Mitsuo Tachibana

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.

Downregulation of KiSS‐1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma

KiSS‐1 is a promising candidate tumor‐suppressor gene and may play a key role in the metastatic cascade. The expression profile and the role of KiSS‐1 in cancer progression are largely unknown in most of the cancers, including gastric cancer. In this study, KiSS‐1 expression was evaluated by RNase protection assay and localization was done by in situ hybridization in 40 gastric cancers and their adjacent normal gastric mucosa. For comparison with clinicopathologic characteristics and patient prognosis, all patients were divided into 2 groups having high and low KiSS‐1 expression by using the median as the cutoff value of KiSS‐1 expression as determined by the RNase protection assay. Gastric cancers with low KiSS‐1 had frequent venous invasion, distant metastasis and tumor recurrence. Accordingly, patients with low KiSS‐1‐expressing tumors had a significantly worse overall and disease‐free survival. In multivariate analysis, KiSS‐1 became the strongest independent prognostic factor among the conventional prognosticators for gastric cancer patients. Collectively, these findings suggest that KiSS‐1 may play a crucial role in gastric cancer invasion and could be a useful target for therapeutic intervention.

Body Mass Index Determines the Success of Lymph Node Dissection and Predicts the Outcome of Gastric Carcinoma Patients

We tried to determine the role of the body mass index (BMI) on the extent of lymph node dissection in gastric cancer surgery. Seven hundred and eighty-seven patients with gastric carcinoma were reviewed. Ninety-two (11%) patients exceeded the upper limit of the optimum BMI. Significantly fewer lymph nodes were removed following D2 (p = 0.002) and ≥D3 (p = 0.023) dissections, and the lymph node ratio was significantly (p = 0.0383) higher in overweight patients. The recurrence-free survival was significantly (p = 0.0297) shorter in T2/T3 cases with high BMI, and BMI (relative risk 1.85) became an independent prognostic factor in multivariate analysis. Higher BMI hampers regional lymph node dissection in gastric cancer patients and became an independent predictor of disease recurrences in T2/T3 gastric cancers.

Prognostic factors after hepatic resection for hepatocellular carcinoma associated with Child-Turcotte class B and C cirrhosis.

OBJECTIVE To evaluate prognostic factors after resection of hepatocellular carcinoma (HCC) in patients with Child-Turcotte class B and C cirrhosis. SUMMARY BACKGROUND DATA Although hepatic resection remains the mainstay in the treatment of HCC and can be performed with low morbidity and mortality rates in patients without cirrhosis, its role is poorly defined for patients with severe cirrhosis. METHODS From 1986 to 1996, partial hepatectomy was performed for HCC in 63 patients with Child-Turcotte class B (n = 46) and C (n = 17) cirrhosis. There were 46 men and 17 women, with an average age of 61.2 years (range 35 to 79 years). Associated conditions were diabetes mellitus in 45, esophageal varices in 32, severe hypersplenism in 26, cholelithiasis in 13, gastroduodenal ulcer in 6, and hiatal hernia, gastric lymphoma, splenic abscess, and pancreatic cyst each in 1. Concomitant surgical procedures were performed for most of these conditions. RESULTS Major complications occurred in 17 patients (27%), six (9.5%) of whom died within 1 month after surgery. The overall in-hospital death rate was 14.3%. Liver failure and intraabdominal sepsis were mostly fatal complications. The overall and disease-free survival rates, respectively, were 70.2% and 64.5% at 1 year, 43.5% and 23.8% at 3 years, and 21.4% and 14.9% at 5 years. Multivariate analysis with the Cox regression model revealed that favorable factors for survival were Child class B, no transcatheter arterial embolization before surgery, young age, and low alanine aminotransferase (ALT) level before surgery. CONCLUSIONS Hepatic resection can provide a favorable result in young patients with HCC complicating Child class B cirrhosis with low hepatitis activity, but transcatheter arterial embolization before surgery should be avoided in such patients.

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.

Esophageal Resection in Elderly Esophageal Carcinoma Patients: Improvement in Postoperative Complications

BACKGROUND Advanced age is considered to be a relative contraindication for radical esophagectomy with a three-field lymph node dissection. METHODS Preoperative risks, postoperative morbidity and mortality, and long-term survival in 55 elderly patients (> or =70 years) who had undergone extensive esophagectomy for esophageal carcinoma were compared with those of 149 younger patients (<70 years). RESULTS Elderly patients had worse preoperative cardiopulmonary function and had more frequent postoperative cardiopulmonary complications compared with younger patients (p < 0.05). The postoperative death rate was not statistically different between the elderly (10.9%) and younger groups (5.4%). When the study period was divided into an early and a late phase, the postoperative death rate dropped significantly (p < 0.05) in recent years (1.4%) when compared with the previous era (10.0%). The overall survival rates were not different between elderly and younger patients. CONCLUSIONS Preoperative cardiopulmonary risk factors and postoperative complications after esophagectomy were more frequently noticed in elderly patients than in younger patients. A dramatic improvement in postoperative death was noticed in recent years. The long-term survival of elderly patients after extended esophagectomy was almost similar to that in younger patients.

Antiangiogenic therapy of human esophageal cancers with thalidomide in nude mice

BACKGROUND Thalidomide (alpha-N-phthalimidoglutarimide) is attracting new attention because of its antiangiogenic effect in corneal neovascularization models. However, the effect of this agent on esophageal carcinoma is yet to be established. METHODS The human esophageal squamous cell carcinoma strains ES63 and ES80 implanted subcutaneously in nude mice were used to evaluate the antiangiogenic effect of thalidomide (200 mg/kg/d) after daily gavage or intraperitoneal administration. Tumor size was measured, and assessment of microvessel density was performed histochemically with Griffonia simplicifolia lectin I. Characterizations of angiogenic growth factors, vascular endothelial growth factor, basic fibroblast growth factor, and thymidine phosphorylase in ES63 and ES80 tumors were done by immunohistochemical staining and reverse transcription-polymerase chain reaction. RESULTS ES63 strongly expressed 3 angiogenic factors, but ES80 showed moderate expression of thymidine phosphorylase and only weak or no expression of vascular endothelial grown factor and basic fibroblast growth factor at protein and messenger RNA levels. In ES63 intraperitoneal injection of thalidomide produced significant (P < .05) inhibition of tumor growth, but there was no effect after gastric gavage. Also, a significantly (P < .0005) lower microvessel density was encountered in the intraperitoneal thalidomide group. However, in the ES80 tumor strain thalidomide had no antiangiogenic effect after either intraperitoneal or oral administration. CONCLUSIONS These data indicate that thalidomide exerts an antiangiogenic effect on solid tumor after intraperitoneal administration. Thalidomide might be one of the hopeful antiangiogenic drugs for solid tumors.

Clinicopathological features of superficial squamous cell carcinoma of the esophagus

BACKGROUND The depth of penetration is the crucial factor determining the prognosis of esophageal carcinoma patients. Patients with superficial esophageal carcinoma have a significantly favorable clinical course compared with those with advanced cancers. The outcome for patients with mucosal cancer is excellent with a 5-year survival rate exceeding 80%. On the other hand, submucosal cancer often metastasizes to lymph nodes or other organs, and the prognosis of these patients is far from satisfactory. METHODS Among 165 patients with squamous cell carcinoma of the esophagus, surgically resected between December 1979 and April 1995, 30 patients (18.2%) had superficial esophageal carcinoma (SEC) confined to the epithelium, lamina propria mucosa, or submucosa. Disease profile and clinicopathological characteristics of these 30 patients were studied. RESULTS The incidence of SEC has increased from 6.3% (2 of 32) in the first 5-year period (1979 to 1984) to 27.4% (20 of 73) in the recent 5-year period (1991 to 1995). Subjective symptoms were present in 2 (13.3%) with 15 mucosal cancers and in 4 (26.7%) with 15 submucosal cancers. The remaining 24 patients (80%) had no subjective symptoms. Twenty-two patients (73.3%) were diagnosed to have the lesions by endoscopic examination at the time of screening for gastric problems, and only 3 were detected by gastrointestinal series. None of the 15 patients with mucosal cancer had lymphatic invasion, venous invasion, or lymph node metastasis. On the other hand, in those with submucosal cancers, 9 (60%) had lymphatic invasion, 5 (33.3%) venous invasion, and 8 (53.3%) lymph node metastases. Twenty-two patients are alive without recurrence. The 3- and 5-year survival rates are 86.7% and 86.7% for patients with mucosal cancer and 72.2% and 65.0% for those with submucosal cancer, respectively. CONCLUSION Esophagectomy with wide lymphadenectomy should be carried out for submucosal cancer, whereas esophagectomy with moderate lymphadenectomy can be preferred for mucosal cancer.

Prognostic significance of perioperative blood transfusions in resectable thoracic esophageal cancer

OBJECTIVE:The perioperative blood transfusions have been associated with tumor recurrence and decreased survival in various types of alimentary tract cancer. There exist, however, contradictory studies showing no relationship between blood transfusions and survival. For patients with esophageal cancer, only one report suggested that blood transfusions did not by itself decrease the chance of cure after esophagectomy.METHODS:Among 235 patients with primary squamous cell carcinoma of the thoracic esophagus between December 1979 and March 1998, 143 patients (60.9%) underwent esophagectomy with curative intent (RO). To exclude the effects of surgery-related postoperative complications, 14 patients who died within 90 days during the hospital stay were excluded. Thus, clinicopathological characteristics and prognostic factors were retrospectively investigated between patients with no or few transfusions (≤2 units) (n = 58), and much transfused patients (≥3 units) (n = 71).RESULTS:Sixty-three patients are alive and free of cancer, and 66 patients are dead. A total of 98 patients (76%) received blood transfusions, whereas 31 patients (24%) had no transfusion. The amount of blood transfused was 1 or 2 units in 27 patients (27.6%), 3 or 4 units in 33 (33.7%), 5 or 6 units in 20 (20.4%), and ≥7 units in 18 (18.4%). The 5-yr survival rate for patients with no or few transfusions was 69%, whereas that for much transfused patients was 31.7% (p < 0.0001). The much transfused patients had more prominent ulcerative tumor, longer time of operation, more estimated blood loss, and more marked blood vessel invasion than the group with no or few transfusions. The factors influencing survival rate were tumor location, Borrmann classification, size of tumor, depth of invasion, number of lymph node metastases, time of operation, amount of blood transfusions, lymph vessel invasion, and blood vessel invasion. Among those nine significant variables verified by univariate analysis, independent prognostic factors for survival determined by multivariate analysis were number of lymph node metastasis (0 or 1 vs≥2, p < 0.0001), amount of blood transfusions (≤2 units vs≥3 units, p < 0.0001), and blood vessel invasion (marked vs non-marked, p= 0.0207).CONCLUSIONS:There is an association between high amount of blood transfusions and decreased survival for patients with resectable esophageal cancer. To improve the prognosis, surgeons must be careful to reduce blood loss during esophagectomy with extensive lymph node dissection and subsequently must minimize blood transfusions.

Expression of Trefoil Factor Family Members Correlates with Patient Prognosis and Neoangiogenesis

Purpose: Trefoil factor family (TFF) peptides are thought to contribute to epithelial protection and restitution by virtue of their protease-resistant nature and their strong affinity for mucins. However, they are often overexpressed in tumors, where they seem to be negative prognostic factors, possibly contributing to tumor spread, although the precise mechanisms have not been defined. Experimental Design: Tissue sections from 111 patients with curatively resected advanced gastric carcinoma were immunohistochemically stained for TFF2, ITF (TFF3), and CD34. Microvessel density was expressed as number and area of microvessels. Results were correlated with clinicopathological characteristics and patient survival. Results: Forty-nine (44.1%) and 41 (36.9%) tumors were immunohistochemically positive for TFF3 and TFF2, respectively. Among the various clinicopathologic variables, overexpression of TFF3 had a significant correlation with patient age only. In addition, a significantly higher prevalence of positive TFF2 staining was detected in large, diffuse tumors and in tumors with lymph node metastasis. The number of microvessels had a significant correlation with both TFF3 and TFF2 staining, whereas the area of microvessels had a significant correlation only with TFF3 staining. Both TFF3 and TFF2 were independent predictors of a worse disease-free survival. TFF3 had a gender-specific negative survival advantage, with a 91.3% disease-free survival in female patients with TFF3-negative advanced gastric carcinoma. Conclusions: Induction of increased tumor vascularity might be one of the mechanisms by which TFFs confer metastatic phenotype and frequent disease recurrence in gastric carcinomas. Female patients with TFF3-negative advanced gastric carcinoma have comparable survival as that reported for patients with early gastric carcinoma.