Etsurou Bandou

Treatment of peritoneal dissemination from gastric cancer by peritonectomy and chemohyperthermic peritoneal perfusion

There is no standard treatment for peritoneal dissemination from gastric cancer. A novel treatment consisting of peritonectomy and intraoperative chemohyperthermic peritoneal perfusion (CHPP) was compared with conventional surgery and CHPP.

Randomized clinical trial of D2 and extended paraaortic lymphadenectomy in patients with gastric cancer.

BackgroundThe survival of patients with advanced gastric cancer after D2 dissection is still poor. Asian surgeons have proposed a more radical lymph node dissection, designated as D4 dissection, where paraaortic lymph nodes are removed in combination with D2 dissection. To evaluate the survival benefit of D4 dissection, a multi-institutional randomized trial of D2 vs D4 gastrectomy was conducted.MethodsPatients enrolled in the study had potentially curable gastric adenocarcinoma at an advanced stage. Patients were randomized to undergo either D2 or D4 gastrectomy.ResultsTwo hundred and ninety-three patients were registered and 269 patients were eligible; 135 patients were allocated to the D2 group and 134 to the D4 group. Five-year survival was 52.6% after D2 surgery and 55.0% after D4 gastrectomy. There was no significant difference in survival between the D2 and D4 groups (χ2 = 0.064; P = 0.801). Hospital deaths occurred in 1 patients (0.7%) in the D2 group and 5 in the D4 group D4 gastrectomy is a more risky surgery than D2 dissection. Seven patients (5.2%) in the D2 and 15 (11.2%) in the D4 group died of causes other than gastric cancer recurrence. Sixty-three patients (46.7%) in the D2 group and 52 (38.8%) in the D4 group had disease recurrence.ConclusionProphylactic D4 dissection is not recommended for patients with potentially curable advanced gastric cancer.

Effective therapy for peritoneal dissemination in gastric cancer

Peritoneal dissemination is the most frequent cause of death from gastric cancer, accounting for death in 20% to 40% of patients. Preoperative intraperitoneal chemotherapy, peritonectomy, intraoperative chemohyperthermic perfusion, and early postoperative intraperitoneal chemotherapy are treatment modalities specifically designed to eliminate peritoneal dissemination and progression. Preoperative intraperitoneal chemotherapy is for containment of peritoneal free cancer cells, and also may facilitate complete eradication of visible peritoneal dissemination by peritonectomy. Further, complete cytoreduction can be achieved more often when peritonectomy is included in the surgical treatment of gastric cancer with peritoneal dissemination. Phase III data shows prolonged survival attributed to complete cytoreduction. Aggressive cytoreduction of peritoneal dissemination by peritonectomy can reduce residual tumor burden to micrometastases on the peritoneal surface that can be treated by intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. Among all these modalities, surgical cytoreduction is probably the most important for survival benefit. If the surgical cytoreduction is visibly incomplete, prolonged survival cannot be expected, despite subsequent treatment. The surgeons goal is to reduce the cancer cell burden to a microscopic level. Continued refinement of phase II studies is needed for maximal benefit and to standardize the technical and chemotherapeutic options of each modality.

Role of VEGF-C and VEGF-D in lymphangiogenesis in gastric cancer

BackgroundThe molecular mechanisms of lymphangiogenesis induced by vascular endothelial growth factor (VEGF)-C and VEGF-D in gastric cancer were studied.MethodsVEGF-C and VEGF-D gene expression vectors were transfected into the gastric cancer cell line KKLS, which did not originally express VEGF-C and VEGF-D, and stable transfectants (KKLS/VEGF-C and KKLS/VEGF-D) were established. The cell lines were inoculated into the subserosal layer of the stomach and subcutaneous tissue of nude mice.ResultsVEGF-C and VEGF-D expression in KKLS/VEGF-C and KKLS/VEGF-D cells was found by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Expression of mouse VEGF receptor (VEGFR)-2 and mouse VEGFR-3 mRNA was detected in the KKLS/VEGF-C and KKLS/VEGF-D gastric tumors. Newly formed lymphatic vessels were detected not only in the periphery but also in the center of the tumors. The intratumor lymphatic vessels connected with the preexisting lymphatic vessels in the muscularis mucosa. The average numbers of lymphatic vessels in KKLS/VEGF-C (52.0 ± 9.5) and KKLS/VEGF-D (16.4 ± 0.6) gastric tumors were significantly higher than that in the KKLS/control vector tumors (4.0 ± 1.4).ConclusionVEGF-C and VEGF-D may induce neoformation of lymphatic vessels in experimental gastric tumors by the induction of VEGFR-3 expression.

Expression of collagenase-3 (matrix metalloproteinase-13) in human gastric cancer

Abstract.Background: Collagenase-3 (matrix metalloproteinase-13; MMP-13) is a recently identified member of the matrix metalloproteinases (MMPs) with broad substrate specificity, and a potential role in tumor metastasis and invasion has been proposed for this enzyme. To date, in gastrointestinal tract tumors, collagenase-3 expression has been reported only in esophageal carcinoma; the presence and possible implications of this enzyme in the progression of gastric cancer are unknown.Methods: In this study, MMP-13 mRNA expression was analyzed in a series of 110 matched gastric adenocarcinomas and the corresponding adjacent normal mucosae as well as in nine gastric cancer cell lines. In addition, the mRNA expression of gelatinase A (MMP-2) and membrane type-1 matrix metalloproteinase (MT1-MMP), two MMPs which have the ability to activate MMP-13 in vitro, was also examined in the same cases and cell lines. The production and localization of MMP-13, MMP-2, and MT1-MMP were investigated by immunohistochemistry, immunofluorescence, Western blot analysis, and zymography.Results: MMP-13 mRNA was expressed in 23 of the 110 carcinomas (21%), and MT1-MMP mRNA was expressed in 45 (40%), but no MMP-13 or MT1-MMP mRNA was detected in any of the normal mucosae. Also, eight of the nine gastric cancer cell lines expressed mRNA of MMP-13, and in each cell line there was coordinate expression with either MT1-MMP or MMP-2 mRNA. MMP-13 and MT1-MMP were detected at the bases of invadopodia of the cultured cancer cells as well as in the invasive front of the tumors, as shown by immunofluorescence and immunohistochemistry, respectively. Western blot analysis revealed the presence of MMP-13 protein in those cell lines and carcinomas that expressed its mRNA. On zymography, almost all cell lines that expressed MMP-13 showed gelatinolytic bands corresponding to the active form of MMP-13 or one of its intermediate forms. Also, zymographic analysis of the tumor specimens revealed strong gelatinolytic bands of MMP-13 and MMP-2, whereas these bands in normal mucosa were weak. There was no significant relationship between MMP-13 mRNA expression and histologic type, lymph node metastasis, wall invasion, or distant metastasis. However, patients with MMP-13 mRNA-positive tumors had a poorer prognosis than those with MMP-13-mRNA-negative cancer. Furthermore, patients with simultaneous expression of MMP-13 and MT1-MMP mRNA showed the poorest prognosis, as compared with those having tumors expressing either MMP-13 or MT1-MMP, or neither MMP-13 nor MT1-MMP mRNA.Conclusion: These findings suggest that MMP-13 expression may contribute to the progression of gastric cancer, and its coordinate overexpression with MT1-MMP and/or MMP-2 may have a cooperative effect in the progression of gastric cancer.

Proliferative activity of micrometastases in the lymph nodes of patients with gastric cancer

Immunohistochemically detectable isolated tumour clusters (ITCs) with a diameter of less than 0·2 mm have been regarded as non‐metastatic lesions, because of a lack of proliferative activity. This study investigated the proliferative activities of ITCs.

Role of MMP-7 in the formation of peritoneal dissemination in gastric cancer.

Background. Matrix metalloproteinase-7 (MMP-7) is an important matrix-degrading enzyme that has a large role in the invasion and metastasis of cancer. To discover the mechanism of the formation of peritoneal dissemination in gastric cancer, we studied the mRNA and protein expression of MMP-7 in primary gastric cancers and peritoneal dissemination.Methods. MMP-7 expression in primary gastric cancers (136 patients) was studied by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), and the results were compared with chinicopathological parameters.Results. MMP-7 mRNA was expressed in 28 (53%) of 53 primary gastric cancers, but not in normal gastric mucosa, fibroblasts, or mesothelial cells. An immunohistochemical method demonstrated that MMP-7 immunoreactivity was found on the cell membrane and cytoplasm of cancer cells. Among 136 primary tumors, 70 (53%) tumors overexpressed MMP-7, and MMP-7 tissue status had significant positive correlation with serosal involvement, lymph node metastasis, poor differentiation of cancer, and peritoneal dissemination. Patients with MMP-7-positive tumor had significantly poorer survival and more frequently died of peritoneal recurrence than did those with MMP-7-negative tumors. All 6 examined peritoneal disseminations expressed MMP-7 mRNA, and 13 of 14 peritoneal disseminations showed immunoreactivity to anti-human MMP-7 monoclonal antibody. Logistic regression analysis showed that MMP-7 immunohistological status was an independent risk factor for peritoneal dissemination, and patients with MMP-7 mRNA-positive tumors had a 9.9-fold higher relative risk for peritoneal metastasis.Conclusion. These results strongly suggest that MMP-7 may have a large role in the formation of peritoneal dissemination in gastric cancer, and that clonal selection of cancer cells with MMP-7 overexpression may occur during the invasion of intraperitoneal free cancer cells from the peritoneal surface into the subperitoneal tissue. MMP-7 tissue status in the primary tumor may be a good indicator of peritoneal dissemination.

The Natural History of Free Cancer Cells in the Peritoneal Cavity

Peritoneal dissemination is established through a multistep process [1]. The first step is the detachment of cancer cells from the serosal surface of the primary tumor; the detached cancer cells are referred to as “peritoneal free cancer cells” (Fig. 2.1b, process 1). E-cadherin is the key molecule for the homophilic cell-cell adhesion [2], and the deleted expression of E-cadherin or abnormalities on the E-cadherin gene have a role in the detachment of cancer cells [3]. Namely, cancer cells with reduced expression of E-cadherin easily detach from the serosal surface and become peritoneal free cancer cells. In gastric cancer, abnormal expression of E-cadherin is more frequently found in poorly differentiated adenocarcinoma than in differentiated adenocarcinoma, and peritoneal dissemination is the main form of metastasis in poorly differentiated adenocarcinoma of the stomach [4]. Open image in new window Fig. 2.1 b Peritoneal free cancer stained with Papanicolaou staining

Diagnostic value of preoperative RT-PCR-based screening method to detect carcinoembryonic antigen-expressing free cancer cells in the peritoneal cavity from patients with gastric cancer

Background: At present the most reliable method for the diagnosis of peritoneal micrometastasis of gastric cancer is peritoneal wash cytology, but the sensitivity of this method is low. The aim of the present study was to verify whether carcinoembryonic antigen (CEA) reverse transcriptase–polymerase chain reaction (RT‐PCR) assay can enhance the sensitivity and specificity of conventional cytology, and to determine how this technique can improve the accuracy of peritoneal recurrence.

Advances in the Management of Gastric Cancer with Peritoneal Dissemination

Prognosis of patients with peritoneal carcinomatosis (PC) from gastrointestinal cancer is poor, with a median overall survival of only 3 months [1], [2], and a 5-year survival rate of less than 1% [3]. Furthermore, no survival advantage was found after gastrectomy and lymph node dissection in this context, and therefore simple gastrectomy without additional lymphadenectomy is the optimal strategy for patients with PC [4]. In addition, there is no standard treatment and no effective anticancer drug for peritoneal dissemination. At present, intravenous 5-fluorouracil (5-FU) has been used alone [5] or in combination with other anticancer drugs FAM [6] and FAMTX [7] for chemotherapy of advanced gastric cancer. However, systemic chemotherapy does not improve the survival of patients with peritoneal dissemination [8], [9], because only a small amount of drug reaches the peritoneal cavity after intravenous administration.