Toshiyuki Fujii

Prognostic Impact of Hypoxia-Inducible Factors 1α and 2α in Colorectal Cancer Patients: Correlation with Tumor Angiogenesis and Cyclooxygenase-2 Expression

Purpose: 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. Experimental Design: In this study, we examined HIF [HIF-1α (HIF1) and HIF-2α (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. Results: 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. Conclusions: 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.

Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma

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.

Role of stromal collagen in immunomodulation and prognosis of advanced gastric carcinoma.

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 Coxs 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.

Predictive factors and timing for liver recurrence after curative resection of gastric carcinoma

BACKGROUND Advanced and reliable diagnostic methods in order to identify the site of recurrence of gastric cancer in an early stage are needed. METHODS One hundred twenty patients whose recurrence was confirmed after curative resection for gastric cancer were enrolled in this study. RESULTS 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 Borrmanns 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. CONCLUSIONS This information may help to design a better follow-up program and appropriate treatment strategy for gastric cancer patients with liver metastasis.

Does Fibrin Glue Reduce Lymph Leakage (Pleural Effusion) after Extended Esophagectomy? Prospective Randomized Clinical Trial

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.

Surgical treatment for locally advanced (T4) squamous cell carcinoma of the thoracic esophagus.

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.

Acute cholecystitis and cholelithiasis developed after esophagectomy

BACKGROUND Although the prevalence of gallstone disease after gastrectomy is reported to be high, its prevalence after esophagectomy is scarcely reported. MATERIALS AND METHODS 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. RESULTS 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). CONCLUSION 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.

Prognosis of Patients with T2N0 Tumors in the Alimentary Tract: Should They Be Considered as Early Cancers?

Background: T1N0 tumor of the alimentary tract has an excellent long-term prognosis, however, the prognosis of T2N0 tumor has not been uniformly elucidated. Material and Methods: 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. Results: 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). Conclusion: 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.