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Publications (16)

  • [Show abstract] [Hide abstract] ABSTRACT: Angiogenesis plays an important role in a multitude of biological processes including those of tumorigenesis and cancer progression. Hypoxia is the prime driving factor for tumor angiogenesis and the family of hypoxia-inducible factors (HIFs) plays a pivotal role in this process. The role of HIF in tumor angiogenesis has been underscored in different carcinomas but yet to be reported for colorectal carcinomas. In this study, we examined HIF [HIF-1alpha (HIF1) and HIF-2alpha (HIF2)] expression in 87 curatively resected colorectal carcinoma samples, and the results were correlated with clinicopathological factors, microvessel density, cyclooxygenase 2 expression, and patient prognosis. HIF1 (44.8%) was more frequently expressed than HIF2 (29.9%). Most of the clinicopathological factors representing the tumor aggressiveness were significantly correlated with overexpression of HIF2 but not with HIF1 expression. HIF2 expression had direct correlation with microvessel density and cyclooxygenase 2 expression. and, in contrast, HIF1 expression had a weak but significant inverse correlation in T1 and T2 tumors only. HIF2 expression alone and the combined expression of HIF1 and HIF2 had significant impact on patient survival. In the multivariate analysis, however, only the combined expression of HIF1 and HIF2 remained independently significant. Taken together, our results suggest that HIF2 expression may play an important role in angiogenesis and that the combined expression of HIF1 and HIF2 may play an important role in tumor progression and prognosis of colorectal carcinomas. Therefore, HIF expression could be a useful target for therapeutic intervention.
    Article · Jan 2005 · Clinical Cancer Research
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    [Show abstract] [Hide abstract] ABSTRACT: Exactly what role does tumor-derived Fas ligand (FasL) play in cancer: maintaining the immune privilege site or inducing a pro-inflammatory effect? One possible hypothesis is that tumor-associated macrophages (TAM) act as the mediator that enables apoptosis of anti-tumor immune cells without FasL-related inflammation. We have evaluated the tumor FasL expression and TAM along the tumor margin and/or in cancer stroma, and their impact on the infiltration of immune-competent cells into the tumor nest. Tissue specimens from consecutive 84 advanced gastric carcinoma patients, who had undergone a curative resection, were evaluated for TAM (CD68+ cells), tumor FasL expression and immune status (CD8 + T cells). A high number of TAM significantly correlated with lymph node metastasis, intestinal type tumor and FasL expression. Although TAM had a tendency for an inverse correlation with the number of CD8+ T cells within the tumor nest (nest CD8) (p=0.0592), there was no correlation between FasL expression and nest CD8 (p=0.2158). This inverse association was found to be stronger in cases with both FasL-positive and high TAM tumors than in others (p=0.0139). The combination parameter of FasL-positive and high TAM became an independent prognostic factor in Cox's multivariate analysis, along with the pT status, nest CD8 and tumor cell apoptosis. We suggest that TAM works harmoniously with tumor-derived FasL and serves as a barrier against the infiltration of CD8+ T cells into the cancer nest.
    Full-text Article · Jan 2005 · Anticancer research
  • [Show abstract] [Hide abstract] ABSTRACT: Risk analysis of pulmonary complications after extended esophagectomy with three-field lymph node dissection (3FLND) has been little reported in the literature. Risk factors of developing postoperative pneumonia after extended esophagectomy and its effects on in-hospital death and overall long-term survival were compared between 38 patients who developed pneumonia and 80 patients who did not. Eight patients died of postoperative complications during the hospital stay after esophagectomy. Seven of those 8 patients developed pneumonia, whereas 31 patients of 110 patients who were discharged from the hospital developed pneumonia (P < 0.01). Pneumonia occurred more frequently in elderly patients (P < 0.01), in heavy smokers (P < 0.05), in patients with preoperative pulmonary obstructive dysfunction (P < 0.05), and in patients who received 3 U or more perioperative blood transfusion (P < 0.05). Five-year overall survival rate (26.7%) of 38 patients who developed pneumonia was significantly worse than 53.4% who did not develop pneumonia (P < 0.01). Multivariate analysis of prognostic factors for overall survival showed that pathological tumor stage (hazard ratio 5.380, P < 0.01) and pneumonia (hazard ratio 2.369, P < 0.01) were independent risk factors. Postoperative pneumonia is correlated with in-hospital death and poorer long-term survival after extended esophagectomy with 3FLND. Elderly patients with a history of heavy smoking and poor pulmonary function should be regarded as a high-risk group of patients for developing pneumonia and very careful selection is required before subjecting such patients to extended esophagectomy.
    Article · Nov 2004 · Journal of Surgical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Matrix metalloproteinases (MMPs) and cyclooxygenase (COX) enzymes play pivotal roles in the metastatic process of colorectal cancers. Inhibition of both MMPs and COX could be an attractive option for the inhibition of cell growth and invasion. Two human colorectal cancer cell lines, LS174T and HT29, were challenged with MMP inhibitor (doxycycline), selective COX-2 inhibitor (NS-398), or a combination of these agents to evaluate cancer cell proliferation and invasion. Dose-dependent growth inhibition was observed in both cell lines when they were treated with a single therapy. These effects were not related to MMP-2 or MMP-9 expression potential of the cell lines. Doxycycline (10 microg/mL) induced G(0)/G(1) arrest, and 20 microg/mL provoked annexin V positivity and up-regulated caspase-3 activity in HT29 cells. However, 20 microg/mL doxycycline caused no distinct apoptotic change in LS174T cells. Although MMP expression was not inhibited by 5 to 10 microg/mL doxycycline or 50 to 100 micromol/L NS-398, MMPs' activities were down-regulated by these concentrations. Cellular invasion was noticed in LS174T cells, but their capacity for invasion was diminished by these inhibitors. The antiproliferative and antiinvasive effects of the combination therapy were more pronounced. Doxycycline (5 microg/mL) with 50 micromol/L NS-398 inhibited cell proliferation and doxycycline (5 microg/mL) with 100 micromol/L NS-398 attenuated MMP expression and activity, as well as capacity for invasion, compared with single therapy. These data suggest that combination therapy consisting of an MMP inhibitor with a COX-2 inhibitor is an attractive approach to the treatment of colorectal cancers. The use of this treatment regimen for chemoprevention or treatment of colorectal cancers should be considered in future clinical trials.
    Article · May 2004 · Journal of Laboratory and Clinical Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Regenerating gene I (REG) was identified as a growth factor for pancreatic islet beta cells. Enhanced REG expression was observed during the healing of gastric mucosa. REG expression was observed in various tumors including gastric carcinoma, but to the authors' knowledge, the correlation between REG expression and clinicopathologic characteristics and patient prognosis have not been evaluated. The REG messenger RNA level was analyzed by Northern blot analysis and localization was performed by in situ hybridization and immunohistochemistry in gastric adenocarcinoma specimens. The correlations between REG expression and clinicopathologic features and survival of the patients were analyzed. Of the 68 patients studied, 24 (35%) were positive for REG. There was a significant consistency in the intensity and localization of REG transcript and protein expressions. REG expression was enhanced in advanced T classification tumors and in tumors that were not well differentiated. A significant number of metastatic lymph nodes were present in REG-positive tumors. Overall and disease-free survival were found to be poor for patients with REG-positive tumors. REG expression was reported to be an independent predictor of overall patient survival. Determination of REG expression may help to identify aggressive gastric tumors and to tailor appropriate therapy for patients with REG-positive tumors.
    Full-text Article · Apr 2004 · Cancer
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    [Show abstract] [Hide abstract] ABSTRACT: Tumor-associated macrophages (TAMs) have varying functions depending on the microenvironment of tumor tissue. We studied the biological role of TAMs in gastric cancer on the basis of their spatial distribution in the cancer tissue. Tissue specimens from 84 advanced gastric carcinoma (pT2; 41 cases, pT3; 43 cases) patients who had undergone a curative resection were stained for TAM (CD68+ cells), incidence of tumor cell apoptosis (TUNEL) and host immune status (CD8+ T cells). CD68+ and CD8+ T cells infiltrated into the cancer cell nests or in close contact with cancer cells were considered as nest TAMs and nest CD8, respectively. Nest TAMs had a very strong direct correlation with frequency of tumor cell apoptosis (p < 0.0001) and degree of nest CD8 (p = 0.0004). The 5-year disease-free survival rate in the high-nest TAM category (87%) was significantly higher than in the low-nest TAM group (44%) (p = 0.0002). Among the several prognostic factors, nest TAM, nest CD8 and pT stage became independent predictors of patient survival (p = 0.016, p = 0.001 and p = 0.029, respectively) in Cox's multivariate analysis. These results suggested that the aggregation of TAMs within tumor nest had a beneficial effect on host in terms of augmented cytotoxicity and antigen presentation.
    Full-text Article · Nov 2003 · Anticancer research
  • [Show abstract] [Hide abstract] ABSTRACT: Fibrin glue has been shown to be effective in improving postoperative chylothorax following various thoracic procedures and in reducing lymphorrhea after axillary dissection. It is unknown, however, whether fibrin glue is effective in reducing lymph leakage (pleural effusion) after esophagectomy. A series of 43 consecutive patients with thoracic esophageal cancer who underwent extended esophagectomy were prospectively randomized to two groups: group A (n = 21), in whom 3 ml of fibrin glue was applied to the dissected mediastinum; and group B (n = 22), in whom fibrin glue was not applied. The time of drain removal and the volume of the thoracic drainage were compared. All data were expressed as the mean +/- standard deviation. There were no significant differences in the clinicopathologic characteristics between the two groups. None of the patients developed chylothorax or died during their hospital stay. The daily volume from the thoracic drain (457 +/- 273 ml) was significantly (p < 0.05) larger on postoperative day (POD) 1 in group A than in group B (298 +/- 158 ml) and tended to be larger (p < 0.10) on PODs 4 and 6 in group A than in group B. The cumulative drainage volume was significantly (p < 0.05) larger on PODs 4 to 6 and POD 9, and it tended to be larger (p < 0.10) on PODs 1, 3, 7, 8, 10, and 11 in group A than in group B, suggesting that the cumulative drainage volume in group A was consistently larger than that in group B. The cumulative numbers of patients with a drain remaining in place were not significantly different for the two groups (p = 0.4683). Three patients in group A, however, had prolonged insertion (> 20 days) of the chest tube. There were no significant differences in the incidence of postoperative chest-related complications. No patients in group A developed viral infectious disease during the long-term follow-up. Application of fibrin glue to the dissected mediastinum seems to induce postoperative lymph leakage and thus be responsible for prolonged chest tube insertion in some patients. Hence the use of fibrin glue cannot be recommended for reducing lymph leakage after esophagectomy.
    Article · Jul 2003 · World Journal of Surgery
  • Toshiyuki Fujii · Mitsuo Tachibana · Dipok Kumar Dhar · [...] · Naofumi Nagasue
    [Show abstract] [Hide abstract] ABSTRACT: Combination chemotherapy is increasingly practiced for treating malignancies with greater sensitivity and less toxicity. Paclitaxel is a potent anti-tumor agent but has dose-limiting side-effects, whereas thalidomide is an orally active anti-angiogenic drug but less than sufficient to exert anti-tumor effect as a single agent. Nude mice bearing hypervascular (LS174T) and less vascular (HT29) colon carcinomas were challenged with either a non-cytotoxic dose of paclitaxel, thalidomide or a combination of paclitaxel and thalidomide. Significant growth retardation was noticed only in the combination treatment group of LS174T tumors. Microvessel density data indicated a significantly low count in the combination treatment group compared to the others. Trends of decreased expression of angiogenic growth factors and increased apoptotic index were noticed in the combination treatment group. The results of this study underscore the therapeutic efficacy of concomitant use of paclitaxel and thalidomide in the treatment of highly vascular colorectal tumors in a xenograft model.
    Article · May 2003 · Anticancer research
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    Satoshi Ohno · Toshiyuki Fujii · Shuhei Ueda · [...] · Naofumi Nagasue
    [Show abstract] [Hide abstract] ABSTRACT: Advanced and reliable diagnostic methods in order to identify the site of recurrence of gastric cancer in an early stage are needed. One hundred twenty patients whose recurrence was confirmed after curative resection for gastric cancer were enrolled in this study. Liver recurrence was evident in 41 patients. Advanced age, tumor invasion into subserosa, intestinal and mixed type of histology, Borrmann type 0 to 2, tumor diameter (<6.5 cm), and tumor marker (carcinoembryonic antigen and alpha-fetoprotein) elevation were related to liver recurrence. By logistic regression analysis, independent risk factors for liver recurrence included Borrmann's classification, histology, and tumor marker elevation. The median time from the primary operation to liver recurrence was shortest in the tumor marker elevation group when compared with other independent predictors. This information may help to design a better follow-up program and appropriate treatment strategy for gastric cancer patients with liver metastasis.
    Full-text Article · Mar 2003 · The American Journal of Surgery
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    [Show abstract] [Hide abstract] ABSTRACT: Although the prevalence of gallstone disease after gastrectomy is reported to be high, its prevalence after esophagectomy is scarcely reported. Gallbladder disease following an esophagectomy was prospectively evaluated in 237 patients with esophageal cancer by abdominal ultrasonography twice a year up to five years postoperatively. The median follow-up period was 18.6 months. One patient (0.4%) developed acute acalculous cholecystitis postoperatively, and 13 patients (5.5%) developed gallstone disease during the follow-up period. Nine (69%) of these 13 patients developed gallstone disease within two years, and another two patients developed the disease three years after esophagectomy. Another patient developed gallbladder debris at 35 months postoperatively, and one developed gallbladder polyps at 33 months. Seven of the 13 patients with gallstone disease underwent cholecystectomy between 13 and 125 months after esophagectomy: two developed acute cholecystitis; two had associated common bile duct stones; the remaining three patients had upper abdominal pain. Nine of the 13 patients who developed gallstone disease showed a history of alcoholism, whereas only 81 of 224 patients without gallstone disease had a similar history (P<0.05). A certain number of patients with esophageal carcinoma and a history of alcoholism develop cholelithiasis within three years after esophagectomy, and subsequently undergo cholecystectomy during the follow-up period.
    Full-text Article · Mar 2003 · Canadian journal of gastroenterology = Journal canadien de gastroenterologie
  • [Show abstract] [Hide abstract] ABSTRACT: To further investigate the underlying mechanism of the systemic spread of esophageal squamous cell carcinoma. Out of 151 patients who underwent a curative esophageal resection, 41 (27.1%) developed recurrent esophageal cancer. Nine recurrences (22%) were distant-hematogenous, 17 (41.5%) non-hematogenous, and 15 (36.5%) mixed. Hematogenous deposits accompanied 58.5% of the recurrences. The relation between several clinicopathological factors and the pattern of recurrence was evaluated. Univariate analysis recognized the lack of adjuvant chemoradiation, the tumor location in the lower esophagus and the tumor dedifferentiation as promoting factors for hematogenous recurrence. Poorly differentiated or undifferentiated tumors presented a significantly higher microvessel density than moderately or well differentiated tumors. Tumor differentiation and tumor lower localization were independent predictors of hematogenous recurrence. Patients with poorly differentiated or undifferentiated tumors, which are located at the lower esophagus and present high microvessel density, should be considered at high risk for hematogenous recurrences after extended esophagectomy.
    Article · Jan 2003 · Hepato-gastroenterology
  • [Show abstract] [Hide abstract] ABSTRACT: T1N0 tumor of the alimentary tract has an excellent long-term prognosis, however, the prognosis of T2N0 tumor has not been uniformly elucidated. Between February 1981 and April 2000, 75, 424 and 327 patients with node-negative esophageal, gastric and colorectal carcinomas, respectively, underwent curative resection and were included in this study. Long-term prognosis of those node-negative patients stratified by the T-stage were evaluated retrospectively. The 5-year survival rates of patients with T1N0 and T2N0 esophageal tumors were 95.7 and 93.3%, respectively, however those with T3N0 tumor was only 47.6% (p < 0.01). Similarly, the 5-year survival rates of gastric cancer patients with T1-2N0 tumors was 100%, however those with T3N0 and T4N0 tumors were 55.6 and 44.4%, respectively (p < 0.01). The 5-year survival rates of colorectal cancer patients with T1N0 and T2N0 tumors were 97.3 and 97.5%, respectively. In contrast, those with T3N0 and T4N0 tumors were 78.6 and 58.3%, respectively (p < 0.05, T1N0, T2N0 vs. T3N0; p < 0.001, vs. T4N0). Patients with T2N0 tumors have an excellent long-term prognosis like T1N0 tumors and both categories could be classified as early cancer in the alimentary tract cancers.
    Article · Oct 2002 · Digestion
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    [Show abstract] [Hide abstract] ABSTRACT: Esophageal cancer is one of the most malignant tumors, with a dismal prognosis in spite of recent advances in early diagnosis and extended lymphadenectomy. These patients need to be stratified according to prognostic variables for precise identification of high-risk group. Seventy-six patients with esophageal carcinoma were uniformly treated with curative intent between 1980 and 1992 with at least 6 years follow-up. Results and prognostic factors of long-term survival were analyzed by univariate and multivariate analyses. Thirty patients (39.5%) survived 6 years, and the remaining 46 patients died within 6 years: recurrent esophageal cancer in 27 and causes unrelated to esophageal cancer in 19. The 1-, 2-, 3-, and 6-year overall survival rates in all 76 patients were 77.6%, 57.9%, 53.9%, and 39.5%, respectively. The factors influencing survival rate verified by univariate analysis were Borrmann classification (0, 1 vs. 2, 3), size of tumor (< or =3.0 vs. >3.0 cm), depth of invasion (T1, 2 vs. T3, 4), pN category (pN0 vs. pN1), number of lymph node metastasis (< or =4vs. >4), metastatic lymph node ratio (< or =0.1 vs. >0.1), time of operation (< or =480 vs. >480 min), and amount of perioperative blood transfusion given (< or =2 vs. >2 U). Among the significant variables independent prognostic factors for survival determined by multivariate analysis were metastatic lymph node ratio and amount of blood transfusion. A significant number of patients can thus apparently be cured of esophageal carcinoma by extensive resection. Patients with many metastatic lymph nodes and much blood transfusion, on the other hand, should receive appropriate treatment against such esophageal carcinoma.
    Full-text Article · Jun 2002 · Langenbeck s Archives of Surgery
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    [Show abstract] [Hide abstract] ABSTRACT: PTEN is a candidate tumor-suppressor gene in a variety of malignant tumors. The prognostic importance of PTEN product protein (PTEN) and its correlation with clinicopathologic characteristics have yet to be delineated in patients with esophageal carcinoma. Specimens from 97 patients with esophageal squamous cell carcinoma were used for the immunohistochemical evaluation of PTEN expression. PTEN expression was detected in the nucleus in 48 specimens (49.5%). There were statistically significant correlations between nuclear PTEN expression and macroscopic tumor classification, T stage, and American Joint Committee on Cancer (AJCC) stage (P < 0.01), indicating that PTEN expression was down-regulated by advancement of the disease process. There were no statistically significant correlations between nuclear PTEN expression and the intensity and extent of cytoplasmic PTEN expression. The 10-year overall survival rate was significantly better in patients with positive nuclear PTEN expression (n = 48 patients) compared with the rate in patients with negative nuclear PTEN expression (n = 49 patients; P < 0.01). The results of a multivariate analysis of factors that were prognostic for survival showed that AJCC stage (P < 0.05; relative risk, 2.038) and negative nuclear PTEN expression (P < 0.05; relative risk, 1.825) were significant factors indicative of poor survival. Nuclear PTEN expression may be a favorable biologic marker and a useful prognostic indicator in patients with esophageal squamous cell carcinoma.
    Full-text Article · Apr 2002 · Cancer
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    Satoshi Ohno · Mitsuo Tachibana · Toshiyuki Fujii · [...] · Naofumi Nagasue
    [Show abstract] [Hide abstract] ABSTRACT: Although several hypotheses have been proposed explaining the mechanisms of the immune-privileged status of malignant tumors, the exact pathway is yet to be explored. Tumor stroma plays a vital role in the prognosis of cancer patients; however, the immunomodulatory impact of gastric cancer stroma has not been reported. We have evaluated the amount of stromal collagen and its impact on the infiltration of immune-competent cells into the tumor cell nest in gastric carcinoma. Tissue specimens from 84 advanced gastric carcinoma patients who had undergone a curative resection were evaluated for host immune status (CD8+ T cells), tumor stromal reaction (AZAN staining), tumor Fas ligand expression and incidence of tumor cell apoptosis (by TUNEL). The number of apoptotic tumor cells (apoptotic index [AI]) increased proportionally with an increase in the number of CD8+ T cells within the cancer cell nest (nest CD8) (p = 0.0001). Nest CD8 was inversely correlated with the amount of stromal collagen (p < 0.0001). Nest CD8 and AI became independent predictors of patient survival (p = 0.0023 and p = 0.044, respectively) in Cox's multivariate analysis. The amount of stromal collagen was found to be a significant predictor of disease relapse in univariate analysis (p = 0.0010) but not in multivariate analysis (p = 0.4729). In conclusion, increased nest CD8 produced a survival advantage by inducing tumor cell apoptosis in gastric carcinoma patients. Increased tumor stromal collagen worked as a barrier for CD8+ T-cell infiltration and might be one of the mechanisms of tumor escape from the host immune attack.
    Full-text Article · Feb 2002 · International Journal of Cancer
  • [Show abstract] [Hide abstract] ABSTRACT: It is still difficult to decide on the treatment modalities for advanced esophageal carcinoma when the prognostic factors of T4 esophageal cancer are not fully understood. In this article, we report that among 71 patients with T4 thoracic esophageal cancer, 49 underwent esophagectomy, 9 had curative resection (R0 group), and 40 had palliative resection (R1/2 group). A total of 22 patients had palliative treatments: bypass in 5 (bypass group), gastrostomy or jejunostomy in 6 (stoma group), and radiochemotherapy alone in 11 (nonoperation group). Clinicopathologic characteristics were retrospectively investigated. Treatment-related deaths occurred in 7 (10%): none in R0, 3 (8%) in R1/2, 3 (60%) in bypass, and 1 (17%) in stoma group. Swallowing was improved in 50 (70%) patients: 9 (100%) in R0, 30 (75%) in R1/2, 1 (20%) in bypass, 3 (50%) in stoma, and 7 (64%) in the nonoperation group. One-, two-, and three-year overall survival rates were 56%, 22%, and 22% in the R0 group and 35%, 19% and 6% in the R1/2 group, respectively (p = 0.19). In the bypass, stoma, and nonoperation groups, none survived 1.6 years. The factors influencing the survival rate of the 49 patients undergoing esophagectomy were grade of lymph node metastasis, amount of perioperative blood transfusion, lymph vessel, and blood vessel invasion. Among these, independent prognostic factors for survival were amount of blood transfusion (-6 units vs. -7 units, p <0.0001) and grade of lymph node metastasis [none- or peritumoral [lymph nodes adjacent to the main tumor or at a nearby location (<3 cm) from the tumor] metastasis vs. more distant metastasis [lymph nodes at a distant location (> 3 cm)], p = 0.016]. Bypass and stoma operation neither prolonged the survival nor improved the difficulty of swallowing compared with radiochemotherapy alone. Esophagectomy can achieve the best improvement of swallowing and the longest survival with an acceptable mortality rate. Esophageal carcinoma patients with T4 disease and distinct metastasis in the lymph nodes at a distant location (>3 cm) from the primary tumor may not benefit from an esophageal resection.
    Article · Feb 2002 · Dysphagia