Wei-Jao Chen

Long-term prognosis of patients with biliary atresia: a 25 year summary.

Objective: The purpose of this study was to delineate the long-term prognosis of biliary atresia (BA) in Taiwan. Study Design: From 1976 to 2000, 185 children were diagnosed with BA, 22 underwent exploratory laparotomy without Kasai operation, and 163 underwent Kasai operation, of which 141 cases had long-term follow-up and formed the basis of this study. The outcome was analyzed. Results: Among the 141 BA children studied who underwent Kasai operation, 115 (81.6%) had recoloration of stools, and 86 (61.0%) became jaundice-free (bilirubin <20 μmol/L). The resolution of jaundice and the absence of repeated cholangitis contributed to better outcome. Five and 10 year survival rates with native liver were 35% and 31%, respectively. Liver transplantation was performed in 19 patients (all but 2 with a living-related donor), and 15 (79%) survived. Five and 10 year overall survival rates for BA patients were 41.9% and 40.2%, respectively. Conclusions: The study delineated the long-term outcome of BA in an Asian country other than Japan. Survival with native liver after a Kasai operation in Taiwan was similar to that in the American and European series. Limited donors for liver transplantation in the years of the study accounted for the poor overall prognosis of BA patients in this series.

Free Radical Scavenging Activity of Fullerenol on the Ischemia-reperfusion Intestine in Dogs

Abstract. Fullerenol, a water-soluble C60-fullerene derivative, has been demonstrated to have the capability to scavenge free radicals in vitro and in vivo. The purpose of this study was to investigate whether fullerenol can scavenge the free radicals that are massively induced during ischemia-reperfusion (I/R) injury of the small intestine, either preventively or therapeutically. Clamping the superior mesenteric artery and vein for 60 minutes to induce I/R injury was performed on male mongrel dogs. Thirty dogs were divided into three groups (10 in each): The control (C) group received no medication; the preventive (P) group received fullerenol (1 mg/kg) intravenously 30 minutes before ischemia; the therapeutic (T) group received the same dose of fullerenol immediately after reperfusion. This study was an experimental randomized trial. Intestinal segments were obtained 10, 20, 30, and 60 minutes after reperfusion; and blood samples and specimens of major organs were taken 60 minutes after reperfusion. Concentrations of lipid peroxidation products, including conjugated diene (CD) and malondialdehyde (MDA), and the level of glutathione (GSH) in intestinal tissue were determined. Serum indicators of liver and renal function were measured. Histologic examination of the small intestine and major organs were also performed. A significant increase in intestinal MDA and CD contents was detected at 30 and 60 minutes after reperfusion. The tissue GSH content, in contrast, was decreased 60 minutes after reperfusion. Administration of fullerenol diminished these changes both preventively and therapeutically. Liver and renal functions were within normal limits in all groups. Moreover no obvious histopathologic additional damage could be found in either the P or the T group. It is suggested that fullerenol can be considered a powerful scavenger for the free radicals induced by I/R injury of the small intestine.

Cyr61Induces Gastric Cancer Cell Motility/Invasion via Activation of the Integrin/Nuclear Factor-KB/Cyclooxygenase-2 Signaling Pathway

Purpose: Cysteine-rich 61 (Cyr61/CCN1) is involved in many different types of tumor development and progression. Nonetheless, the role of Cyr61 in human gastric cancer has not yet been fully characterized. Experimental design: We addressed the issue by immunohistochemical staining of 81 gastric adenocarcinoma specimens. Liposome-mediated transfection was used to introduce a Cyr61 expression vector into gastric cancer AGS cell lines. Transfectants were tested in invasion assay by a Boyden chamber. Furthermore, a cyclooxygenase-2 (COX-2) reporter assay and gel mobility shift assay were done to investigate the potential signal pathway of Cyr61. Results: Patients with gastric adenocarcinoma whose tumor displayed high expression of Cyr61 correlated well with aggressive lymph node metastasis, more advanced tumor stage, histologic diffuse type, and early recurrence. Stable transfection of Cyr61 into the AGS cell line strongly enhanced its invasive activity. The overexpression of Cyr61 into AGS cells significantly increased the expression of COX-2 mRNA, protein, and enzymatic activity. Gel mobility shift assays further showed that the nuclear factor-κB (NF-κB) pathway was evidently activated in Cyr61-expressing AGS cells. Function-neutralizing antibody to αvβ3 but not αvβ5 effectively suppressed Cyr61-mediated NF-κB activation, COX-2 gene expression, and cell invasiveness. Conclusions: Cyr61 may contribute to the malignant progression of gastric cancer by promoting tumor cell motility/invasion through up-regulation of the functional COX-2 via an integrin αvβ3/NF-κB-dependent pathway.

Hepatocellular carcinoma in children: Clinical review and comparison with adult cases

BACKGROUND Hepatocellular carcinoma (HCC) in children was rarely reported and usually included with hepatoblastoma in most studies of pediatric liver malignancies despite different clinical behaviors. The authors report their experience in pediatric HCC and discuss its differences from adult HCC. METHODS A retrospective review of radiographic, laboratory, pathological, and therapeutic data in 55 children with HCC was performed. The liver function was graded by modified Childs classification. Kaplan-Meier survival curves in various therapeutic and Childs groups were plotted, and log-rank test was used to detect differences among survival curves. RESULTS Although children with HCC mostly presented with advanced disease at diagnosis, disturbances of liver function were unremarkable. Sixty-eight percent of cases concurred with liver cirrhosis. The median survivals for resectable, chemotherapeutic, and untreated HCCs were 23, 3, and 2 months, respectively. Resectable HCC significantly posed a much better prognosis. However, the resectability was unsatisfactory (18.2%). Resection was limited because of anatomic unfeasibility including bilateral involvement (62.5%), portal vein thrombi (41.7%), distant metastasis (29.1%), para-aortic lymphadenopathy (18.8%), inferior vena cava thrombi (16.7%), and hilar invasion (6.3%). Distant metastasis was the most ominous for survival in children with unresectable HCC. CONCLUSIONS HCC behaved somewhat differently between children and adults. Surgical resection represented the best hope of long-term survival. The outcome in children could not keep up with that in adults because of a diagnostic delay. Hence, alpha-fetoprotein and sonography screening in carrier children should be worthwhile.

Hepatocellular carcinoma in childhood. Clinical manifestations and prognosis

From December 1964 to November 1989, 71 children from 3 to 17 years of age with the eventual diagnosis of hepatocellular carcinoma (HCC) presented at the National Taiwan University Hospital (Taipei, Taiwan, Republic of China). Forty‐three of them had pathologic proof, whereas 28 were diagnosed on a clinical and laboratory basis. A male predominance (M:F = 3.2:1) was noticed. Most patients presented in a late, advanced stage. Abdominal pain and abdominal mass were the major symptoms and signs, followed by anorexia, fever, and internal bleeding. Hydrocele, purpura, and obstructive jaundice were rare presenting symptoms. Hepatosplenomegaly, superficial venous engorgement, and ascites were the main physical signs. The prognosis for such children with HCC was very poor. Only 10% of the patients survived longer than 1 year after the onset of the initial symptom. Among 49 patients who could be followed, only two had long‐term survival of over 5 years. One patient had a small HCC with internal bleeding, whereas the other had a large HCC with abdominal distention. Both received surgical resection, and a resection was repeated for tumor recurrence in the patient with the large mass. The resectability of these 71 patients was low (9.8%). Resectability and nonicterus seemed to be the factors indicating favorable prognosis. Observation indicated that the prognosis for children with symptomatic HCC is grave but surgical resection, whenever possible, should be carried out.

Effects of Fish Oil in Parenteral Nutrition

OBJECTIVE Fish oil is a rich source of omega-3 fatty acids (FAs), especially eicosapentaenoic acid and docosahexaenoic acid. The existing data suggest that eicosapentaenoic acid and docosahexaenoic acid are the active agents in fish oil. A number of clinical trials have shown that dietary fish oil supplementation has antiatherogenic properties and immunomodulation effects. Fish oils are not used widely in parenteral nutrition because fish oil emulsions have not been commercially available until very recently. Studies concerning the use of fish oil in parenteral route are rare. METHODS We reviewed the effect of parenteral fish oil infusion on lipid metabolism and immune response in normal and disease conditions. RESULTS Studies showed that the main effects of parenteral infusion of fish oil are: 1) incorporation of omega-3 FAs into cellular membranes of many cell populations that consequently influence the disease process of some disease conditions, 2) an effect on eicosanoid metabolism leading to a decrease in platelet aggregation and thrombosis, 3) amelioration of the severity of diet-induced hepatic steatosis, 4) less accumulation of lipid peroxidation products in liver tissue, and 5) immunomodulation effects and therapeutic benefits in animal disease models or various disease conditions of humans. Most of these studies suggested that parenteral infusion of omega-3 FAs have clinical beneficial effects comparable to those of dietary administration. However, different effects of omega-3 and omega-6 FAs in some situations has been reported. For example, plasma triacylglycerol levels were not lowered after fish oil infusion in normal or diabetic rats when compared with those of safflower oil or soybean oil infusion. The reason for the difference remain unclear. CONCLUSION The metabolic and immunologic effects of parenteral use of omega-3 FAs requires further evaluation, especially in some disease conditions.

GRP78 expression correlates with histologic differentiation and favorable prognosis in neuroblastic tumors

Glucose‐regulated protein 78 (GRP78), an endoplasmic reticulum protein, is essential for the differentiation of neuroblastoma cells and is selectively induced when the cells are undergoing apoptosis. These findings suggest that GRP78 may affect the tumor behavior of neuroblastoma. Our study evaluates the association of clinicopathologic factors and patient survival with the expression of GRP78 in patients with neuroblastoma. GRP78 expression in 68 neuroblastic tumors was investigated semiquantitatively by immunohistochemistry. GRP78 mRNA and protein levels in 7 tumor tissues were also quantified by real‐time PCR and Western blot respectively and correlated well with the immunohistochemical results. Forty (58.8%) of the 68 neuroblastic tumors showed positive GRP78 expression. The percentage of positive GRP78 immunostaining increased as the tumor histology became differentiated (p = 0.001). Furthermore, positive GRP78 expression strongly correlated with early clinical stages (P = 0.002) but inversely correlated with MYCN amplification (p = 0.001). Kaplan‐Meier analysis showed that patients with positive GRP78 expression did have better survival than those with negative expression (5‐year survival rate, 72.9% and 23.4% respectively, p < 0.001). Multivariate analysis further showed that GRP78 expression was an independent prognostic factor. Moreover, GRP78 expression predicted better survival in patients with either undifferentiated or differentiated histologies. GRP78 expression still had significant prognostic value when the analysis was restricted to tumors of advanced stages or without MYCN amplification. Thus, GRP78 can serve as a novel independent favorable prognostic factor for patients with neuroblastoma.

Congenital choledochal cyst: With observations on rupture of the cyst and intrahepatic ductal dilatation

Abstract Sixteen patients with choledochal cysts were encountered in 13 yr. In three the cyst had ruptured and in two there was intrahepatic ductal dilatation. Observations concerning diagnosis, surgical management, and the complications of treatment are made in detail.

Cysteine-Rich 61 (CCN1) Enhances Chemotactic Migration, Transendothelial Cell Migration, and Intravasation by Concomitantly Up-Regulating Chemokine Receptor 1 and 2

Cysteine-rich 61 (Cyr61; CCN1) plays an important role in tumor development and progression in many kinds of human malignancies. Here, we further show the enforced expression of the Cyr61 gene or treatment with recombinant Cyr61 protein enhanced expression of chemokine receptors CXCR1 and CXCR2 in gastric cancer AGS cells. Attenuation of Cyr61 levels in MKN-45 cells by transfecting with antisense Cyr61 significantly reduced the level of CXCR1 and CXCR2. It is suggested that Cyr61 tightly regulates the downstream genes CXCR1 and CXCR2 in gastric cancer cells. Supportively, reverse transcription–PCR and immunohistochemical analysis of human gastric adenocarcinoma showed that there was a high correlation between the expression level of Cyr61 and CXCR1/CXCR2. The up-regulated functionality of CXCR1 andCXCR2 in Cyr61-overexpressing AGS cells could facilitate their chemotactic migration toward interleukin-8, a physiologic ligand of CXCR1 and CXCR2. In addition, the Cyr61-mediated up-regulation of CXCR1/CXCR2 also contributed to transendothelial migration, as well as intravasation in a chick embryo model. Pharmacologic and genetic approaches revealed that phosphoinositide 3-kinase (PI3K)/Akt, but not extracellular signal-regulated kinase 1/2 or p38, signaling pathway is requisite for the up-regulation of CXCR1/CXCR2 mRNA and protein induced by Cyr61. Function-neutralizing antibody to integrin αvβ3, but not α2β1, effectively abolished Cyr61-elicited Src activation and the subsequent PI3K/Akt pathway. Antagonists toward integrin αvβ3, Src kinase, and PI3K/Akt not only suppressed CXCR1/CXCR2 elevation but also blocked chemotactic migration induced by Cyr61. In conclusion, we suggest that Cyr61 promotes interleukin-8–dependent chemotaxis, transendothelial migration, and intravasation by induction of CXCR1/CXCR2 through integrin αvβ3/Src/PI3K/Akt–dependent pathway. (Mol Cancer Res 2007;5(11):1111–23)

Effects of medium-chain and long-chain triacylglycerols in pediatric surgical patients

Medium-chain triacylglycerols (MCTs) have been shown to provide better nutritional support than long-chain triacylglycerols (LCTs). This study compares the efficacy of MCT combined with LCT with LCT alone in pediatric patients with surgical stress. Two groups of patients (n = 19 in each) received equivalent amounts of glucose (12 g. kg. d) and amino acids (2 g. kg. d), but one group received 10% Lipofundin MCT/LCT and the other received 10% LCT (1.5 g. kg. d) in a randomized study. Total parenteral nutrition (TPN) was given for 14 d. Blood and urine samples were collected before and after TPN administration for determination of various biochemical parameters. Indirect calorimetry was also performed to determine respiratory quotients and fuel utilization. After 14 d of TPN in the MCT/LCT group, there was a significantly higher blood lymphocyte percentage, a decreasing tendency of serum asparate aminotransferase and of total and direct bilirubin (P < 0.05). These changes were not observed in the LCT group. A significantly better nitrogen balance and a higher ketogenesis from day 3 were observed in the MCT/LCT group. The MCT/LCT group showed a more marked increased utilization of fat than the LCT group, whereas carbohydrate oxidation was less in the MCT/LCT group than in the LCT group (P < 0.05). In children after surgery, MCT/LCT is more protein sparing and induces a better immune response when compared with LCT-containing lipid emulsion. A TPN regimen containing MCT/LCT is likely to result in rapid oxidation of fats for energy without compromising the respiratory system.