Involvement of the nuclear factor-κB signaling pathway in the regulation of CXC chemokine receptor-4 expression in neuroblastoma cells induced by tumor necrosis factor-α.

Metastasis is a hallmark of malignant neuroblastoma and is the main reason for therapeutic failure and recurrence of the tumor. The CXC chemokine receptor-4 (CXCR4), a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1α (SDF-1α), is expressed in various types of tumor. This receptor mediates the homing of tumor cells to specific organs that express the ligand, CXCL12, for this receptor and plays an important role in tumor growth, invasion, metastasis and angiogenesis. In the present study, the inflammatory cytokine, tumor necrosis factor­α (TNF­α) upregulated CXCR4 expression in neuroblastoma cells and increased migration to the CXCR4 ligand SDF­1α. In addition, this effect was dependent upon NF-κB transcriptional activity, as blocking the NF-κB pathway with pyrrolidinedithiocarbamic acid ammonium salt suppressed TNF-α­induced upregulation of CXCR4 expression and reduced the migration towards the CXCR4 ligand, SDF-1α. Treating neuroblastoma cells with TNF-α resulted in the activation of nuclear factor-kappa B (NF-κB) and subsequently, the translocation of NF-κB from the cytoplasm to the nucleus. Using immunohistochemistry, NF­κB and CXCR4 were significantly correlated with each other (P=0.0052, Fisher's exact test) in a cohort of neuroblastoma samples (n=80). The present study indicates that the inflammatory cytokine, TNF-α, partially functions through the NF­κB signaling pathway to upregulate CXCR4 expression to foster neuroblastoma cell metastasis. These findings indicate that effective inhibition of neuroblastoma metastasis should be directed against the inflammatory cytokine-induced NF­κB/CXCR4/SDF­1α signaling pathway.

Expression of the reversion-inducing cysteine-rich protein with Kazal motifs and matrix metalloproteinase-14 in neuroblastoma and the role in tumour metastasis.

Neuroblastoma is the most common malignant tumour in infancy; the reversion-inducing cysteine-rich protein with Kazal motifs gene (RECK) is a tumour suppressor gene. Previous studies show that RECK inhibits tumour invasion and metastasis through negative regulation of the matrix metalloproteinase (MMP)-2, MMP-9 and MMP-14. Therefore, we wanted to detect the expression of RECK and MMP-14 in neuroblastomas to assess the correlation between the expression levels of these proteins, and to investigate the roles in the metastasis and development of the tumour. PV-6000 immunohistochemistry method was used to detect the expression levels of RECK and MMP-14 in 36 samples of neuroblastoma tissue. Samples from paraffin wax-embedded specimens and the complete clinicopathological data of 36 neuroblastoma and 10 ganglioneuroma patients were collected. The rate of expression of the RECK protein in the neuroblastoma was low (16.7%). Furthermore, it reduced with the increase in the invasive depth and distant metastasis (P = 0.015; P < 0.05). The rate of expression of the MMP-14 protein in the neuroblastoma was high (58.3%) and increased with the increase in the extent of invasive depth and distant metastasis (P = 0.002; P < 0.05). The expression of the RECK protein correlated negatively with that of MMP-14 (r = -0.418; P < 0.05). Low levels of the RECK protein are expressed in the neuroblastoma, while the MMP-14 protein is expressed at high levels. The RECK and MMP-14 proteins may serve as markers in the estimation of the extent of metastasis and dissemination of the neuroblastoma.

Surgical management of giant liver tumor involving the hepatic hilum of children.

BACKGROUND: Surgical management of giant liver tumors involving the hepatic hilum tends to be very difficult. The present study assessed the feasibility and safety of resection of such liver tumors. METHODS: We evaluated 27 patients with liver tumors involving the hepatic hilum. The patients ranged in age from 3 months to 14 years (mean, 4.2 years). Of the 27 cases, 23 were resected completely during the past 10 years. The other four cases did not undergo operation because of their parents' decisions to discontinue treatment; these cases had multiple space-occupying lesions in addition to tumors involving the hepatic hilum. Before resection, the tumor was fully exposed and an occluding tape was placed around the vena cava when necessary. RESULTS: The hepatectomies were performed under intermittent portal triad clamping; 23 cases were successfully resected without postoperative mortality or morbidity. The mean operation duration was 205 min and mean blood loss was 120 ml. Pathological diagnoses included hepatoblastoma (n = 9), endotheliosarcoma (n = 1), mesenchymal hamartoma (n = 4), teratoma (n = 1), adenoma (n = 3), and hepatocellular carcinoma (n = 4). The nine cases with benign liver tumors were healthy at follow-up at 11 months to 9 years after operation. Of the 14 cases with malignant tumors, six died from recurrence, metastasis, or other complications. The other eight cases were still alive without clinical tumors. CONCLUSIONS: Resecting giant liver tumors involving the main hepatic veins and/or the retrohepatic vena cava, although challenging, is feasible and safe.

Clinical applications of computerized tomography 3-D reconstruction imaging for diagnosis and surgery in children with large liver tumors or tumors at the hepatic hilum.

The present study assessed the benefits of 3-D reconstruction of spiral computerized tomography (CT) scans for the diagnosis of and surgical guidance to large liver tumors or tumors at the hepatic hilum. We retrospectively analyzed the cases of 18 children with large liver tumors or with tumors at the hepatic hilum treated in past 5 years. The ages ranged from 45 days to 14 years. Ten cases were examined using the three-dimensional reconstruction using 64 slice spiral CT and eight patients underwent conventional CT or conventional enhanced CT scanning. In 16 cases, the volume of tissue removed exceeded one-third the entire volume of the liver (considered "large" tumors). The largest tumor removed weighed 4.8 kg. In two cases, the excised tissue represented less than one-third of the total liver volume, but in these cases the location of the tumor was considered "complex" due to the proximity to major hepatic vessels. Seven tumors were located in the right lobe, three in the left lateral segment, three in medial segment, three extended beyond the right lobe and two extended beyond the left lateral segment. Pathological diagnoses included hepatoblastoma (n = 9), hepatocellular carcinoma (n = 2), mesenchymal hamartoma (n = 4), teratoma (n = 1) and adenoma (n = 2). The 3-D reconstructed images could be rotated to view the image from several sides, were semitransparent and allowed for the measurement of tumor size and determination of spatial relation to blood vessels. All 18 children had curative resections as indicated by "tumor-free" microscopic margins. No major intra- or postoperative complications were encountered. Three-dimensional CT imaging can provide high quality images of the tumors and location of the tumor relative to vital hepatic blood vessels. This technique offers a kind of comparatively accurate method compared with traditional imaging techniques, it could help the surgeon identify the tumor borders accurately and devise a comparative safe surgical strategy. With its help the surgeon could identify vital hepatic blood vessels before operation, so they can avoid massive hemorrhaging and avoid massive hemorrhaging during operation. This technique should be more widely applied in the resection of large or complex liver tumors.

Management strategy for congenital choledochal cyst with co-existing intrahepatic dilation and aberrant bile duct as well as other complicated biliary anomalies.

The purpose of this study was to investigate and discuss imaging methods and management strategies for congenital choledochal cyst with co-existing intrahepatic dilation and aberrant bile duct as well as other complicated biliary anomalies. In this study we reviewed and analyzed 72 patients with congenital choledochal cyst, ranging in age from 15 days to 12 years old and who were seen at our hospital during the past 12 years, from January 1993 to October 2005. The image manifestation and clinical significance of patients with co- existing intrahepatic biliary dilation and aberrant bile duct were carefully examined during operation via MRCP, cholangiography and choledochoscope. Twenty-two cases (30.1%) presented with intrahepatic bile duct dilation and 12 of these were of the cystic type. That is, the orifice of the dilated intrahepatic tract that converged into the common hepatic duct showed membrane or septum-like stenosis. In 10 cases the dilation tapered off from the porta hepatis to the initiating terminals of the intra-hepatic bile ducts and was not accompanied by stenosis. An aberrant bile duct was observed in 2 of the cases. In 3 cases, the right and left hepatic ducts converged at the choledochal cyst. In conclusion, the imaging methods for intrahepatic bile duct dilation possess important clinical significance. Further, for hepatojejunostomy with radical excision of a choledochal cyst, additional operative procedures for intrahepatic stenosis, possible bile duct malformation and pancreaticobiliary common duct calculi can potentially reduce postoperative complications.

[Correlation between expression of MMP-2, MMP-9, TIMP-2, TIMP-1 and metastasis of neuroblastoma].

OBJECTIVE: To study MMP-2, MMP-9, TIMP-2 and TIMP-1 expression, and their association to invasion and metastasis of neuroblastoma (NB). METHODS: The staining status was compared of MMP-2, MMP-9, TIMP-2 and TIMP-1 in cryostat sections of tumor tissue in 35 NB patients by immunohistochemistry. RESULTS: Strong expression of MMP-2 was detected only in 2 patients with early stage NB (group A without metastasis), but in 9 and 10 respectively with advanced stage NB (group B with local metastasis and group C with distant metastasis) (compared to group A, P < 0.01). Strong MMP-9 staining was found in 4, 8 and 11 patients for group A, B and C patients (group A vs group C, P < 0.05). The expression of TIMP-2 was the strongest in 4 group A patients, but it decreased with progression of the disease. There was no statistical difference in TIMP-1 expression among the three groups of patients. CONCLUSION: MMP-2, MMP-9 expression may be related to metastasis and progression of neuroblastoma, while TIMP-2 may have an inhibitory effect.