Postoperative chemoradiotherapy following pancreaticoduodenectomy. Impact of dose-volumetric parameters on the development of diabetes mellitus.

PURPOSE: The purpose of this research was to analyze the relationship between dose-volumetric parameters and the development of diabetes mellitus (DM) in patients treated with chemoradiotherapy (CRT) following curative resection for upper gastrointestinal (GI) cancers. PATIENTS AND METHODS: Medical records of patients who underwent postoperative CRT following curative resection, either pancreaticoduodenectomy (PD) or pylorus preserving pancreaticoduodenectomy (PPPD) for upper GI cancers including pancreas, biliary, ampullary, and duodenal cancers, between January 2006 and December 2008 were retrospectively reviewed. A total of 42 patients who were regularly followed for at least 2 years were included for analysis. Dose-volumetric parameters such as remnant pancreatic volume, mean dose, maximum dose (Dmax), and percentage of volume receiving specific dose or more were obtained from pre- and postoperative CT scan images and treatment plan. RESULTS: Dmax and V50 (percentage of volume receiving at least 50 Gy) were statistically significant factors for the development of DM (p = 0.013, p = 0.031, respectively). The sensitivity and specificity of Dmax was 0.875 and 0.559, with cut-off value of 51.1 Gy, respectively. V50 had sensitivity of 0.875 and specificity of 0.618 for cut-off value of 16 %. No patient-related factor other than pretreatment cerebrovascular events was associated with the development of DM. On multivariate analysis, V50 was the only factor with statistical significance (p = 0.028), whereas Dmax showed borderline significance (p = 0.079). CONCLUSION: V50 was the only independent factor associated with the development of diabetes and may function as guideline to predict the development of DM in patients receiving CRT following curative resection.

Pharmacokinetics of oltipraz and its major metabolite (RM) in patients with liver fibrosis or cirrhosis: relationship with suppression of circulating TGF-beta1.

Oltipraz is a potential candidate drug for the treatment of liver fibrosis (LF) and liver cirrhosis (LC). The pharmacokinetics of oltipraz and its major rearranged metabolite (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine (RM)) were evaluated after single-dose (30-90 mg) and multiple-dose (60 mg b.i.d. or 90 mg q.d. for 24 weeks) oral administration of oltipraz to patients with LF or LC. Oltipraz was safe and well tolerated in both studies. In the single-dose study, the area under the plasma concentration-time curve (AUC), peak plasma concentration (C(max)), and terminal half-life (t(1/2)) of oltipraz as well as the AUC of its RM were dose dependent. Oltipraz was rapidly absorbed; the time to reach C(max) (T(max)) was 2-4 h. The conversion of oltipraz to RM was also rapid and substantial (AUC of RM from time 0 to the last measured concentration (AUC(last, RM))/AUC(last, oltipraz), 42-61%). In the multiple-dose study, the level of transforming growth factor-beta1 (TGF-beta1) (a blood fibrosis marker) was suppressed at steady-state plasma concentrations of approximately 20-60 ng/ml of oltipraz or of approximately 60-140 ng/ml of oltipraz plus RM. Overall, the pharmacokinetics, safety, and efficacy of oltipraz suggest that it may be helpful in the treatment of patients with LF or LC, at an optimal dosing regimen.

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer.

Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3-/- mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3-/- bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3-/- epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3+/- mice ( approximately 18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3+/- mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.

Complete blood count reflects the degree of oesophageal varices and liver fibrosis in virus-related chronic liver disease patients.

To optimize management of chronic liver disease (CLD), a simple and noninvasive test to determine oesophageal varices (EV) and liver fibrosis is necessary. We performed a cohort study in a single tertiary care centre in order to devise a simple index reflecting EV and liver fibrosis. We derived an index reflecting EV which resulted from portal hypertension (the first part) and evaluated the index's ability to detect liver fibrosis which resulted in portal hypertension (the second part). Five hundred fifty-six patients (the first part, n = 409, mean age = 55.4 years, EV prevalence = 34.0%; the second part, n = 147, mean age = 48.8 years, cirrhosis prevalence = 12.9%) with virus-related CLD were included. P2/MS [(platelet count [10(9)/L])(2)/(monocyte fraction [%] x segmented neutrophil fraction [%])] was derived to detect EV. The area under the receiver-operating characteristic curve (AUROC) of P2/MS was 0.916 (95% confidence interval, 0.879-0.954) for detecting EV, and 0.905 (0.862-0.947) for detecting high-risk EV (grade >or= II or with red colour signs). P2/MS had AUROCs of 0.952 (0.904-0.999) and 0.873 (0.792-0.955) for histological cirrhosis (METAVIR F4) and significant fibrosis (METAVIR F2-F4), respectively, which were significantly greater than those of AST-to-platelet count ratio index (0.658, P < 0.001; 0.644, P = 0.003) and FIB-4 (0.776, P = 0.031; 0.707, P = 0.026). The predictive values of P2/MS were maintained at similar accuracy in subsequent validation sets. Our study suggests that P2/MS comprising only the complete blood count results is an efficient and noninvasive marker reflecting the presence of EV and the grade of liver fibrosis in patients with virus-related CLD. An independent external validation of P2/MS is required.

ADMA regulates angiogenesis: genetic and metabolic evidence.

Endothelium-derived nitric oxide (NO) plays an important role in transducing the effects of angiogenic factors. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We used a murine model of hindlimb ischemia to investigate whether genetic or metabolic changes in ADMA levels could impair angiogenic response in vivo. Hindlimb ischemia was surgically induced in C57BL/6J mice, apo E-deficient mice, or transgenic mice overexpressing dimethylarginine dimethylaminohydrolase (DDAH). Some animals were also treated with the NOS antagonist L-nitro-arginine, or the NO precursor L-arginine. Angiogenesis was quantified in the hindlimb skeletal muscle by capillary/myocyte ratio. Plasma or tissue ADMA levels were measured by HPLC. In normal mice, hindlimb ischemia increased tissue ADMA twofold, and reduced DDAH and NOS expression. This was associated with a reduced NOS activity (by over 80%) three days following surgery. On day seven, a threefold increase in DDAH expression and a fall in tissue ADMA levels were associated with a sevenfold increase in NOS activity, whereas NOS expression did not increase above baseline. In DDAH transgenic mice, the elevation of ADMA and decrement in NOS activity was blunted during hindlimb ischemia. Plasma ADMA levels were increased in apo E-mice (1.79 +/- 0.45 versus 1.07 +/- 0.08 pmol/l; p = 0.008). Capillary index was significantly reduced in apo E-mice up to seven weeks after surgery (0.25 +/- 0.05 versus 0.62 +/- 0.08; p < 0.001). The effect of hypercholesterolemia on capillary index was reversed by L-arginine, and (in wild-type mice) mimicked by administration of the NOS antagonist L-nitro-arginine. In conclusion, metabolic or genetic changes in plasma and tissue ADMA levels affect tissue NO production and angiogenic response to ischemia.

Induction of apoptosis in p53-deficient human hepatoma cell line by wild-type p53 gene transduction: inhibition by antioxidant.

We investigated the role of wild-type (wt)-p53 as an inducer of apoptotic cell death in human hepatoma cell lines. Following the retrovirus-mediated transduction of the wt-p53 gene, Hep3B cells lacking the endogenous p53 expression began to die through apoptosis in 4 h. They showed a maximal apoptotic death at 12 h, whereas HepG2 cells expressing endogenous p53 did not. However, the transduction of the wt-p53 gene elicited growth suppression of both Hep3B and HepG2 cells. P21(WAF1/CIP1), a p53-inducible cell cycle inhibitor, was induced, not only in Hep3B cells undergoing apoptosis, but also in HepG2 cells. The kinetics of the p21(WAF1/CIP1) induction, DNA fragmentation, and growth suppression of the Hep3B cells showed that DNA fragmentation and growth suppression progressed rapidly following p21(WAF1/CIP1) accumulation. N-acetyl-cysteine or glutathione, potent antioxidants, strongly inhibited the DNA fragmentation, but did not reduce the elevated level of p21(WAF1/CIP1). These findings suggested that p21(WAF1/CIP1) was not a critical mediator for the execution of p53-mediated apoptosis, although it contributed to the growth inhibition of cells undergoing apoptosis. Furthermore, p53-mediated apoptosis could be repressed by antioxidants.

Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to hepatocellular carcinogenesis.

The transforming growth factor-beta (TGF-beta) receptor complex and its downstream signaling intermediates constitute a tumor suppressor pathway. In many cancers, expression of TGF-beta type II receptor (TbetaR-II) is markedly decreased. In the present study, we show that the hepatocytes isolated from 15-day-old, but not 9-month-old, mice heterozygous for the deletion of the TbetaR-II gene are slightly less sensitive to the growth-inhibitory effect of TGF-beta when compared with wild-type littermates of same age. In addition, the proliferation index of hepatocytes as indicated by bromodeoxyuridine incorporation is mildly increased in the heterozygous mice. These subtle changes in cellular phenotype did not result in either gross or microscopic abnormality of the liver. The treatment of these mice with the chemical carcinogen, diethylnitrosamine, results in a significantly enhanced tumorigenesis in the liver when compared with the wild-type littermates. Our results demonstrate the gene-dosage effect of TbetaR-II and indicate that the reduced expression of TbetaR-II in mice increases susceptibility to tumorigenesis in the liver.

Expression of the G1-S modulators in hepatitis B virus-related hepatocellular carcinoma and dysplastic nodule: association of cyclin D1 and p53 proteins with the progression of hepatocellular carcinoma.

Deranged expression of cell cycle modulators has been reported to contribute to the development and progression of hepatocellular carcinoma (HCC). However, their expression patterns remain poorly understood in hepatitis B virus (HBV)-related HCC, which constitutes about 65-70% of HCC in Korea. The aims of this study were to evaluate the expressions of G1-S modulators in HBV-related HCCs and dysplastic nodules (DNs), and to correlate with the histopathologic features of HCCs. Immunohistochemical expressions of cyclin D1, cyclin E, p53, p27, p21, p16, Rb, and PCNA proteins were investigated in 80 HCCs and 22 DNs. Cyclin D1 overexpression showed positive relationships with advanced tumor stage, poor differentiation, larger tumor size, microvascular invasion, intrahepatic meta-stasis, no tumor capsule formation, infiltrative growth, aberrant p53 expression, and high PCNA labeling index (LI) of HCC (p<0.05). Aberrant p53 expression showed positive relationship with poor differentiation of HCC (p<0.01). Expression of cyclin D1 or p53 was not observed in DNs. The p27 LI and p16 LI were lower in HCCs with intrahepatic metastasis (p<0.05). Cyclin D1 overexpression and aberrant p53 expression could be associated with the progression of HBV-related HCC, and might have a less crucial role in the DN-HCC sequence. In addition, elevated expression of p27 and p16 proteins might have inhibitory action to the intrahepatic metastasis of HBV-related HCC.

Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis.

We provide anatomic and functional evidence that nicotine induces angiogenesis. We also show that nicotine accelerates the growth of tumor and atheroma in association with increased neovascularization. Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated fibrovascular growth in vivo. In a mouse model of hind-limb ischemia, nicotine increased capillary and collateral growth, and enhanced tissue perfusion. In mouse models of lung cancer and atherosclerosis, we found that nicotine enhanced lesion growth in association with an increase in lesion vascularity. These effects of nicotine were mediated through nicotinic acetylcholine receptors at nicotine concentrations that are pathophysiologically relevant. The endothelial production of nitric oxide, prostacyclin and vascular endothelial growth factor might have a role in these effects.

Fatal submassive hepatic necrosis associated with tyrosine-methionine-aspartate-aspartate-motif mutation of hepatitis B virus after long-term lamivudine therapy.

We present a case of infection with lamivudine-resistant mutant hepatitis B virus (HBV) that fatally exacerbated hepatitis following the emergence of HBV with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif in an immunocompetent patient who was receiving long-term lamivudine therapy. Restriction fragment length polymorphism analysis showed that the YMDD-motif mutant was the predominant form of circulating HBV at the time of the fatal exacerbation, and a necropsy specimen of the liver revealed submassive hepatic necrosis without steatosis.

Relationship between expression of the sodium/iodide symporter and 131I uptake in recurrent lesions of differentiated thyroid carcinoma.

The sodium/iodide symporter (NIS) is known to be responsible for the active accumulation of iodide within the thyroid gland. We evaluated the relationship between the expression of NIS in primary or lymph node lesions and iodine-131 uptake in recurrent lesions of differentiated thyroid cancer. In 67 patients with differentiated thyroid cancer (5 follicular and 62 papillary carcinomas), the expression of NIS was analysed by immunohistochemical staining using polyclonal antibodies against human NIS. We used paraffin block tissues of primary tumours or metastatic lesions, and also assessed 131I uptake in recurrent lesions of thyroid cancer on post-operative 131I whole-body scan. Immunohistochemical staining was positive in 22 patients (32.8%), including 2 of 5 follicular and 20 of 62 papillary carcinomas. Recurrence was confirmed in 40 patients pathologically or clinically by serum thyroglobulin, 131I scan, fluorine-18 fluorodeoxyglucose positron emission tomography and/or computed tomography. Among these 40 patients, 28 showed positive uptake on 131I scan. Fourteen tumour specimens out of 28 (50%) were positive by NIS immunohistochemical staining. The remaining 12 patients with recurrent cancer showed negative 131I scans, and all specimens were negative by NIS immunohistochemical staining. Thus, NIS immunohistochemical staining predicted 131I uptake in recurrent cancer with a 100% positive predictive value and a 46.2% negative predictive value. There was no difference in the positivity of NIS according to the site of recurrence on 131I scan. Outcome of 131I therapy could be assessed in 22 of the 28 patients who showed 131I uptake in recurrent lesions. Patients with positive NIS immunostaining responded to 131I therapy better than did patients with negative immunostaining (P<0.05). In conclusion, NIS immunohistochemical staining showed a high positive predictive value in predicting iodine uptake. Positive immunohistochemical staining of human NIS in primary or lymph node lesions may predict 131I accumulation and effectiveness of 131I therapy in recurrent lesions.

Congenital monoblastic leukemia with 9;11 translocation in monozygotic twins : a case report.

We report an autopsy case of congenital monoblastic leukemia that developed in monozygotic twins. The twin presented with progressive hepatosplenomegaly at 4 weeks after birth. One twin died of massive bleeding and hypovolemic shock before the treatment started. At autopsy, the liver was diffusely enlarged and showed a diffuse whitish discoloration except for the subcapsular and perivenular areas. Microscopic examination disclosed infiltration of histiocyte-like atypical cells along the sinusoids and portal areas of the liver. Spleen, lymph nodes and choroid plexus were also infiltrated by the tumor cells. However, bone marrow involvement of the tumor was minimal although multifocal. On immunohistochemical staining, these atypical cells were reactive for CD68 (PGM-1) and lysozyme, suggesting that the tumor cells might have been derived from mono- histiocyte. Cytogenetic study revealed 9;11 translocation, which is frequently associated with acute monoblastic leukemia. To the best of our knowledge, this is the first report of congenital monoblastic leukemia of monozygotic twins in Korea.

In vivo antitumor effect of herpes simplex virus thymidine kinase gene therapy in rat hepatocellular carcinoma: feasibility of adenovirus-mediated intra-arterial gene delivery.

Transfer of the herpes simplex virus-thymidine kinase gene, followed by the administration of ganciclovir (HSV-tk/GCV), has been a major approach for cancer gene therapy. We investigated the antitumor effect of the HSV-tk/GCV strategy with the rat orthotopic hepatocellular carcinoma (HCC) model and the tumor-selective gene delivery by an adenovirus-mediated gene transfer through the hepatic artery. The complete antitumor effect was demonstrated, after the treatment with GCV in rat HCC established by the implantation of HSV-tk transferred rat HCC cells. The in vivo bystander effect was also observed. The marked infiltration of CD4+ and CD8+ T lymphocytes, macrophages and NK cells were found in the tumor area. After the injection of adenovirus carrying the LacZ gene into the hepatic artery, the selective expression of transgene in the tumor cell was achieved. These findings indicate that the HSV-tk/GCV strategy, using an adenoviral vector, could be a promising avenue for the treatment of hepatocellular carcinoma.

Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin's lymphoma.

Tumor necrosis factor-related apoptosis-inducing ligand-receptor 1 (TRAIL-R1) and tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) are cell-surface receptors involved in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell-death signaling. TRAIL-R1 and TRAIL-R2 genes have recently been mapped to chromosome 8p21-22, which is a frequent site of allelic deletions in many types of human tumors, including non-Hodgkin's lymphoma (NHL). Because TRAIL/TRAIL receptor system plays an important role in lymphocyte homeostasis, we hypothesized that the mutations of TRAIL-R1 and TRAIL-R2 may be involved in the development of NHL and that such mutations may be responsible for the allelic losses of 8p21-22 in NHL. In this study, we analysed the entire coding region of TRAIL-R2 gene and the death domain region of TRAIL-R1 gene for the detection of the somatic mutations in a series of 117 human NHLs using polymerase chain reaction (PCR)-based single strand conformation polymorphism (SSCP) analysis. Overall, eight tumors (6.8%) were found to have two TRAIL-R1 gene mutations or six TRAIL-R2 gene mutations. Interestingly, of the eight mutations, six missense mutations (two TRAIL-R1 and four TRAIL-R2) were detected in the death domains and one nonsense mutation of TRAIL-R2 was detected just before the death domain. Our data suggest that somatic mutations of TRAIL-R1 and TRAIL-R2 genes may play a role in the pathogenesis of some NHLs and that TRAIL-R1 and TRAIL-R2 genes might be the relevant genes to the frequent loss of chromosome 8p21-22 in human NHL.

Cyclin D1 overexpression in hepatocellular carcinoma.

BACKGROUND/AIMS: Cyclin D1 gene amplification and cyclin D1 protein overexpression have been reported in various human tumors, including hepatocellular carcinoma (HCC). However, their significance is still controversial. In the present study, we examined the expression of cyclin D1 and its relationships to p53 and Ki-67 in HCCs. METHODS: The expression and topological distribution of cyclin D1, p53 and Ki-67 in 50 cases of HCC were examined immunohistochemically, and the relationship between the expression of these proteins and their pathologic features was investigated. RESULTS: Overexpression of cyclin D1 was noted in 58% of the HCC cases, and significantly associated with a well-differentiated histology and a low Ki-67 labeling index (LI). Cyclin D1 overexpression was also observed in all (7 of 7) dysplastic nodules and in non-neoplastic hepatocytes. On the other hand, aberrant p53 expression was detected in 36% of the cases, which showed positive relationships with poor differentiation, portal vein invasion, and KI-67 LI. Only eight of the 50 cases examined (16%) were positive for both cyclin D1 and p53, which showed only a small number of cyclin D1-positive cells. There was no significant relationship between the expressions of cyclin D1 and p53. CONCLUSIONS: Our results suggest that cyclin D1 overexpression may be an early event in hepatocarcinogenesis and that it plays a role in tumor differentiation. In addition, cyclin D1 expression is not correlated with tumor cell proliferation in HCCs.

Sequential changes in hepatocarcinogenesis induced by diethylnitrosamine plus thioacetamide in Fischer 344 rats: induction of gankyrin expression in liver fibrosis, pRB degradation in cirrhosis, and methylation of p16(INK4A) exon 1 in hepatocellular carcinoma.

To clarify the sequential changes in pRB and p16 during different stages of hepatocarcinogenesis such as fibrosis, cirrhosis, hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC), male Fischer 344 rats were singly injected with diethylnitrosamine (DEN), immediately followed with phenobarbital for 1 wk and then thioacetamide (TAA) for 39 wk in drinking water. Rats were killed at 9, 20, 30, and 40 wk after DEN initiation and changes of pRB level, p16 gene hypermethylation, and in vivo gankyrin expression were examined. Histologic examination showed stepwise appearances of fibrosis, cirrhosis, HCA, and HCC at weeks 9, 20, 30, and 40, respectively. Hypermethylation of p16 exon 1 was not found until HCA but appeared in 50% of the rats with HCC accompanied by complete loss of its mRNA expression. The amount of glutathione S-transferase--gankyrin bound to pRB and pRB degradation in the liver depended on the concentration of gankyrin and incubation time. Gankyrin expression preceded pRB degradation in liver cirrhosis. In conclusion, gankyrin expression induced in liver fibrosis accelerated the degradation of pRB during liver cirrhosis, and inactivation of p16 exon 1 by DNA hypermethylation occurred during the progression of tumor cells to poorly differentiated HCC. Inactivation of pRB and/or p16 resulted in complete loss of regulation in the cell-division cycle during early and late stages, respectively, of hepatocarcinogenesis. Mol. Carcinog. 30:138--150, 2001.

Protein kinase C activation by PMA rapidly induces apoptosis through caspase-3/CPP32 and serine protease(s) in a gastric cancer cell line.

Phorbol 12-myristate 13-acetate (PMA) rapidly induced cell death in SNU-16 gastric adenocarcinoma cells. DNA ladder formation and caspase-3/CPP32 activation were observed in PMA treated cells indicating that PMA induces apoptosis. z-DEVD-fmk, specific inhibitor of caspase-3/CPP32, inhibited the induction of apoptosis by PMA, demonstrating that caspase/CPP32 are critically involved in PMA-induced apoptosis. The serine protein inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride effectively blocked apoptosis, and also prevented caspase-3/CPP32 activation. Go6983, a specific inhibitor of PKC, almost completely suppressed apoptosis and caspase-3/CPP32 activation. Furthermore, 1,2-dihexanoyl-sn-glycerol, an endogenous activator of PKC, induced apoptosis detected by DNA fragmentation and Hoechst 33258 nuclear staining. From these results, we conclude that PMA is not only a tumor promoter, but can also induce apoptosis in gastric cancer cells. PMA-induced apoptosis appears to be mediated through activation of protein kinase C, and the activation of serine protease(s) and caspase-3/CPP32 may be the molecular mechanisms by which PMA induces apoptosis.

Expression of Fas and Fas-related molecules in human hepatocellular carcinoma.

Many tumor cells, including hepatocellular carcinoma (HCC), express both Fas and its ligand on their surfaces, and it has remained a mystery why such cells do not spontaneously become apoptotic. In the current study, we analyzed the alterations of Fas structure and the expression of Fas and Fas ligand (FasL) and of Fas pathway inhibitors, including soluble Fas (sFas), Fas-associated phosphatase-1 (FAP-1), and bcl-2, in 50 cases of human HCC. Monoallelic loss of the Fas gene, as determined by loss of heterozygosity with intragenic polymorphisms, was observed in 5 of the 34 informative cases (15%), but none of the 50 cases showed Fas gene mutation. Expression of Fas and FasL was detected in 44 (88%) and 50 (100%) cases, respectively. sFas messenger RNA, as analyzed by in situ reverse-transcription polymerase chain reaction was expressed in 42 of the 50 cases (84%), and FAP-1 expression was observed in 40 of the 50 cases (80%). In contrast, none of the 50 cases showed bcl-2 expression. Our results showed that the majority of the HCCs (88%) coexpressed a death receptor, Fas and its cognate ligand, FasL, but all HCCs showed one or more alterations of the Fas pathway molecules known to inhibit Fas-mediated apoptosis. These findings suggest that the expression of sFas and FAP-1 and, in part, loss of Fas expression, rather than Fas gene alteration or bcl-2 expression, may be involved in the Fas resistance of HCC in vivo and that these mechanisms may play important roles in the pathogenesis of human HCC. HUM PATHOL 32:250-256.

Nuclear localization of beta-catenin is an important prognostic factor in hepatoblastoma.

In this study, mutational and immunohistochemical analyses of beta-catenin were performed in 30 hepatoblastomas, to assess the prevalence of alterations of the Wnt pathway with respect to clinicopathological parameters and survival. Four missense mutations of beta-catenin (13.3%) were detected and there was strong immunoreactivity for beta-catenin in the cytoplasm and/or the nucleus in 97% of hepatoblastomas. Nuclear and cytoplasmic staining was demonstrated in 19 of 30 tumours (63%), while ten revealed only cytoplasmic staining. Statistically, this nuclear beta-catenin staining was significantly higher in the embryonal (Fisher exact test; p=0.00393) or undifferentiated type (p=0.00156) of hepatoblastoma than in the fetal type, but there was no difference between clinical stages I and II and clinical stages III and IV (p=0.175). Cumulative survival curves showed that nuclear beta-catenin staining (generalized Wilcoxon test; p=0.0088), undifferentiated histological type (p=0.0305), and clinical stages III and IV (p=0.0107) were significantly correlated with shorter survival time in these patients. Moreover, Cox multivariate analysis provides evidence that nuclear beta-catenin staining is the most important prognostic factor for survival (p=0.0090). It is therefore concluded that immunohistochemical analysis of beta-catenin might be a useful clinical tool for estimating the prognosis for patients with hepatoblastoma.

Interferon-alpha treatment of chronic hepatitis C in children with hemophilia.

BACKGROUND: In children with hemophilia, hepatitis C virus (HCV) is the major cause of chronic liver disease. In this study, long-term efficacy of interferon-alpha was studied to determine the factors that predict a sustained response to interferon therapy in young children with hemophilia who have chronic hepatitis C. METHODS: Seventeen Korean children with hemophilia and chronic hepatitis C were treated with 3.7 million units/m2 of interferon-alpha2a three times weekly for 6 months. Liver biopsy, pretreatment serum HCV RNA quantitation with competitive reverse transcription assay, and HCV genotyping with reverse hybridization assay were performed. RESULTS: Hepatitis C virus genotypes 1a, 1b, and 2a were found in three (18%), five (29%), and six (35%) patients, respectively. Interferon-alpha was well tolerated, and the frequency of bleeding did not increase. Of the 17 patients, 7 (41%) had a sustained response for 3 years after the end of therapy. Patients with a sustained response had lower pretreatment serum HCV RNA levels. One (13%) of eight patients with genotype 1 and five (83%) of six with genotype 2 had a sustained response (P < 0.05). CONCLUSIONS: Interferon-alpha treatment of chronic hepatitis C in children with hemophilia was safe and effective in producing sustained responses. The pretreatment serum HCV RNA level and viral genotype may be predictive factors for sustained response to interferon therapy.