Hideki Tabara

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.

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.

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.

Tumor vascularity predicts recurrence in differentiated thyroid carcinoma

BACKGROUND New prognosticators are necessary for optimizing the extent of thyroidectomy and adjuvant radiotherapy in differentiated thyroid carcinoma. METHODS Tumor microvessel density (MVD), expression of thymidine phosphorylase (dThdPase) and CD68 stained macrophages were evaluated in 71 differentiated thyroid carcinomas by an immunohistochemical method. RESULTS The recurrence-free survival was significantly (P <0.05) shorter in patients with hypervascular tumors but was not related to the dThdPase expression. Significant (R = 0.323, P <0.001) correlation between dThdPase expression score and increment in MVD was documented. Frequent high MVD and dThdPase expression were encountered in tumors >3 cm. Twenty-two of the 27 (82%) patients expressing high dThdPase were also evaluated positive for CD68 (P <0.001). CONCLUSIONS Tumor MVD might be a new prognostic indicator of differentiated thyroid carcinoma, whereas dThdpase expression with high MVD might serve to identify a subgroup of thyroid carcinoma patients as potential candidates for adjuvant radiotherapy.

Thymidine phosphorylase (platelet-derived endothelial cell growth factor), microvessel density and clinical outcome in hepatocellular carcinoma

BACKGROUND/AIMS Angiogenesis plays an important role in tumor growth and metastasis. It is regulated by angiogenic factors. Thymidine phosphorylase (platelet-derived endothelial cell growth factor) is one such factor. Although the significance of platelet-derived endothelial cell growth factor has been studied for several types of tumor, the expression of platelet-derived endothelial cell growth factor and its correlation with microvessel density or clinicopathological factors in hepatocellular carcinoma are unknown. We evaluated microvessel density and platelet-derived endothelial cell growth factor expression in hepatocellular carcinoma to determine whether microvessel density and platelet-derived endothelial cell growth factor expression are correlated with the clinicopathological factors of hepatocellular carcinoma. METHODS Using immunohistochemical staining with anti-platelet-derived endothelial cell growth factor antibody and the ELISA method, we evaluated the correlation among platelet-derived endothelial cell growth factor expression, microvessel density and clinicopathological factors in 84 hepatocellular carcinoma patients. Microvessels were stained with anti-human von Willebrand factor (anti-Factor VIII) and anti-CD34. RESULTS In the surrounding liver, there was a significant correlation between microvessel density and platelet-derived endothelial cell growth factor expression (p=0.002), and hepatitis C virus-positive livers had higher microvessel densities than otherwise (p=0.003). However, this correlation was not found for hepatocellular carcinoma, but hepatitis C virus-positive tumors had higher expression of platelet-derived endothelial cell growth factor (p=0.018). Microvessel density in hepatocellular carcinoma obtained by Factor VIII staining inversely affected the recurrence-free survival rate (p=0.0416), but the microvessel density by CD34 staining was not a significant predictor. CONCLUSIONS This study indicates that platelet-derived endothelial cell growth factor may not be a major regulator of angiogenesis of hepatocellular carcinoma, but this enzyme may play an important role in hepatocarcinogenesis cooperating with hepatitis C virus. Also, the density, not of sinusoid-like vessels, but of larger vessels in hepatocellular carcinoma could be a prognostic factor for hepatocellular carcinoma.

Long-term Survival of Transmural Advanced Gastric Carcinoma following Curative Resection: Multivariate Analysis of Prognostic Factors

Abstract. Patients with transmural (T2N0–T3N2) advanced gastric carcinoma comprise the largest group with uncertain outcome. These patients must be stratified according to the prognostic variables so the high risk group can be precisely identified. A total of 152 patients with transmural advanced gastric carcinomas were uniformly treated with a curative intent between 1979 and 1989 with at least a 7-year follow-up. Results and prognostic factors of long-term survival were analyzed by univariate and multivariate analyses. Seventy-five (49%) patients with advanced gastric carcinoma survived more than 7 years, which indicates the curative nature of surgery for gastric carcinoma. Seventeen variables were evaluated by univariate analysis. In the multivariate analysis, patients age [> 70 years, relative risk (RR) 2.4)], intraoperative blood loss (> 500 ml, RR 1.7), blood vessel invasion (RR 2.3), ratio of invaded dissected lymph nodes (> 0.2, RR 3.0), and tumors penetrating the serosa (RR 3.9) were the independent prognostic variables. The results of this study indicate that extensive lymphadenectomy and minimal intraoperative blood loss might be helpful for improving patient survival following a curative resection. Patients with vessel invasion, serosal involvement, and those > 70 years of age should be considered at high risk and require appropriate adjuvant therapy to prolong survival.

One-lung or two-lung ventilation during transthoracic oesophagectomy?

The purpose of this study was to determine the safety of onelung ventilation (OLV) during transthoracic oesophagectomy. Changes in circulatory and respiratory variables during and after operation were compared in patients receiving OLV or conventional two-lung ventilation (TLV). Thirty patients undergoing transthoracic oesophagectomy were randomly divided into either the OLV or the TLV group. During thoracotomy,FiO2 was kept to 1.0. The PaO2 in the OLV group decreased from the prethoracotomy value of 467 ± 84 mmHg to 227 ± 162 mmHg during OLV. This decrease was greater than the decrease from 484 ± 79 mmHg to 380 ± 119 mmHg in the TLV group (P < 0.05). The shunt ratio increased in the OLV group from 20 ± 7% to 35 ± 13% during OLV which was greater than the increase in the TLV group (26 ± 7% from 17 ± 8%) (P < 0.05). Other variables and the incidence of the complications, however, were little different between the two groups during and after OLV and up to POD 3. It is concluded that OLV is as safe as TLV during oesophagectomy.RésuméCette étude vise à évaluer la sécurité de la ventilation unipulmonaire (OLV)pendant l’oesophagectomie transthoraciaue. Les modifications aux variables circulatoires et respiratoire pendant et après l’intervention sont comparées chez des patients en OLV ou sous ventilation conventionnelle bipulmonaire (TLV). Trente patients subissant une oesophagectomie transthoracique sont répartis au hasard entre les groupes OLV et TLV. Pendant la thoracotomie, laFiO2 est maintenue à 1,0. Dans le groupe OLV, la PaO2 baisse pendant l’OLV de la valeur préthoracotomie de 467 ± 84 mmHg à 227 ± 162 mmHg. Cette baisse est plus importante que la baisse de 484 ± 79 mmHg à 380 ± 119 mmHg qui survient dans le groupe TLV (P < 0,05). La fraction de shunt augmente dans le groupe OLV de 20 ± 7% à 35 ± 13% pendant l’OLV, ce qui constitue une augmentation plus importante que l’augmentation constatée dans le groupe TLV (de 17 ± 8% à 26 ± 7%) (P < 0,05). Cependant, les autres variables et l’incidence des complications ne diffèrent pas entre les deux groupes pendant et après OLV jusqu’au troisième jour postopératoire. Pendant l’oesophagectomie, la marge de sécurité est la même entre OLV et TLV.

Concurrent Expression of Angiogenic Growth Factors and Neovascularization during Tumourigenesis in Colorectal Carcinoma Patients

Details of concurrent expression of angiogenic growth factors (AGFs) and microvessel density (MVD) in human colorectal adenomas and carcinomas remain obscure. Eighty lesions, 20 each from colorectal adenoma, Tis, T1 and T2 cancers were evaluated immunohistochemically for basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), thymidine phosphorylase (dThdPase) and MVD. MVD (p = 0.0001) and bFGF expression (p = 0.0001) increased in the order of adenoma, Tis, T1 and T2 cancers. VEGF expression was same in adenomas and cancers while dThdPase was weak in adenomas but strongly expressed in invasive carcinomas ( > T1). MVD had positive correlation with tumour size in small (< or = 4 cm) colorectal cancers. Concurrent expression of AGFs was noticed in invasive carcinomas. bFGF seems to be the strongest among the three AGFs expressed during colorectal carcinogenesis and had a significant correlation with tumour MVD. Concurrent expression of multiple AGFs is a crucial step in the transition from non-invasive to invasive carcinoma.

nm23 in the primary and metastatic sites of gastric carcinoma. Relation to AFP-producing carcinoma.

Tumor metastasis is the major cause of treatment failure and death in cancer patients. The present study was designed to extrapolate the association of nm23 expression with acquisition of metastatic potential of gastric carcinoma with special reference to the alpha-fetoprotein-producing gastric carcinoma (APGC). The primary tumor with surrounding normal mucosa and metastatic lymph nodes of 30 patients with APGC and 29 randomly selected matched controls of non-AFP gastric carcinoma (NAGC) were immunostained for nm23 and an image analyzer system was used for quantitative evaluation. Overexpression of nm23 was noted in 71% (42/59) of the primary tumors and 18% (10/55) of the metastatic tumors and there was no difference between the APGC and NAGC groups. The overexpression of nm23 in the primary tumors correlated with tumor invasion, metastasis and progression in all cases and similar results were obtained in the APGC and NAGC groups except for the tumor stage which was insignificant in the APGC group. The patient survival was adversely affected by the overexpression of nm23 in the primary sites and downregulation in the metastatic sites in all cases but lost their significance in the multivariate analysis. However, nm23 status did not affect patient survival in the APGC group.