradually increased, although only HCC showed significantly elevated proliferation activity. The differences of PCNA-LIs and TUNEL-LIs, measured in each case, were 1.7 +/- 1.89 in cirrhotic nodules, 3.6 +/- 2.43 in low-grade DNs, 7.9 +/- 5.69 in high-grade DNs, 16.2 +/- 2.87 in HCC subnodules of high-grade DNs, 28.2 +/- 13.97 in small HCCs. At all stages of hepatocarcinogenesis, the rates of cell proliferation were higher than apoptosis, allowing a preferential net gain of (pre)neoplastic cells, and it was significantly increased in small HCCs. In regenerative cirrhotic nodules, 14% (4 cases) showed higher rates of apoptosis than proliferation. CONCLUSIONS: The regulation/dysregulation of apoptosis of (pre)neoplastic cells as well as of proliferation may play an important role in the process of hepatocarcinogenesis.

Teratoid hepatoblastoma: multidirectional differentiation of stem cell of the liver.

Hepatoblastoma is the most common malignant hepatic neoplasm of childhood, showing a wide spectrum of epithelial and mesenchymal components. Teratoid hepatoblastoma, which reveals multiple lines of tissue differentiation such as mucinous epithelium, melanin pigment, endocrine differentiation, glial and mesenchymal components, has rarely been observed. We report a case of teratoid hepatoblastoma in a 22-month-old girl. She had been diagnosed with hepatoblastoma through percutaneous needle biopsy of the liver and treated with 10 chemotherapy cycles of epirubicin, VP-16 and cisplatin and with hepatic artery embolization. After 10 months, an extended left lobectomy was performed. Grossly, a multinodular, partly well-demarcated, solid mass (7 x 5 cm) with dense fibrosis and focal cystic change occupied almost the entire specimen. There was extensive necrosis due to preoperative treatment. Microscopically, the tumor showed multiple lines of differentiation, which was composed of embryonal, fetal hepatocytes and mesenchymal elements with numerous foci of osteoid. There were also other components showing endodermal, neural, melanocytic and endocrine differentiation. These teratoid components were considered relatively resistant to preoperative chemotherapy, in contrast to extensive necrosis of both embryonal and fetal hepatocytes. These teratoid features of hepatoblastoma are considered to be a multidirectional differentiation of the small epithelial cells or stem cells of the tumor.

Replacements of amino acid residues at subsites and their effects on the catalytic properties of Rhizomucor pusillus pepsin, an aspartic proteinase from Rhizomucor pusillus.

Site-directed mutagenesis was carried out to investigate the functional roles of amino acid residues of Rhizomucor pusillus pepsin (RMPP) in substrate-binding and catalysis. Mutations of two amino acid residues, E13 in the S3 subsite and N219 in the S3/S4 subsites, caused marked changes in kinetic parameters for two substrate peptides with different sequences. Further site-directed mutagenesis at E13 suggested that E13 plays a critical role in forming the correct hydrogen bond network around the active center. In the crystal structure of Rhizomucor miehei pepsin (RMMP), which is an aspartic proteinase produced by Rhizomucor miehei and shows 81% amino acid identity to RMPP, the Oepsilon atom of N219 forms a hydrogen bond with the N-H of isovaline in pepstatin A, a statine-type inhibitor, at the P3 position, suggesting that the loss of the hydrogen bond causes an unfavorable arrangement of the P3 residue. Among the mutants constructed, the E13A mutant showed a 5-fold increase in the ratio of clotting versus proteolytic activity without significant loss of clotting activity. This mutant may present a promising candidate for a useful milk coagulant.

Relation of apolipoprotein E polymorphism to clinically diagnosed Alzheimer's disease in the Korean population.

The gene for human apolipoprotein E (APOE) is found on the long arm of chromosome 19 (19q13.2) and exists in three common allelic forms, epsilon2, epsilon3, and epsilon4. The APOE epsilon4 allele is overrepresented in Alzheimer's disease (AD) and is accepted as a genetic risk factor. Some studies reported a protective effect of the APOE epsilon2 allele for AD. However, there are some ethnic variations in the proportion of different APOE alleles and their relationship to AD. We examine the distribution of APOE alleles from 30 AD patients and 158 controls in Korea. The control subjects were all cognitively intact unrelated Koreans. The frequencies of APOE alleles in AD patients were 18.3% (epsilon2), 58.3% (epsilon3), and 23.3% (epsilon4). The corresponding frequencies in controls were 13.3% (epsilon2), 72.5% (epsilon3), and 14.2% (epsilon4). The frequency of the APOE epsilon2 allele in AD patients was not significantly different from that in controls. When statistical analysis was conducted after the exclusion of the APOE epsilon2 allele, the frequency of the APOE epsilon4 allele in AD patients was significantly higher than that in controls (P < 0.05). These results support that the APOE epsilon4 allele plays a role as a risk factor for AD in Koreans and suggest that the APOE epsilon2 allele may not play a protective role in the development of AD in Koreans.

Lower gastrointestinal bleeding due to cytomegalovirus ileal ulcers in an immunocompetent man.

Cytomegalovirus (CMV) infections are commonly reported in severely immunocompromised hosts and ulcers of the alimentary tract are frequently observed in systemic CMV infections. However, invasive and ulcerative disease of the gastrointestinal (GI) tract caused by CMV has also been reported in healthy adults. Many reports show that a CMV infection can produce localized ulcerations in the esophagus, stomach, small intestine, and colon in nonimmunocompromised individuals. The most common site of involvement by CMV infection in the GI tract is the colon followed by the upper GI tract and the least common site is the small intestine. Although GI bleeding is one of the major presenting symptoms of patients with CMV infections of the GI tract, lower GI bleeding due to CMV ileal ulcers in immunocompetent patients, to our knowledge, has not been reported in the English literature. Recently, we experienced a case of lower GI bleeding due to CMV ileal ulcers in a 57-year-old man who had no evidence of immunocompromise. This case suggests that small intestinal ulcers due to CMV infection should be included in the differential diagnosis of lower GI bleeding even in immunocompetent hosts.

Hepatic iron deposition on MR imaging in patients with chronic liver disease: correlation with serial serum ferritin concentration.

BACKGROUND: To evaluate the relationship between magnetic resonance (MR) imaging grading of iron deposition and serial serum ferritin concentration in patients with chronic viral liver diseases. METHODS: In 80 patients with viral hepatitis and cirrhosis, MR images including T2*-weighted gradient echo images (echo time > or = 6.5 ms) were reviewed. The grades of parenchymal iron deposition and iron-containing nodules in the liver and spleen and the liver-to-muscle and spleen-to-muscle signal intensity ratios were compared with the most recent, the mean, the lowest, and the highest values from all available serum ferritin levels. RESULTS: The serum ferritin concentration was significantly correlated with the grades of iron deposition in liver and spleen and with the grades of iron-containing nodules seen on MR images (p < 0.05). Liver-to-muscle signal intensity ratio was weakly correlated with the ferritin concentrations. Among categories of ferritin concentration, correlation with MR grades was highest for mean ferritin concentration (r = 0.487, p < 0.001). CONCLUSION: MR imaging grades of hepatic iron and siderotic nodules correlate with serum ferritin, especially with the mean levels.

Increased proliferation activities of vascular endothelial cells and tumour cells in residual hepatocellular carcinoma following transcatheter arterial embolization.

AIMS: Transcatheter arterial embolization induces extensive ischaemic necrosis or hypoxia via the obstruction of the hepatic artery in hepatocellular carcinoma (HCC). Ischaemia is strongly correlated with an increased expression of angiogenic factor and stimulates an increase in angiogenesis, including endothelial cell proliferation. The aim of this study was to evaluate whether ischaemic necrosis induced by transcatheter arterial embolization could increase the proliferative activities of intratumoral endothelial cells or tumour cells in the residual HCC. METHODS AND RESULTS: Using a double immunohistochemical technique (Ki67 antibody to determine the proliferative activity and CD34 antibody to highlight the intratumoral endothelial cells), we performed immunohistochemical staining for 24 HCCs treated by transcatheter arterial embolization. Seven HCCs without any preoperative transcatheter arterial embolization and nine cirrhosis cases were also studied as the control cases. The residual tumour was then divided into five areas at 0.5 mm intervals, according to the distance from the necrotic margin induced by embolization. The Ki67 labelling indices of the intratumoral endothelial cells and tumour cells were counted in each area. The correlation between the indices and the corresponding distance from the ischaemic necrosis was analysed. The Ki67 labelling index of intratumoral vascular endothelial cells in the area less than 0.5 mm from the necrotic margin (area 1) was 10.60 +/- 3.64% (mean +/- SD), which was twofold greater than those of the other areas more than 0.5 mm from the margin (areas 2--5) and those of the control HCCs without preoperative transcatheter arterial embolization. In addition, the proliferation labelling index of the tumour cells was 35.77 +/- 11.45% (mean +/- SD) in area 1. This was higher than those of areas 2--5 and control HCCs without preoperative transcatheter arterial embolization. There was a positive correlation between the proliferation of both endothelial and tumour cells and ischaemic necrosis (P < 0.05). CONCLUSIONS: Our study suggests that the proliferative activity of intratumoral endothelial cells and tumour cells is increased by ischaemic necrosis induced by transcatheter arterial embolization, and its effect is maximal in the area adjacent to the necrosis (less than 0.5 mm from the necrotic margin).