Michio Maeta

Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C

Continuous hyperthermic peritoneal perfusion (CHPP) with a solution that contains mitomycin C (CHPP‐M) has been clinically introduced as a prophylactic treatment for peritoneal recurrence of gastric cancer with serosal invasion. Two studies, each with a treated and a control group, were performed. In the historical control study the postoperative 3‐year survival rate of patients (73.7%) in the treated group (n = 38) was significantly higher than the survival rate (52.7%) of those in the control group (n = 55) (P < 0.04). In the random control study the survival rate (83%) of patients in the treated group (n = 26) was also higher than that (67.3%) of those in the control group (n = 21) in the 30 months that followed gastric surgery. However, there was no significant difference. In the historical control study with respect to the postoperative complications, anastomotic leak was observed in 8.5% of patients who were given CHPP‐M and 12.8% patients who did not have CHPP‐M. In the random control study anastomotic leak was observed in 3.1% of patients who had CHPP‐M and 7.1% of patients who did not have CHPP‐M. The incidence of adhesive ileus in patients having CHPP‐M did not increase in historical or random control groups. Postoperative prolonged intestinal paresis or chemical peritonitis were not induced by CHPP‐M. These results indicate that CHPP‐M is a simple, safe, and readily available prophylactic therapy for peritoneal recurrence that may follow gastric cancer surgery.

Intraperitoneal thermochemotherapy for prevention of peritoneal recurrence of gastric cancer. Final results of a randomized controlled study

Background. Continuous hyperthermic peritoneal perfusion (CHPP) with a solution that contained 10 μg/ml mitomycin C was devised initially as a method for intraperitoneal thermochemotherapy. The authors conducted a randomized clinical trial to evaluate the efficacy of CHPP as a prophylactic treatment for prevention of peritoneal recurrence of gastric cancer with serosal invasion.

Less invasive surgery for early gastric cancer based on the low probability of lymph node metastasis

BACKGROUND Less invasive treatment is the current trend in many surgical fields. Most patients with early gastric cancer do not have lymph node metastasis. Thus extensive resection of the stomach and extended lymph node dissection do not appear to be necessary. METHODS In a retrospective study, 890 consecutive patients with early gastric cancer who had undergone standard gastrectomy were assessed for depth of invasion, gross appearance, and maximum diameter of the tumor to examine the possibility of limiting the extent of lymph node dissection. A variety of limited gastrectomies have been developed and now include endoscopic mucosal resection, wedge resection, segmental gastrectomy, limited proximal gastrectomy, and distal hemigastrectomy. RESULTS A retrospective study revealed that extensive lymph node dissection did not improve the survival of patients with early gastric cancer. Endoscopic mucosal resection was suitable for cancers of the depressed type of less than 1 cm in diameter and the elevated type of less than 2 cm in diameter. Wedge, segmental, or limited proximal gastrectomy was suitable for the elevated type of 2 to 3 cm in diameter. The elevated type of more than 3 cm in diameter and the depressed type of 1 to 3 cm in diameter sometimes involved metastasis to group 1 nodes. The depressed type of more than 3 cm in diameter sometimes involved metastasis to group 2 nodes. Thus such cases should be treated by gastrectomy with dissection of potentially metastatic lymph nodes. CONCLUSIONS Limitation of the extent of gastrectomy and lymph node dissection may be possible, depending on the gross appearance and size of the tumor.

Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue

It has been reported that decreased numbers of dendritic cells (DCs) are correlated with poor prognosis in some types of malignancy, such as gastric cancer. However, factors that determine the density of DCs have not been characterized. It was recently reported that vascular endothelial growth factor (VEGF) inhibits the functional maturation of DCs from CD34+ precursors. In this study, we analysed the relationship between the expression of VEGF and the density of DCs in gastric carcinoma tissues by immunohistochemical staining. The extent of infiltration by DCs was graded from marked to slight on the basis of the mean densities of DCs. The prognosis of patients with marked infiltration was significantly better than that of patients with slight infiltration among patients who had undergone curative resection. Multivariate analysis showed that infiltration by DCs was an independent prognostic indicator. Furthermore, there was an inverse correlation between the density of DCs and the expression of VEGF Our results suggest that expression of VEGF might be associated with tumour progression and poor prognosis not only because VEGF stimulates angiogenesis, but also because it allows tumours to escape from attack by the immune system in patients with gastric carcinoma.

The expression of transforming growth factor-β1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric carcinoma

Transforming growth factors β (TGFs β) are involved in a variety of important cellular functions, including cell growth and differentiation, adhesion, migration, extracellular matrix formation, and immune function. Moreover, it has been reported that TGFs β are correlated with angiogenesis. However, the role of TGF‐β as an angiogenic factor in gastric carcinoma is still unclear.

Expression of vascular endothelial growth factor correlates with hematogenous recurrence in gastric carcinoma

BACKGROUND It has recently been reported that the microvessel density in a tumor correlates with hematogenous metastasis in gastric carcinoma. The aim of this study was to evaluate the relationship between the expression of vascular endothelial growth factor (VEGF), which was thought to be a potent angiogenesis-promoting factor, and hematogenous recurrence in advanced gastric carcinoma. METHODS The expression of VEGF and the density of the microvessels were examined by immunohistochemistry in patients with advanced gastric carcinoma with serosal invasion who had undergone curative resection. RESULTS The prognosis of patients with a VEGF-negative tumor was significantly better than that of patients with a VEGF-positive tumor. Multivariate analysis by Cox proportional hazards model showed that the expression of VEGF was an independent prognostic indicator. The expression of VEGF provided a significant estimate of relative risk for the development of hematogenous recurrence by multivariate logistic regression analysis. The microvessel count in VEGF-positive tumors was significantly higher than that in VEGF-negative tumors. CONCLUSIONS VEGF is associated with hematogenous recurrence. Assessment of the expression of VEGF may therefore prove valuable in identifying patients with gastric carcinoma at high risk for recurrence who would benefit from adjuvant therapy.

Significant correlation between micrometastasis in the lymph nodes and reduced expression of E-cadherin in early gastric cancer

Background. E-cadherin has been recognized as an impor-tant factor associated with tumor metastasis. However, the relationship between micrometastasis in the lymph nodes and the expression of E-cadherin in the primary tumor in gastric cancer remains unclear.Methods. Two consecutive sections of 4522 lymph nodes from 162 patients with early gastric cancer were prepared for simultaneous hematoxylin and eosin (H&E) and cytokeratin (CK) staining. Sections of primary tumors from 135 of these patients were prepared for E-cadherin immunostaining.Results. The incidence of lymph node involvement was significantly increased, from 6.8% (11/162 patients) by H&E staining, to 27% (43/162 patients) by CK immunostaining (P < 0.0001). Micrometastasis in the lymph node was found in 32 of 151 (21%) patients who had no lymph node metastasis evidenced by H&E staining. Micro-lymph node metastasis was frequently found in tumors with a diameter more than 1.0 cm, of those that were poorly differentiated, deeply invaded, showed lymphatic on vascular invasion, and in those that showed reduced expression of E-cadherin. Loss of expression of E-cadherin in the primary tumor was closely correlated with micro-lymph node metastasis. Patients with tumors with micro-lymph node metastasis detected by CK immunostaining had a significantly lower 5-year survival rate (P < 0.01) than those without such metastases.Conclusion. Tumors more than 1.0 cm in diameter and those that exhibit poor differentiation, deep invasion (i.e., to the submucosa), lymphatic or vascular invasion, and reduced expression of E-cadherin are risk factors for lymph node metastasis in early gastric cancer. Thus, it is recommended that cancers confined to the mucosa (m-cancers) that are more than 1.0 cm in diameter should not be treated with limited surgery without lymphadenectomy.

A prospective pilot study of extended (D3) and superextended para-aortic lymphadenectomy (D4) in patients with T3 or T4 gastric cancer managed by total gastrectomy☆

BACKGROUND Japanese surgeons have been actively performing extended lymphadenectomy (D2, removal of perigastric nodes and nodes along the left gastric, common hepatic, celiac and splenic arteries; or D3, D2 plus removal of nodes in the hepatoduodenal ligament, in the retropancreatic space and along the vessels of the transverse mesocolon). In recent years interest has expanded to superextended lymphadenectomy (D4) of nodes around abdominal aorta (para-aortic lymph nodes from aortic hiatus to aortic bifurcation). Because the therapeutic value of this D4 procedure remains controversial, we initiated a prospective study to compare D3 and D4 lymphadenectomy. METHODS Seventy patients with T3 or T4 gastric cancer and without macroscopic metastasis to the para-aortic nodes treated by potentially curative total gastrectomy were randomized to D4 (group A, n = 35) and D3 (group B, n = 35) lymphadenectomies. RESULTS Metastases to para-aortic nodes were found in 4 patients. Postoperative survival after D4 resection was not statistically significant between the groups. Postoperative morbidity for group A was greater. In group A 4 patients had postoperative retention of intra-abdominal fluid (lymphorrhea) and 4 others had prolonged diarrhea. One patient in each group died of postoperative complications. CONCLUSIONS Surgical treatment of microscopic disease in grossly normal para-aortic lymph nodes may generate occasional long-term survivors. Selecting appropriate candidates who might benefit from D4 resections needs to be refined. On the basis of this study, a nationwide study should be considered.

Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric carcinoma

The expression of variant isoforms of CD44 is correlated with the ability of tumor cells to metastasize in some clinical carcinomas. In this study, the serum concentration of soluble splice isoforms of CD44 that shared exon variant 6 (sCD44v6) were measured and the histologic expression of CD44v6 in tumors from patients with gastric carcinoma examined.

The expression of thymidine phosphorylase correlates with angiogenesis and the efficacy of chemotherapy using fluorouracil derivatives in advanced gastric carcinoma

SummaryThe expression of thymidine phosphorylase (TP) and the density of microvessel in advanced gastric carcinoma were examined by immunohistochemistry to evaluate the significance of TP. The expression of TP was negative in 72 cases, positive in 54. The microvessel density correlated with the expression of TP. In total cases, patients with TP-positive tumours survived longer than those with TP-negative tumours. In patients treated with fluorouracil derivatives (FUs), the expression of TP significantly correlated with favourable prognosis and with unfavourable prognosis in those not treated with FUs. The patients with TP-positive tumours, the prognosis of patients treated with FUs was significantly better than that of those not treated with FUs. In patients with TP-positive tumours, treatment with FUs and lymph node metastasis were independent prognostic factors according to the Cox proportional hazards model. Depth of invasion and lymph node metastasis were independent prognostic factors in patients with TP-negative tumours. The determination of the expression of TP might be useful for predicting the efficacy of post-operative chemotherapy using FUs to prevent recurrence in advanced gastric carcinoma patients who undergo curative gastrectomy.