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Biomedical subjects

Hirokazu Nagawa

Publications and source records attributed to Hirokazu Nagawa.

At least 19 recordsLinked to original sources
PubMed2007

Tissue factor expression is a clinical indicator of lymphatic metastasis and poor prognosis in gastric cancer with intestinal phenotype.

BACKGROUND AND OBJECTIVES: Tissue factor (TF), which normally safeguards vascular integrity by inducing hemostasis upon injury, has received widespread attention in the pathogenesis of cancer progression and metastasis. Aberrantly expressed TF in cancer cells has been reported to be associated with advanced stages of malignancy in various cancers. METHODS: The expression of TF and microvessel density (MVD) were immunohistochemically evaluated in 207 gastric cancers, and their relationship with clinicopathological features was examined. RESULTS: TF was preferentially expressed (41.8%) in intestinal-type cancer at a significantly higher rate than that in diffuse-type cancer (12.1%, P<0.0001). The expression of TF was associated with advanced stage of disease and showed a positive correlation with a higher rate of lymphatic and venous invasion and lymphatic metastasis in intestinal-type, but not in diffuse-type carcinoma. Moreover, TF expression was associated with high MVD in the tumor and a worse outcome only in intestinal-type carcinoma. CONCLUSIONS: TF may be critically involved in tumor progression in intestinal-type, but not in diffuse-type, gastric carcinoma. The difference in clinical features between these two histological types might be partially dependent on TF expression profile.

Adenocarcinoma↗
PubMed2007

Prognosis and risk factors of metastasis in colorectal carcinoids: results of a nationwide registry over 15 years.

BACKGROUND: Colorectal carcinoids are often described as low-grade malignant. However, no study has compared the survival between patients with colorectal carcinoids and those with carcinomas, in a large series. In addition, no global consensus has been established on the crucial determinants of metastasis in colorectal carcinoids. AIM: To determine the predictive factors for metastasis in colorectal carcinoids and clarify their prognosis compared with adenocarcinomas. METHODS: Data of all patients diagnosed as having colorectal carcinoids were extracted from a large nationwide database of colorectal tumours, the Multi-Institutional Registry of Large-Bowel Cancer in Japan, for the period from 1984 to 1998. Risk factors for lymph node (LN) metastases and distant metastases were analysed among those who were undergoing surgery, by univariate and multivariate analysis. Cancer-specific survival was also compared between patients with colorectal carcinoids and those with adenocarcinomas registered in the same period. RESULTS: Among the 90 057 cases of colorectal tumours that were diagnosed, a total of 345 cases of carcinoids were identified, including 247 colorectal carcinoids of those undergoing surgery. Risk factors for LN metastasis were tumour size >/=11 mm and lymphatic invasion, whereas those for distant metastasis were tumour size >/=21 mm and venous invasion. Colorectal carcinoids without these risk factors exhibited no LN metastasis or distant metastasis. Cancer-specific survival of patients with colorectal carcinoids without metastasis was better than that of those with adenocarcinomas. However, the survival was similar between carcinoids and adenocarcinomas if the tumours had LN metastasis or distant metastasis. CONCLUSIONS: The presence of metastasis in colorectal carcinoids could lead to survival that is as poor as in adenocarcinomas. Tumours </=10 mm and without lymphatic invasion could be curatively treated by local resection, but others would need radical LN dissection.

Adenocarcinoma↗
PubMed2006

Phosphorylation of ribosomal p70 S6 kinase and rapamycin sensitivity in human colorectal cancer.

We investigated the Akt-mTOR pathway and effects of rapamycin using human colorectal cancer cell lines. LoVo and CaRI reduced proliferative activity in response to rapamycin in a dose-dependent manner. The phosphorylation of Akt and p70 S6K was prominent in these cells. Rapamycin quickly downregulated phospho-S6K but not phospho-Akt. Therefore, phospho-S6K is considered a good indicator of the activated Akt-mTOR pathway as well as rapamycin sensitivity in colorectal cancer cells. By immunohistochemical study, nearly 40% of adenomas and carcinomas of the colorectum exhibited either partial or whole positive staining for phospho-S6K, suggestive of rapamycin-sensitive lesions.

Antibiotics, Antineoplastic↗
PubMed2006

Effect of a selective thromboxane A2 synthetase inhibitor on the systemic changes induced by circulating pancreatic phospholipase A2.

BACKGROUND: In acute pancreatitis, pancreatic phospholipase A(2) (PLA2) in the circulating blood hydrolyzes phospholipids contained in plasma lipoproteins, liberating eicosanoid precursors that are subsequently converted to various eicosanoids. The pathophysiological significance of eicosanoid synthesis via this pathway is unknown. The aim of this study was to clarify the role of thromboxane A(2) (TXA(2)) synthesis by circulating pancreatic PLA(2) in the pathogenesis of the systemic complications of acute pancreatitis. METHODS: Guinea pigs were divided into two groups: a control group and an ozagrel group, which received intravenous administration of ozagrel, a selective TXA(2) synthetase inhibitor. Pancreatic PLA(2) was infused intravenously in both groups for 30 min, and systemic changes during the infusion were examined. RESULTS: In the control group, there was an increase in plasma thromboxane B(2) (TXB(2)) concentration, a decrease in mean arterial pressure and heart rate, a decrease in arterial base excess (BE), bicarbonate concentration (HCO(3) (-)), and pH, a decrease in platelet count and plasma fibrinogen concentration, and a shortened prothrombin time during the infusion of pancreatic PLA(2). In the ozagrel-treated group, changes in plasma TXB(2) concentration, BE, HCO(3) (-), and platelet count were significantly inhibited. CONCLUSIONS: TXA(2) synthesis by circulating pancreatic PLA(2) contributes to metabolic acidosis and thrombocytopenia during acute pancreatitis.

Acute Disease↗
PubMed2006

Proposal of a new and simple staging system of colorectal liver metastasis.

AIM: To create a new, simple and useful staging system for colorectal liver metastasis analogous to the Tumor Node Metastasis classification system of International Union Against Cancer. METHODS: A retrospective review was undertaken of 81 consecutive patients who underwent partial hepatectomy for colorectal liver metastases (group 1). Clinical and pathological features of both primary and metastatic liver cancers were entered into a multivariate analysis to determine independent variables helpful in accurately predicting long-term prognosis after hepatectomy. Using selected variables, we created a new staging system like TNM classification. The usefulness of the new staging system was examined in a series of 92 patients from another hospital (group 2). RESULTS: Multivariate analysis showed that 81 patients in group 1 had significant multiple hepatic tumors with the largest tumor being more than 5 cm in diameter, resectable extrahepatic distant metastases, and independent prognostic factors for poor survival after hepatectomy. Using these three variables, we created a new staging system to classify patients with colorectal liver metastases. Finally, our new staging system classified the patients both in group 1 and in group 2. CONCLUSION: Our new staging system of colorectal liver metastasis is simple and useful for staging patients.

Adult↗
PubMed2006

Proposal of criteria to select candidates with colorectal liver metastases for hepatic resection: comparison of our scoring system to the positive number of risk factors.

AIM: To select accurately good candidates of hepatic resection for colorectal liver metastasis. METHODS: Thirteen clinicopathological features, which were recognized only before or during surgery, were selected retrospectively in 81 consecutive patients in one hospital (Group I). These features were entered into a multivariate analysis to determine independent and significant variables affecting long-term prognosis after hepatectomy. Using selected variables, we created a scoring formula to classify patients with colorectal liver metastases to select good candidates for hepatic resection. The usefulness of the new scoring system was examined in a series of 92 patients from another hospital (Group II), comparing the number of selected variables. RESULTS: Among 81 patients of Group I, multivariate analysis, i.e. Cox regression analysis, showed that multiple tumors, the largest tumor greater than 5 cm in diameter, and resectable extrahepatic metastases were significant and independent prognostic factors for poor survival after hepatectomy (P < 0.05). In addition, these three factors: serosa invasion, local lymph node metastases of primary cancers, and post-operative disease free interval less than 1 year including synchronous hepatic metastasis, were not significant, however, they were selected by a stepwise method of Cox regression analysis (0.05 < P < 0.20). Using these six variables, we created a new scoring formula to classify patients with colorectal liver metastases. Finally, our new scoring system not only classified patients in Group I very well, but also that in Group II, according to long-term outcomes after hepatic resection. The positive number of these six variables also classified them well. CONCLUSION: Both, our new scoring system and the positive number of significant prognostic factors are useful to classify patients with colorectal liver metastases in the preoperative selection of good candidates for hepatic resection.

Adult↗
PubMed2006

Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers.

Promoter methylation of the mismatch repair gene plays a key role in sporadic microsatellite instability (MSI) colorectal cancers. However, promoter methylation often occurs in proximal colon cancers, and molecular phenotypes underlying MSI cancers in distal colon have not been fully clarified. Our goal was to clarify the difference between MSI and microsatellite stability (MSS) cancers and, furthermore, to determine distinct characteristics of proximal and distal MSI cancers. By DNA microarray analysis of 84 cancers (33 MSI and 51 MSS), we identified discriminating genes (177 probe sets), which predicted MSI status with a high accuracy rate (97.6%). These genes were related to phenotypic characteristics of MSI cancers. Next, we identified 24 probe sets that were differentially expressed in proximal and distal MSI cancers. These genes included promoter methylation-mediated genes, whose expression was significantly down-regulated in proximal MSI cancers. Among discriminating genes between MSI and MSS, nine methylation-mediated genes showed down-regulation in MSI cancers. Of these, 7 (77.8%) showed down-regulation in proximal MSI cancers. Furthermore, methylation-specific PCR confirmed that frequency of hMLH1 promoter methylation was significantly higher in proximal MSI cancers (P = 0.0317). These results suggested that there is a difference between proximal and distal MSI cancers in methylation-mediated influence on gene silencing. In conclusion, using DNA microarray, we could distinguish MSI and MSS cancers. We also showed distinct characteristics of proximal and distal MSI cancers. The inactivation form of hMLH, per se, differed between proximal and distal MSI cancers. These results suggested that distal MSI cancers constitute a distinct subgroup of sporadic MSI cancers.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Expression pattern of leptin and leptin receptor (OB-R) in human gastric cancer.

AIM: To examine the expression of leptin and its receptor, OB-R, in normal gastric mucosa and neoplasia. METHODS: By immunohistochemical staining using specific antibodies, we evaluated the expression of leptin and OB-R in 207 gastric carcinomas (100 early and 107 advanced carcinomas) and analyzed their relationship with clinicopathological features. RESULTS: Both normal gastric epithelium and carcinoma cells expressed a significant level of leptin. In cases with OB-R staining, carcinoma cells showed OB-R-positive expression, but the intensity was weaker than that in normal mucosa. The expression of OB-R showed a significant correlation with the level of leptin expression. The expression levels of both leptin and OB-R tended to increase as the depth of tumor invasion or TMN stage increased (P < 0.01). Lymph node metastasis was detected in 49.5% (47/95) of leptin-strong cases and in 50.5% (48/95) of OB-R-positive cases, and the rate was 33% (37/112) in leptin-weak cases and 17% (19/112) in OB-R-negative cases. Both venous and lymphatic invasion also tended to be observed frequently in positive tumors as compared with negative tumors. Interestingly, in the 96 leptin- or OB-R-positive tumors, hematogenous metastasis was detected preoperatively in 3 (3.1%) patients. In contrast, none of the carcinomas that lacked expression of leptin and OB-R showed hematogenous metastasis. CONCLUSION: Overexpression of leptin and expression of OB-R may play a positive role in the process of progression in gastric cancer. Functional upregulation of leptin/OB-R may have a positive role in the development and initial phase of progression in gastric cancer.

Adenocarcinoma↗
PubMed2006

Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis.

Sulforaphane (SUL), one of the isothiocyanates (ITCs), has recently been focused due to its inhibitory effects on tumor cell growth in vitro and in vivo, which is dependent on the direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of SUL and its mechanism of action. Using the human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of SUL on the various steps of angiogenesis, including the proliferation of endothelial cells, tubular formation, and matrix metalloproteinase (MMP) production. Sulforaphane induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on cell apoptosis. Also SUL inhibited tube formation on matrigel, but did not affect MMP production. The present results demonstrate the anti-angiogenic activity of SUL and its potential use as an anti-cancer drug is suggested.

Angiogenesis Inhibitors↗
PubMed2006

Hyperfibrinogenemia is associated with lymphatic as well as hematogenous metastasis and worse clinical outcome in T2 gastric cancer.

BACKGROUND: Abnormal hemostasis in cancer patients has previously been described, however the correlation between the plasma fibrinogen level and cancer metastasis and prognosis has not been reported in a large-scale clinical study. METHODS: Preoperative plasma fibrinogen levels were retrospectively examined in 405 patients who underwent surgery for advanced gastric cancer. The association of fibrinogen levels with clinical/pathological findings and clinical outcome was evaluated. RESULTS: There was a positive correlation between plasma fibrinogen levels and the depth of invasion (p < 0.05). Hyperfibrinogenemia (>310 mg/dl) was independently associated with lymph node (Odds Ratio; 2.342, P = 0.0032) and liver (Odds Ratio; 2.933, P = 0.0147) metastasis, not with peritoneal metastasis in this series. Patients with hyperfibrinogenemia showed worse clinical outcome in T2 gastric cancer, however, there was no correlation of plasma fibrinogen level with prognosis in T3/T4 gastric cancer. CONCLUSION: Our results might support the idea that hyperfibrinogenemia can augment lymphatic and hematogeneous metastasis of advanced gastric cancer, which is major determinant of the prognosis in T2 gastric cancer. Therefore, in the situation without peritoneal involvement, hyperfibrinogenemia is a useful biomarker to predict the possible metastasis and worse clinical outcome in T2 gastric cancer.

Aged↗
PubMed2006

Prospective surveillance effectively reduced rates of surgical site infection associated with elective colorectal surgery at a university hospital in Japan.

At a university hospital in Japan, the introduction of prospective surveillance and subsequent interventions was effective in reducing the rate of surgical site infection associated with elective colorectal surgery from 27.5% to 17.8% of surgeries. Japan should both recognize the importance of broader surveillance for surgical site infection and establish its own nationwide surveillance database.

Colorectal Surgery↗
PubMed2006

Prediction of sensitivity of rectal cancer cells in response to preoperative radiotherapy by DNA microarray analysis of gene expression profiles.

Preoperative radiotherapy has been widely used to improve local control of disease and to improve survival in the treatment of rectal cancer. However, the response to radiotherapy differs among individual tumors. Our objective here was to identify a set of discriminating genes that can be used for characterization and prediction of response to radiotherapy in rectal cancer. Fifty-two rectal cancer patients who underwent preoperative radiotherapy were studied. Biopsy specimens were obtained from rectal cancer before preoperative radiotherapy. Response to radiotherapy was determined by histopathologic examination of surgically resected specimens and classified as responders or nonresponders. By determining gene expression profiles using human U95Av2 Gene Chip, we identified 33 novel discriminating genes of which the expression differed significantly between responders and nonresponders. Using this gene set, we were able to establish a new model to predict response to radiotherapy in rectal cancer with an accuracy of 82.4%. The list of discriminating genes included growth factor, apoptosis, cell proliferation, signal transduction, or cell adhesion-related genes. Among 33 discriminating genes, apoptosis inducers (lumican, thrombospondin 2, and galectin-1) showed higher expression in responders whereas apoptosis inhibitors (cyclophilin 40 and glutathione peroxidase) showed higher expression in nonresponders. The present study suggested the possibility that gene expression profiling may be useful in predicting response to radiotherapy to establish an individualized tailored therapy for rectal cancer. Global expression profiles of responders and nonresponders may provide insights into the development of novel therapeutic targets.

Combined Modality Therapy↗
PubMed2006

Hypertriglyceridemia is positively correlated with the development of colorectal tubular adenoma in Japanese men.

AIM: To determine the real association between serum lipid levels and colonic polyp formation. METHODS: We performed a large scale retrospective study to analyze the correlation between the incidence of colorectal adenoma or carcinoma and the fasting serum levels of total cholesterol (TC) and triglycerides (TG) in patients who underwent total colonoscopy for screening for colon cancer. RESULTS: Both levels were significantly elevated in patients with adenomas as compared with patients without any neoplastic lesion (TC 207.6+/-29.5 vs 199.5+/-34.3, n=4883, P<0.001; TG 135.0+/-82.2 vs 108.7+/-71.5, n=4874, P<0.001). The difference was significant in patients with tubular adenoma but not in those with villous or serrated adenoma. Multiple logistic regression analysis including age and sex revealed that TG was an independent correlation factor in male (P<0.01), but not in female patients. The level of TG in patients with invasive carcinoma did not show a significant elevation from that in patients with adenoma. These findings suggest that hypertriglyceridemia is an independent risk factor for colonic adenoma in men. CONCLUSION: Although a high level of serum triglyceride does not appear to be mechanically involved in the development of carcinoma, reduction of serum TG and intensive surveillance with total colonoscopy may have benefit in men with hypertriglyceridemia.

Adenoma↗