Akira Kabashima

Role of Transforming Growth Factor-β1 in Invasion and Metastasis in Gastric Carcinoma

PURPOSE Transforming growth factor-beta1 (TGF-beta1) is a major modulator of cellular proliferation and extracellular matrix formation. We determined the role of TGF-beta1 in invasion and metastasis in gastric cancer. MATERIALS AND METHODS We detected TGF-beta1 expression in primary and lymph node metastatic lesions of gastric cancer, using an antibody and in situ hybridization. The plasma TGF-beta1 levels in the peripheral vein and in the tumor drainage vein were assayed. RESULTS In the cytoplasm of cancer cells, TGF- beta1 was immunostained in 35.9% (78 of 217) of primary gastric carcinomas, and this expression was confirmed by in situ hybridization. Of 59 gastric carcinomas with a TGF-beta1-negative primary tumor, metastatic lymph nodes were positive for TGF-beta1 staining in 32 cases (54.2%). Positive staining of TGF-beta1 in gastric cancer tissues was closely related to serosal invasion, infiltrative growth, and lymph node metastasis. Multivariate analysis showed that the expression of TGF-beta1 was an independent risk factor for serosal invasion and infiltrative growth of the tumor. The plasma level of TGF-beta1 did not differ between TGF-beta1-negative and -positive groups. There were also no differences in plasma TGF-beta1 levels among each tumor stage, between the peripheral and the tumor drainage veins, and between preoperative and postoperative testings. CONCLUSION Transforming growth factor-beta1 is closely related to the invasion and metastasis of gastric cancer, and production of TGF-beta1 in the tumor does not contribute to the total amount of TGF-beta1 in the blood circulation. We interpret our observations to mean that in a tumor microenvironment, TGF-beta1 alters the biologic behavior of the tumor.

Clinical significance of vascular endothelial growth factor‐C (VEGF‐C) in breast cancer

Vascular endothelial growth factor‐C (VEGF‐C) is a specific ligand which induces lymphangiogenesis. We examined the expression of VEGF‐C protein to determine its role in the progression of breast cancer. Immunohistochemical analysis revealed that VEGF‐C was overexpressed in 39 of 98 breast cancer specimens (39.8%) but not in adjacent normal mammary glands. The expression of VEGF‐C showed a significant correlation with lymphatic vessel invasion (p=0.0004). It is noteworthy that the 5‐year disease free survival rate of the VEGF‐C positive group was significantly poorer than that of negative group (p=0.0356). We suggest that as expression of VEGF‐C is not implicated in lymphatic spread, it may prove to be a promising marker to predict the recurrence of breast cancer.

Overexpression of vascular endothelial growth factor C is related to lymphogenous metastasis in early gastric carcinoma.

Vascular endothelial growth factor C (VEGF-C) is considered to be potentially lymphangiogenic and can selectively induce hyperplasia of the lymphatic vasculature. In this study, we clarified the clinicopathological features of early gastric carcinoma (EGC) that has metastasized to the lymph nodes, as well as the correlation between lymphogenous metastases in EGC and the expression of VEGF-C and VEGF. We selected 35 cases of lymph node metastasis-positive [n(+)] EGC and 70 cases of lymph node metastasis-negative [n(–)] EGC for the present study. The expression of VEGF and VEGF-C was investigated with immunohistochemical staining using monoclonal antibodies against VEGF and VEGF-C. Clinicopathologically, there were significant differences in median size (4.1 ± 2.4 vs. 2.4 ± 1.7 cm), lymphatic invasion (54 vs. 4%) and venous invasion (23 vs. 3%) between n(+) EGC and n(–) EGC. Immunohistochemically, the incidence of positive expression of VEGF-C in lymphatic invasion-positive EGC (36%) was significantly higher than that in lymphatic invasion-negative EGC (14%). The incidence of positive expression of VEGF-C in n(+) or venous invasion-positive EGC tended to be higher than that in n(–) or venous invasion-negative EGC. In conclusion, lymphatic invasion was significantly increased in VEGF-C-positive EGC.

Gastric or intestinal phenotypic expression in the carcinomas and background mucosa of multiple early gastric carcinomas.

The differences in phenotypic expression between multiple early gastric carcinomas (EGCs) and solitary EGCs were evaluated in this study.

Phenotypic Expression of Colorectal Adenocarcinomas with Reference to Tumor Development and Biological Behavior

The purpose of this study is to clarify the correlation between cell differentiation and tumor development, including tumor aggressiveness and biological behavior. Eighty‐three cases of advanced colorectal adenocarcinoma were randomly selected. Using immunohistochemical staining with antibodies to CD10, MUC2 and human gastric mucin (HGM), the colorectal adenocarcinomas could be classified into five types (18 small intestinal, 27 large intestinal, 2 gastric, 9 mixed and 27 unclassified). Each type had characteristic features. The small‐intestinal type showed a relatively lower incidence of lymphatic permeation and higher venous invasion. The large‐intestinal type showed a low incidence of venous invasion and lymph node metastasis. The mixed type revealed female and right‐side‐dominant distribution, large tumor size, high incidence of mucinous carcinoma, and low incidence of venous invasion. Gastric type was seen in only two cases (2%), which exhibited high histologic grade, lymphatic permeation and lymph node metastasis with no venous invasion. Such phenotypic classifications are considered to be useful not only for evaluation of the biological behavior of the carcinoma, but also for analysis of tumorigenesis.

Combined Evaluation of Expressions of p53 and p21 Proteins as Prognostic Factors for Patients with Gastric Carcinoma

Background: The tumor suppressor gene p53 is a nuclear protein which plays a key role in tumor progression by regulating DNA repair, cell division and apoptosis. One major function of wild-type p53 is to control the onset of DNA replication at the G1-S boundary by inducing p21 protein, which promotes cell cycle arrest by inhibiting the phosphorylation of the cyclin-dependent kinases’ complexes and blocking cell cycle progression to the S-phase. Methods: 195 human gastric cancer specimens were prepared for immunohistochemical staining, using antibodies against p53 and p21. Clinicopathological factors and the clinical prognosis were examined for each indicator. Results: Of those 195, positive rates of p53 and p21 were 37.9% (74/195) and 42.6% (83/195), respectively. p53-negative patients had a better 5-year survival rate compared with positive ones (p < 0.05), and p21-positive cases had better 5-year survival rate compared with negative ones (p < 0.05). Four separate groups were prepared, based on expressions of p53 and p21, and the prognoses were compared. The incidence of the p53(–)/p21(+) group was 27.2% (53/195 cases) and that of the p53(–)/p21(–), p53(+)/p21(–) and p53(+)/p21(+) groups was totally 72.8% (142/195 cases). The 5-year survival time of the former group was 67.5% and was significantly longer than the combined 5-year survival time of the latter groups of 45.9% (p < 0.05). Conclusions: The incidence in cases where functions of either or both of p53 and p21 proteins were diminished exceeded 70% of all the cases. The survival time for the p53(–)/p21(+) group with proper functions of both proteins and the signal pathway was significantly longer. The combined evaluation of expressions of p53 and p21 proteins in gastric cancer tissues aids in predicting the clinical prognosis for surgically treated gastric cancer patients.

Long term survival of patients with stage IV gastric carcinoma

Survival of patients with Stage IV (based on general rules established by the Japanese Research Society for Gastric Cancer) gastric carcinoma often is unfavorable. Among patients with a poor prognosis, a few do survive > 5 years. The authors examined pathologic and biologic features of tumors of long term survivors.

Pure laparoscopic right hepatectomy in the semi-prone position using the intrahepatic Glissonian approach and a modified hanging maneuver to minimize intraoperative bleeding.

PurposeAlthough laparoscopic liver resection has been widely adopted, performing a pure laparoscopic right hepatectomy remains a challenging procedure. The aim of this report is to evaluate the efficiency of a pure laparoscopic right hepatectomy (PLRH) in the semi-prone position using the intrahepatic Glissonian approach and a modified hanging maneuver.MethodsPure laparoscopic right hepatectomy was performed in the semi-prone position with the use of an intrahepatic Glissonian approach and modified hanging maneuver for patients with primary liver cancer (n = 3) and metastatic liver cancer (n = 1).ResultsThe intraoperative total blood loss was only 95–140 g (mean: 126.2 g). None of the patients required a blood transfusion, and no serious complications were encountered. The durations of the surgeries ranged from were 308 to 445 min (mean: 394.8 min). The postoperative hospital stay was 8–11 days (mean 9.5 days).ConclusionPure laparoscopic right hepatectomy in the semi-prone position using the intrahepatic Glissonian approach and a modified hanging maneuver is thus considered to be a safe modality, which minimizes intraoperative bleeding.

Comparison of enteral nutrition with combined enteral and parenteral nutrition in post-pancreaticoduodenectomy patients: a pilot study

BackgroundMany clinical studies have demonstrated that early postoperative enteral nutrition (EN) improved the postroperative course. Post-pancreaticoduodenectomy (PD), patients tend to suffer from postoperative nausea, abdominal distention, and diarrhoea, causing difficulty in the introduction of EN. In this pilot study, we investigated the appropriate nutritional mode post-pancreatic surgery.MethodsBetween October 2006 and March 2007 2 postoperative nutritional methods were implemented in 17 patients in a prospective single-centere study. Eight patients received only enteral nutrition (EN group) and 9 patients received enteral nutrition combined with parenteral nutrition (EN + PN group).ResultsThere were no differences in the patient characteristics and postoperative morbidity between the 2 groups. The rate of discontinuance of enteral feeding was significantly high in the EN group, and the duration of enteral feeding was significantly longer in the EN + PN group. The central venous line was retained for a significantly longer period in the EN + PN group, but there was no difference in the frequency of catheter-related infection between the 2 groups.ConclusionEN combined with PN is more adequate for patients after pancreatic surgery.

Smoking-related increase of O6-methylguanine-DNA methyltransferase expression in squamous cell carcinoma of the esophagus

DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) has a defensive role against alkylating agents associated with increased incidence of malignant tumors. The aim of the current study was to elucidate the significance of immunohistochemical expression of MGMT in squamous cell carcinoma (SCC) of the esophagus, with a special reference to the correlation of smoking. Immunohistostaining of MGMT was performed in the specimens collected from 100 patients with SCC of the esophagus. The relationship between the personal history of smoking and MGMT expression was examined and the value of Brinkman index was compared between patients with and without MGMT expression. Fifty-five SCCs (55.0%) had a positive response to MGMT inununostaining. The proportion of patients who had tumors with MGMT expression among patients with smoking habits was 62.0% (49 out of 79), which was significantly higher than that among patients without smoking habits (28.6%, 6 out of 21; P=0.005). The mean value of Brinkman index in patients who had tumors with MGMT expression (1189+/-604) was significantly higher than that in patients who had tumors without MGMT expression (871+/-656; P=0.020). Our results suggested that MGMT expression in esophageal SCC might be correlated with smoking habits of the patients.