[Perioperative management of two patients with renal malignant tumor involving the vena cava].

Two patients underwent resection of renal malignant tumors involving vena cava. Such tumors occasionally extend to the inferior vena cava with tumor thrombus and invasion to the lymph nodes and adjacent organs. Perioperative management of patients with these tumors is difficult because of the risk of pulmonary embolism and massive bleeding, and requires appropriate cooperation among the surgical team. In case 1, a 56-year-old man, renal cell carcinoma with tumor thrombus had extended into the intrahepatic vena cava. It was resected after isolating the liver from vena cava and incising the cross-clamped inferior vena cava without extracorporeal circulation or blood transfusion. A prosthetic graft replaced the inferior vena cava. In case 2, a 64-year-old woman, renal pelvis cancer adhered to the inferior vena cava and the mesentery with enlarged lymph nodes. It was separated from the inferior vena cava and removed with the ascending colon. The patient received a blood transfusion of approximately 2,000ml. Cardiomyopathy associated with a left ventricular outflow tract pressure gradient of 100mmHg required perioperative management. After surgery, both patients underwent controlled ventilation in the intensive care unit. After recovery, they were discharged without complications. We discuss perioperative management, with regard to the level of the tumor extension and perioperative complications.

Transcriptional factor Prox1 plays an essential role in the antiproliferative action of interferon-γ in esophageal cancer cells.

BACKGROUND: We previously reported interferon-γ (IFN-γ)-induced apoptosis in 10 (32%) of 31 esophageal squamous cell carcinoma (ESCC) cell lines. However, the molecular basis of antiproliferative action by IFN-γ remains elusive. Here we demonstrate that IFN-γ induces transcriptional factor Prox1, and we explore the link between Prox1 and the IFN-γ system in ESCC cells. METHODS: By using ESCC cell lines, we investigated the relationship between p53 mutations and the responsibility to IFN-γ, and studied the role of Prox1 in the antiproliferative effect of IFN-γ by knockdown and overexpression methods. RESULTS: p53 mutations were found in seven of nine ESCC cell lines responsible for IFN-γ. The frequency was not different from that of p53 mutations in total ESCC cell lines (21 of 28 cell lines). Treatment of ESCC cells with IFN-ß but not IFN-γ resulted in increase of p53 messenger RNA (mRNA) expression, whereas IFN-γ but not IFN-ß induced cell growth inhibition of ESCCs harboring p53 mutations. IFN-γ induced Prox1 expression in ESCC cells but not in those transfected with dominant-negative STAT1. Cell growth inhibition by IFN-γ was significantly suppressed in ESCC cells transfected with Prox1 short interfering RNA (siRNA). In addition, overexpression of Prox1 induced antiproliferative effect in ESCC cells. We also demonstrate that Prox1 is expressed in primary esophageal cancer tissues (five of nine samples treated with neoadjuvant chemotherapy before surgery). CONCLUSIONS: Prox1 mediates the antiproliferative effect by IFN-γ in ESCC cells. Prox1 may be a candidate target for novel therapeutic strategies of ESCCs.

Clinicopathological significance of aminopeptidase N/CD13 expression in human gastric carcinoma.

BACKGROUND/AIMS: Aminopeptidase N (APN)/CD13 is a transmembrane ectoenzyme occurring in a wide variety of cells. Recently, APN/CD13 has been reported to be involved in tumor invasion and metastasis. However, precise functions in tumor cells, and its role in gastric carcinoma remain unclear. METHODOLOGY: To evaluate the role of APN/CD13 in gastric carcinoma, we conducted immunohistochemical staining for APN/CD13 in 121 gastric carcinoma specimens, using anti-APN monoclonal antibody. The relationship between APN/CD13 expression and various prognostic factors of gastric carcinoma were investigated. RESULTS: Of the 121 patients with gastric carcinoma studied, 48 were strongly positive, 36 were weakly positive, and 37 were negative. Overall survival rate of the patients with negative APN/CD13 expression was significantly lower than that of the patients with positive APN/CD13 expression. APN/CD13 expression was negatively associated with lymph node metastasis. Multivariate analysis showed APN/CD13 expression to be a significant prognostic factor. CONCLUSIONS: Decreased expression of APN/CD13 was associated with a poor prognosis. Hence, our results demonstrate that the immunohistochemical detection of APN/CD13 could provide useful information as one of the prognostic factors in gastric cancer.

STAT1 activation-induced apoptosis of esophageal squamous cell carcinoma cells in vivo.

BACKGROUND: The induction of apoptosis might be a promising treatment for cancers refractory to conventional therapies, such as esophageal cancer. In this study, we examined whether epidermal growth factor-induced growth inhibition results from apoptosis of esophageal squamous cell carcinoma (SCC) cells as a result of STAT1 activation and evaluated whether interferon gamma (IFN-gamma) can induce apoptosis of cancer cells in vivo. METHODS: To assess the function of STAT1, we established stable transfectants expressing dominant-negative STAT1. Apoptosis was assessed by several experimental techniques, including flow cytometry. Differentiation was evaluated by Western blot test with involucrin used as a marker. In vivo, cancer cells were injected into male BALB/c nu/nu mice. Two weeks later, the mice started to receive injections of IFN-gamma or saline into a tail vein four times per week. Concentrations of IFN-gamma in the tumors were analyzed by enzyme-linked immunosorbent assay. Apoptosis was evaluated by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining. RESULTS: Epidermal growth factor inhibited the growth of esophageal SCC cells by causing apoptosis through several pathways involving STAT1 activation. IFN-gamma induced the apoptosis of cancer cells, but it also promoted the differentiation (not apoptosis) of primary cultured cells derived from normal esophageal epithelium. IFN-gamma also inhibited the growth of xenograft tumors of esophageal SCC cells in vivo. CONCLUSIONS: Our results suggest that IFN-gamma is one candidate for cytokine-based therapy of cancer. IFN-gamma-induced STAT1 activation might be involved in the apoptosis of esophageal SCC cells and in the terminal differentiation of normal squamous cells. Further studies of STAT1 signaling pathways may provide the basis for new targeted therapeutic strategies for esophageal SCC.

Chenodeoxycholic acid stimulates the progression of human esophageal cancer cells: A possible mechanism of angiogenesis in patients with esophageal cancer.

Bile acids are known to promote the growth of gastrointestinal cancer. However, the underlying mechanism remains unclear. We examined whether bile acids induce tumor growth via the cyclooxygenase (COX)-2 angiogenic pathway. In vitro, esophageal squamous cell carcinoma (ESCC) cells and esophageal adenocarcinoma cells were studied. Production of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) in response to treatment with chenodeoxycholic acid (CDCA) was assessed by enzyme-linked immunosorbent assay (ELISA). COX-2 protein and VEGF protein were measured by immunoblot analysis, and COX-2 activity was measured by ELISA. In vivo, CDCA was administered to ESCC cell-bearing mice. Tumor tissues were analyzed immunohistochemically, and microvessel density was evaluated. Clinically, 134 patients with ESCC who underwent esophagectomy were studied. In vitro, CDCA induced the production of PGE2 and VEGF in dose- and time-dependent manners, and these effects were attenuated by a selective COX-2 inhibitor, mitogen-activated protein kinases inhibitor, or epidermal growth factor receptor inhibitor. CDCA-induced COX-2 in the cell lysate increased the secretion of VEGF into the culture medium. In vivo, CDCA markedly enhanced tumor growth and increased vascularization. Clinically, patients whose tumors expressed both COX-2 and VEGF had poor outcomes. Our results suggest that bile acids, important constituents of duodenal fluid, stimulate the development of human esophageal cancer by promoting angiogenesis via the COX-2 pathway.

Nicotine induces the fragile histidine triad methylation in human esophageal squamous epithelial cells.

The fragile histidine triad (FHIT) gene has been proposed to have an important role in very early carcinogenesis. Methylation of the FHIT gene is associated with transcriptional inactivation in esophageal squamous cell carcinoma, and FHIT inactivation has been linked to smoking-related carcinogenesis. In this study, we confirmed methylation of the FHIT gene in human esophageal squamous epithelial cells (HEECs) and examined whether nicotine induced alteration of FHIT. Methylation status in the promoter region of the FHIT gene and p16(INK4A) gene was determined by methylation-specific PCR in HEECs exposed to nicotine under various conditions. Methylation status of the FHIT gene was confirmed by DNA-sequencing analysis. Protein expression of Fhit and the DNA methyltransferases (DNMTs) DNMT1 and DNMT3a were assessed by immunoblot analysis. In the absence of nicotine, methylation of the FHIT gene and attenuation of Fhit protein were not detected in HEECs. Nicotine induced the methylation of FHIT gene and attenuated Fhit protein in association with increased expression of DNMT3a. Reexpression of Fhit protein in HEECs was found after cessation of moderate- to long-term exposure to nicotine. Our results show that nicotine induces methylation of the FHIT gene followed by loss of Fhit protein expression in HEECs. Continuous smoking may thus increase the risk of esophageal cancer.

A new specific gene expression in squamous cell carcinoma of the esophagus detected using representational difference analysis and cDNA microarray.

OBJECTIVES: To detect new specific gene expressions in squamous cell carcinoma of the esophagus. METHODS: Representational difference analysis of cDNA (cDNA RDA) was applied to a human esophageal cancer cell line (KYSE170) and a human esophageal epithelial cell line (HEEC-1). RESULTS: LAGE-1 was expressed specifically in KYSE170, but not in HEEC-1. It is also expressed in 27% of esophageal cancer cell lines (3/11) and 33% of esophageal cancer tissues (10/30), but not in other HEECs, normal esophageal epithelium, or other normal tissues except testis, ovary and kidney. The expression of LAGE-1 is strongly correlated with that of MAGE-A1 (p = 0.013, Fisher's exact probability test). Fibronectin, cytokeratin 6B, cytokeratin 19, cyclin D2 and Ten-m2 were detected as candidates for downregulated genes. Reduced expression profiles of them were also identified using cDNA microarrays. The expression of LAGE-1 was induced by 5'-aza-2'-deoxycytidine (5Aza-dC) and trichostatin A (TSA) in esophageal cancer cell lines, which did not express LAGE-1. In HEECs, 5Aza-dC induced LAGE-1 expression, but TSA did not. CONCLUSIONS: LAGE-1 expression was detected in esophageal cancer by cDNA RDA. LAGE-1 might have the potential to be a target antigen for anti-tumoral immunotherapy in esophageal cancers because of its tumor-specific expression similar to that of MAGE-A1.

A strategy for determining which thoracic esophageal cancer patients should undergo cervical lymph node dissection.

BACKGROUND: There is controversy about performing cervical lymph node dissections in all middle and lower thoracic esophageal squamous cell carcinoma patients. The purpose of this study was to evaluate whether intraoperative examination of thoracic paratracheal lymph node by real-time reverse transcription-polymerase chain reaction was worthwhile for selecting patients for cervical lymph node dissection. METHODS: Under informed consent, 30 middle and lower thoracic esophageal squamous cell carcinoma patients were examined for thoracic paratracheal lymph node metastasis intraoperatively by hematoxylin-eosin staining and real-time reverse transcription-polymerase chain reaction for messenger RNA encoding squamous cell carcinoma antigen. When thoracic paratracheal lymph node metastasis was found, cervical lymph node dissection was performed. If the patients had no thoracic paratracheal lymph node metastasis, a randomized study for selection of cervical lymph node dissection was performed. RESULTS: Eleven of 30 patients with middle or lower third thoracic esophageal squamous cell carcinoma had thoracic paratracheal lymph node metastasis. Five of these 11 patients had cervical lymph node metastasis. Nineteen patients who had no metastasis in the thoracic paratracheal lymph nodes were enrolled in a randomized study. Eight of the 19 patients received cervical lymph node dissection and they were found not to have cervical lymph node metastasis. The other 11 patients did not receive cervical lymph node dissection, and there was no cervical lymph node recurrence. CONCLUSIONS: The intraoperative diagnosis of metastasis in the thoracic paratracheal lymph node may be used as an indicator for cervical lymph node dissection in middle and lower thoracic esophageal cancer patients.

Production of prostaglandinE2 via bile acid is enhanced by trypsin and acid in normal human esophageal epithelial cells.

Several reports suggest that duodenogastroesophageal reflux may produce esophagitis, Barrett's esophagus and esophageal carcinoma. And it is well known that the incidence of adenocarcinoma arising from Barrett's esophagus has been increasing during the past decade. On the other hand, cyclooxygenase-2 and prostaglandins, produced by the catalytic reaction of cyclooxygenase-2, are considered to relate to carcinogenesis of the digestive tract and other malignant tumors. Recent reports suggest that cyclooxygenase-2 is induced in Barrett's esophagus and esophageal carcinoma. The purpose of this study is to investigate the reaction of cyclooxygenase-2 expression and prostaglandinE2 production on normal human esophageal epithelial cells cultured with gastroduodenal components. Normal human esophageal epithelial cells were cultured with chenodeoxycholic acid, trypsin and in acidic condition, individually and with different combinations of these three factors. After culturing, cyclooxygenase-2 expression in the cells and amount of prostglandinE2 in culture media was evaluated by immunoblotting and enzyme-immunoassay, respectively after culturing the cells. Cyclooxygenase-2 expression was up-regulated by bile acid and prostaglandinE2 production was enhanced by bile acid with trypsin, acidic condition or both of these components, without a synergistic effect on cyclooxygenase-2 expression. Production of prostaglandinE2 via these factors was suppressed by the cyclooxygenase-2 selective inhibitor JTE-522. The results suggest that duodenogastroesophageal reflux may induce cyclooxygenase-2 expression and prostaglandinE2 production in esophageal epithelial cells, cyclooxygenase-2 specific inhibitors may have a chemopreventive effect on esophageal carcinoma.

Involvement of TSLC1 in progression of esophageal squamous cell carcinoma.

Frequent allelic losses of 11q23 in esophageal squamous cell carcinoma (ESCC) have been reported previously, but no tumor suppressor genes in this region have been identified in ESCC. TSLC1 was identified on chromosome 11q23.2 as a tumor suppressor gene in non-small cell lung cancer by functional complementation of a lung adenocarcinoma cell line. The purpose of this study is to evaluate the role of TSLC1 in ESCC. Loss of TSLC1 expression was observed by reverse transcription-PCR in 75% of the cell lines (27 of 36) and 50% of the primary tumors from ESCC patients (28 of 56). In a clinicopathological analysis, loss of TSLC1 expression correlated significantly with depth of invasion (pT) and status of metastasis (pM; P = 0.012 and 0.036, respectively). Patients with tumors lacking TSLC1 expression tended to have a poorer prognosis than those with tumors expressing TSLC1. (P = 0.079). Moreover, TSLC1 expression was an independent prognostic factor in a multivariate analysis (P = 0.049). Methylation analyses revealed that TSLC1 expression or loss correlated with the promoter methylation status, as determined by bisulfite sequencing, and that TSLC1 expression could be restored by a demethylating agent in certain cell lines. The growth of TSLC1-transfected ESCC cells was significantly suppressed both in vitro and in vivo (P < 0.01), possibly by a G(1) cell cycle arrest. TSLC1 expression also suppressed motility and invasion of ESCC cells in vitro significantly (P < 0.01). These findings suggest that loss of TSLC1 expression has an important role in tumor growth, cell motility, and invasion and is associated with aggressive tumor behavior in ESCC.

Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma.

PURPOSE: CC chemokine receptor 7 (CCR7) plays a critical role in the migration of activated dendritic cells to regional lymph nodes. Recent studies have shown that CCR7 is involved in metastasis in some malignant diseases. The role of CCR7 in esophageal squamous cell carcinoma (SCC) has not yet been clarified. EXPERIMENTAL DESIGN: We performed reverse transcription-PCR analysis for CCR7 in 20 esophageal SCC cell lines and immunohistochemical analysis of 96 esophageal SCC samples. We then performed a cell migration assay, F-actin polymerization, and a phagokinetic assay on esophageal SCC cell lines in the presence of CCL21, a ligand of CCR7. RESULTS: CCR7 mRNA was detected in 9 of 20 esophageal SCC cell lines. Immunoreactive CCR7 was found mainly in esophageal cancer cells. High CCR7 expression was significantly correlated with esophageal SCC lymphatic permeation, lymph node metastasis, tumor depth, and tumor-node-metastasis stage and was associated with poor survival. In vitro studies demonstrated that CCL21 significantly increased the cell migration ability of esophageal SCC cell lines, and pseudopodia formation was induced by CCL21 stimulation. Furthermore, CCL21 markedly enhanced the motility of esophageal carcinoma cell lines by the phagokinetic assay. CONCLUSIONS: The results suggested that the CCR7/CCL21 receptor ligand system may play a role in the lymph node metastasis of esophageal SCC.

Promotion effects of hot water on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats.

This study is to determine the effects of hot water on N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis model. F344 rats received one treatment of hot water 1 ml/kg and NMBA 1 mg/kg, or a combination treatment of NMBA 1 mg/kg pus hot water 1 ml/kg, or/and EGCG (epigallocatechin-3-gallate) 10 mg/kg. The experiment was concluded at the 20th week. Our results showed that the number of tumors and incidence of carcinomas were significantly increased by hot water (65 degrees C) (p<0.05, p<0.03, respectively), as compared with the group which received NMBA injections only. EGCG treatment did not significantly reduce the number or the size of tumours as the temperature of added hot water increased. In addition, PGE2 production was induced by NMBA, and further significantly increased by added hot water (p<0.05). On the other hand, EGCG slightly decreased the elevated PGE2 production, however, this effect of EGCG was offset by hot water. Our study further confirmed that the drinking of hot beverages increased the risk of esophageal carcinogenesis, and the drinking hot tea will abolish the inhibitory effects of EGCG on this disease.

Cell culture in esophageal squamous cell carcinoma and the association with molecular markers.

PURPOSE: We reported previously that the patients in whom cancer cells could be cultured as continuous cell lines had a poor prognosis of esophageal squamous cell carcinoma (ESCC) patients. In this study, to evaluate additional evidence of prognostic significance and the genetic background of cell culture, we analyzed 203 ESCC patients. EXPERIMENTAL DESIGN: Culture samples were obtained from resected 203 primary ESCC (from 1986 to 1998; R0 resection). The expression of six molecular markers was evaluated retrospectively in resected primary esophageal tumors by immunohistochemical analysis, and the capability of establishing cell lines was compared. RESULTS: Thirty-five cell lines (17.2%) were established from 203 ESCC patients: group 1 (n = 35), from whom cancer cells could be cultured as continuous cell lines, and group 2 (n = 168), from whom cell lines could not be established. The cumulative survival rate of patients in group 1 was significantly lower than that of those in group 2 (P = 0.0006). Cox's proportional hazard model revealed that cell culture capability was an independent prognostic factor (risk ratio, 1.98; P = 0.007). Univariate logistic regression analysis revealed that cell culture capability had associations with the following molecular biological factors: cyclin D1, p53, murine double minute 2, p27, and fragile histidine triad gene (P < 0.05). However, multivariate logistic regression analysis revealed that p53 protein accumulation and MDM2 protein expression predict establishment of cell line in ESCC (odds ratio, 7.72 and 8.62, respectively). CONCLUSIONS: Cell culture capability is a significant prognostic factor in ESCC. p53 and MDM2 may have a crucial role in the establishment of ESCC cell lines.

Validation of intra-operative detection of paratracheal lymph node metastasis using real-time RT-PCR targeting esophageal squamous cell carcinoma.

BACKGROUND: We previously reported that there was a significant correlation between paratracheal lymph node (LN) metastasis and cervical LN metastasis in thoracic esophageal squamous cell carcinoma (ESCC) patients. The purpose of this study was to establish an intra-operative detection method of LN micrometastasis (MM) of ESCC using hematoxylin-eosin (HE) staining, immunohistochemistry (IHC) and real-time RT-PCR with a Light Cycler technique, and to evaluate which method, or combination of methods, is most suitable for intra-operative detection of paratracheal LN MM. METHODS: Under informed consent, we obtained 33 dissected paratracheal LN samples from 22 operative patients with ESCC. Afterwards, one LN was separated into three parts by a sharp razor, and each part was checked for metastasis by HE staining, IHC with anti-cytokeratin antibody and real-time RT-PCR for SCC mRNA with a Light Cycler. RESULTS: It took 3 h for detection by real-time RT-PCR, while it took 2 h by IHC. The detection rates of MM by HE staining, IHC and real-time RT-PCR were 50.0, 33.3 and 83.3%, respectively. However, there was a case of false negative detection that was not detected by IHC or PCR. CONCLUSION: The real-time RT-PCR method was useful for intra-operative detection of paratracheal LN metastasis. However, combination analysis of HE staining, IHC and real-time RT-PCR may be desirable because there was a case of false negative detection by IHC and real-time RT-PCR.

Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats.

The present study was conducted to assess the inhibitory effects of EGCG (epigallocatechin-3-gallate) on NMBA-induced rat esophageal tumorigenesis and to seek the potential mechanisms. In experiment I, 81 F344 rats were randomly divided into seven experimental groups according to the different regiments of NMBA 1 mg/kg subcutaneously (s.c.) and EGCG 4 mg/kg or 10 mg/kg orally or intraperitoneally (i.p.). The experiment was terminated at 24 weeks. In experiment II, 48 rats were allocated into two groups, each group contained 24 rats, in which the rats were injected with NMBA 1 mg/kg only or a combination of NMBA 1 mg/kg and EGCG 4 mg/kg i.p. Six rats from each group were sacrificed at the 12th, 16th, 20th and 24th week, respectively. The expression of cyclin D1 and cyclooxygenases (COX-2 and COX-1) was detected using semi-quantitative RT-PCR, and the production of prostaglandin E2 (PGE2) was measured by ELISA. In the groups which were treated with EGCG at a dose of 4 mg/kg i.p., or 10 mg/kg both orally and i.p., the mean number of tumors per rat was significantly reduced to 48, 56 and 61%, respectively (p<0.05). The incidence rate of esophageal carcinomas in the rats that were treated with EGCG 4 mg/kg i.p., was significantly lower than that in the rats which only received NMBA 1 mg/kg (p<0.05). The expression of cyclin D1 and COX-2, and the levels of PGE2 were also decreased by EGCG treatment. These results indicated that EGCG significantly inhibits the NMBA-induced rat esophageal carcinogenesis and it inhibitory effects may partly target cyclin D1 and COX-2 expression, and PGE2 production.

Clinicopathological significance of human macrophage metalloelastase expression in esophageal squamous cell carcinoma.

OBJECTIVE: Human macrophage metalloelastase is referred to as matrix metalloproteinase (MMP-12), its function in tumors is contradictory. The current study was undertaken to investigate the role of MMP-12 in esophageal squamous cell carcinoma (SCC). PATIENTS AND METHODS: We analyzed the levels of MMP-12 mRNA expression in 67 patients with primary esophageal SCC by Northern blot analysis and the tissues were subjected to in situ hybridization analysis for MMP-12. Immunohistochemical staining was performed to detect the macrophages infiltrated in esophageal SCCs. RESULTS: MMP-12 mRNA was detected in 27 of 67 esophageal SCC samples by Northern blot analysis. In situ hybridization and immunohistochemical staining revealed that MMP-12 mRNA signals are located mainly in tumor cells. The frequency of lymph node metastasis was significantly higher in the MMP-12-positive (MMP-12(+)) subgroup than MMP-12-negative (MMP-12(-)) subgroup (p < 0.05); furthermore, invasion was significantly deeper in the MMP- 12(+) subgroup than in the MMP-12(-) subgroup (p < 0.01). MMP-12 mRNA was inversely correlated with prognosis (p < 0.05). However, Cox multivariate analysis revealed that upregulation of MMP-12 was not related to prognosis. CONCLUSIONS: MMP-12 gene expression was associated with the progression of esophageal SCC; however, it was not an independent prognostic factor.

Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural product occurring in grapes and various other plants with medicinal properties associated with reduced cardiovascular disease and reduced cancer risk. To evaluate the possibility and potential mechanism(s) of which resveratrol inhibits N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis, 96 F344 male rats were divided into 10 groups and resveratrol (1 and 2 mg/kg) was administered orally or intraperitoneally (i.p.). In the groups in which resveratrol was administered at 2 mg/kg (orally, for 16 weeks), 1 and 2 mg/kg (i.p., for 16 weeks) and 1 mg/kg (i.p., for 20 weeks), the number of NMBA-induced esophageal tumors per rat was significantly reduced to 78, 62, 54 and 48, respectively (P < 0.05), and the size of maximum tumors in each group with resveratrol treatment was also significantly smaller than that in NMBA alone group (P < 0.05). Although the pathological examination did not indicate significantly decreased incidence of carcinomas by administering resveratrol, the tendency of carcinogensis suppression was observed (P = 0.177). Semi-quantitative RT-PCR and ELISA analysis demonstrated that following NMBA treatment, the expression of COX-1 mRNA was strongly present in tumor tissues, while weakly present in non-tissues; the expression of COX-2 mRNA was induced in both tumor and non-tumor tissues. The production of prostaglandin E(2) (PGE(2)) increased approximately 6-fold, compared with the normal esophageal mucosa. The higher expression of COX-1, the up-regulated COX-2 expression and the increased levels of PGE(2) synthesis were all significantly decreased by administering resveratrol. Our study suggests that resveratrol suppressed NMBA-induced rat esophageal tumorigenesis by targeting COXs and PGE(2), and therefore may be a promising natural anti-carcinogenesis agent for the prevention and treatment of human esophageal cancer.

Indications for abdominal para-aortic lymph node dissection in patients with esophageal squamous cell carcinoma.

BACKGROUND: Abdominal para-aortic lymph node (APAL) dissection of esophageal cancer is not widely accepted. The aim of this article is to propose the indications for APAL dissection in esophageal cancer patients from the viewpoint of micrometastases. METHODS: To evaluate the value of APAL dissection in patients with esophageal cancer, the status of APAL metastases and recurrence in 230 patients with esophageal squamous cell carcinoma (1989 to 1998) was examined retrospectively. On the basis of our findings, 16 patients received a prophylactic APAL dissection from January 1999 to March 2001. Micrometastases in the dissected lymph nodes were examined using cytokeratin staining and reverse transcription-polymerase chain reaction of squamous cell carcinoma antigen messenger RNA. RESULTS: Among the 230 patients who had esophageal squamous cell carcinoma, 21 had APAL metastases (including micrometastases) or APAL recurrence. Among the 21 patients with APAL metastases and recurrence, 20 (95.2%) had metastases (including micrometastases) in perigastric lymph nodes (paracardial and lesser curvature nodes). Among 51 patients with lower thoracic esophageal carcinoma, 13 (25.5%) had APAL metastases or recurrence. On the basis of these results, prophylactic APAL dissection was performed in patients with lower thoracic esophageal cancer who were suspected of perigastric lymph node metastases during operations. APAL metastases (including micrometastases) were detected in 6 (38%) of these patients, and 2 patients with APAL micrometastases survived without recurrence. However, 7 patients had hematogenic recurrence after the operation. CONCLUSIONS: Our results suggested that the indications for APAL dissection were limited. Patients with lower thoracic esophageal cancer who are suspected to have perigastric lymph node metastasis and APAL micrometastases may be considered for APAL dissection.

Paratracheal lymph node metastasis is associated with cervical lymph node metastasis in patients with thoracic esophageal squamous cell carcinoma.

BACKGROUND: We determined which lymph node metastases were associated with cervical lymph node metastases of thoracic esophageal squamous cell carcinoma. METHODS: A total of 6464 lymph nodes derived from 155 consecutive patients with thoracic esophageal squamous cell carcinoma were stained by immunohistochemistry (antibody: AE1/AE3). Lymph node metastases were mapped according to the mapping scheme of the American Thoracic Society, as modified by Casson et al. (Ann Thorac Surg 1994;58:1569-70). Patients were divided into two groups: those with and without cervical lymph node metastasis (CLNM). Mapping data were examined by uni- and multivariate analysis. RESULTS: Hematoxylin and eosin-positive and AE1/AE3-positive lymph node metastases were found in 59% and 77% of patients, respectively. Twenty-one (55%) of 38 patients in the CLNM(+) group and 30 (26%) of 117 patients in the CLNM(-) group had AE1/AE3-positive lymph node metastasis in the thoracic paratracheal lymph node. Paratracheal lymph node metastasis is only one independent factor for (CLNM), whereas upper thoracic paraesophageal lymph node and pulmonal hilar lymph node status were also significant in univariate analysis. Three (43%) of seven patients with cervical jumping metastasis from the thoracic esophagus had micrometastasis in the paratracheal lymph node. CONCLUSIONS: The paratracheal lymph node is most associated with (CLNM) of thoracic esophageal squamous cell carcinoma.