The Development of Peritoneal Metastasis from Gastric Cancer and Rationale of Treatment According to the Mechanism.

In the present article, we describe the normal structure of the peritoneum and review the mechanisms of peritoneal metastasis (PM) from gastric cancer (GC). The structure of the peritoneum was studied by a double-enzyme staining method using alkaline-phosphatase and 5'-nucreotidase, scanning electron microscopy, and immunohistological methods. The fundamental structure consists of three layers, mesothelial cells and a basement membrane (layer 1), macula cribriformis (MC) (layer 2), and submesothelial connective tissue containing blood vessels and initial lymphatic vessels, attached to holes in the MC (layer 3). Macro molecules and macrophages migrate from mesothelial stomata to the initial lymphatic vessels through holes in the MC. These structures are characteristically found in the diaphragm, omentum, paracolic gutter, pelvic peritoneum, and falciform ligament. The first step of PM is spillage of cancer cells (peritoneal free cancer cells; PFCCs) into the peritoneal cavity from the serosal surface of the primary tumor or cancer cell contamination from lymphatic and blood vessels torn during surgical procedures. After PFCCs adhere to the peritoneal surface, PMs form by three processes, i.e., (1) trans-mesothelial metastasis, (2) trans-lymphatic metastasis, and (3) superficial growing metastasis. Because the intraperitoneal (IP) dose intensity is significantly higher when generated by IP chemotherapy than by systemic chemotherapy, IP chemotherapy has a great role in the treatment of PFCCs, superficial growing metastasis, trans-lymphatic metastasis and in the early stages of trans-mesothelial metastasis. However, an established trans-mesothelial metastasis has its own interstitial tissue and vasculature which generate high interstitial pressure. Accordingly, it is reasonable to treat established trans-mesothelial metastasis by bidirectional chemotherapy from both IP and systemic chemotherapy.

5-Aminolevulinic Acid Fluorescence in Detection of Peritoneal Metastases.

BACKGROUND: The value of 5-aminolevulinic acid (ALA) in fluorescence detection of peritoneal metastases and the underlying mechanisms were evaluated in patients with peritoneal surface malignancies. MATERIALS AND METHODS: Oral 5-ALA was administered at a concentration of 20 mg /kg body weight with 50 ml of water 2 hours prior to surgery (n=115). The diagnostic value of 5-ALA based fluorescence production was evaluated following white light inspection during prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Then, peptide transporter PEPT1 (ALA influx transporter) and ATP-binding cassette transporter ABCG2 (porphyrin efflux transporter) gene expression was determined with quantitative real time (qRT)-PCR and pathological diagnoses confirmed for all tissue samples. RESULTS: The 5-ALA based photodynamic detection rate was 17% for appendiceal mucinous neoplasms, 54% for colorectal cancers, 33% for gastric cancers, 67% for diffuse malign peritoneal mesotheliomas, and 89% for epithelial ovarian cancer of peritoneal metastases. 5-ALA was detected in all cases of peritoneal metastases originating from cholangiocarcinomas whereas it was not able to detect any in granulosa cell and gastrointestinal stromal tumor cases. Furthermore, PEPT1 was overexpressed whereas ABCG2 expression was downregulated in tumors detected with fluorescence. CONCLUSIONS: 5-ALA provided 100% specificity and high sensitivity to detect peritoneal metastases in subgroups of patients with peritoneal surface mailgnancies. ALA influx transporter PEPT1 and porphyrin efflux transporter ABCG2 genes are important in tumor specific 5-ALA induced fluorescence in vivo. Further studies should clarify diagnostic utility of 5-ALA in peritoneal surface malignancies.

Peritoneal cancer treatment.

INTRODUCTION: In the past, peritoneal surface malignancy (PSM) was considered as a final stage of cancer, and patients were offered the best supportive care. Recently, a new therapeutic alternative approach based on the combination of surgery with chemotherapy was developed. In this curative intent, the macroscopic disease was treated with cytoreductive surgery (CRS) combined with perioperative chemotherapy, including neoadjuvant chemotherapy, hyperthermic intraoperative intraperitoneal chemotherapy, extensive intraoperative peritoneal lavage and early postoperative intraperitoneal chemotherapy AREAS COVERED: This article reviews the mechanisms of the formation of PSM, quantitative estimation of PSM and residual disease, multimodal treatment, value of laparoscopy, prognostic factors and patients' selection for the multimodal therapy. EXPERT OPINION: Recent studies show that CRS plus intraperitoneal chemotherapy applications confer prolonged survival in patients with PSM from colorectal, gastric, ovarian, appendiceal mucinous carcinoma and diffuse malignant peritoneal mesothelioma. The comprehensive treatment is now justified as state-of-the-art for patients with peritoneal metastasis.

Treatment results of diffuse malignant peritoneal mesothelioma.

During the last 7 years, 21 patients with DMPM were treated. Histologic types were epitheloid type in 18 patients, biphasic type in 2 patients and sarcomatoid type in 1 patient. Preoperative systemic chemotherapy, hyperthermic intraperitoneal chemotherapy(HIPEC) by laparoscopy(LHIPEC), and intraperitoneal(IP) chemotherapy were done in 14, 3 and 1 patients, respectively. Cytoreductive surgery(CRS) was done in 13 patients. Ten patients received HIPEC after CRS. Partial responses were experienced in 4 of 13 patients treated with preoperative systemic chemotherapy. One of three patients treated by LHIPEC showed complete response. Among 13 patients received laparotomy, complete removal of PC was done in 4(31%) patients. The other 9 patients who received incomplete cytoreduction had diffuse involvement on the small bowel and its mesentery. All over 5-year survival was 17%. Patients treated with HIPEC survived significantly longer than non-HIPEC group. Neoadjuvant laparoscopic HIPEC may have a great role in the preoperative control of small PC on the surface of small bowel.

Effects of neoadjuvant intraperitoneal/systemic chemotherapy (bidirectional chemotherapy) for the treatment of patients with peritoneal metastasis from gastric cancer.

Novel multidisciplinary treatment combined with neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS) and peritonectomy was developed. Ninety-six patients were enrolled. Peritoneal wash cytology was performed before and after NIPS through a port system. Patients were treated with 60 mg/m(2) of oral S-1 for 21 days, followed by a 1-week rest. On days 1, 8, and 15, 30 mg/m(2) of Taxotere and 30 mg/m(2) of cisplatin with 500 mL of saline were introduced through the port. NIPS is done 2 cycles before surgery. Three weeks after NIPS, 82 patients were eligible to intend cytoreductive surgery (CRS) by gastrectomy + D2 dissection + periotnectomy to achieve complete cytoreduction. Sixty-eight patients showed positice cytology before NIPS, and the positive cytology results became negative in 47 (69%) patients after NIPS. Complete pathologic response on PC after NIPS was experienced in 30 (36.8%) patients. Stage migration was experienced in 12 patients (14.6%). Complete cytoreduction was achieved in 58 patients (70.7%). By the multivariate analysis, complete cytoreduction and pathologic response became a significantly good survival. However the high morbidity and mortality, stringent patient selection is important. The best indications of the therapy are patients with good pathologic response and PCI ≤ 6, which are supposed to be removed completely by peritonectomy.

Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer.

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. A novel multidisciplinary treatment combining bidirectional chemotherapy [neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)], peritonectomy, hyperthermic intraperitoneal chemoperfusion (HIPEC) and early postoperative intraperitoneal chemotherapy has been developed. In this article, we assess the indications, safety and efficacy of this treatment, review the relevant studies and introduce our experiences. The aims of NIPS are stage reduction, the eradication of peritoneal free cancer cells, and an increased incidence of complete cytoreduction (CC-0) for PC. A complete response after NIPS was obtained in 15 (50%) out of 30 patients with PC. Thus, a significantly high incidence of CC-0 can be obtained in patients with a peritoneal cancer index (PCI) ≤ 6. Using a multivariate analysis to examine the survival benefit, CC-0 and NIPS are identified as significant indicators of a good outcome. However, the high morbidity and mortality rates associated with peritonectomy and perioperative chemotherapy make stringent patient selection important. The best indications for multidisciplinary therapy are localized PC (PCI ≤ 6) from resectable gastric cancer that can be completely removed during a peritonectomy. NIPS and complete cytoreduction are essential treatment modalities for improving the survival of patients with PC from gastric cancer.

Indication of peritonectomy for peritoneal dissemination.

A total of 521 patients with peritoneal carcinomatosis (PC) were treated by peritonectomy and perioperative chemotherapy. Each of the 95, 58, 316, 31, 10 and 11 patients were from gastric, colorectal, appendiceal, ovarian, small bowel cancer and mesothelioma, respectively. The distribution and volume of PC are recorded by the Sugarbaker peritoneal carcinomatosis index (PCI). Peritonectomy was performed with a radical resection of the primary tumor and all gross PC with involved organs, peritoneum, or tissue that was deemed technically feasible and safe for the patient. The postoperative major complication of grade 3 was found in 14%, and total 30-day mortality was 2.7%. The survival of gastric cancer patients with a PCI score ≤ 6 was significantly better than those with a PCI score ≥ 7. In appendiceal neoplasm, patients with PCI score less than 28 showed significantly better survival than those with PCI score greater than 29. The survival of colorectal cancer patients with a PCI score ≥ 11 was significantly poorer than those with a PCI score ≤ 10. Among the various prognostic factors in appendiceal neoplasm and gastric cancer patients, CC-0 complete cytoreduction was the most important independent prognostic factor. Peritonectomy is done to remove macroscopic disease and perioperative intraperitoneal chemotherapy to eradicate microscopic residual disease aiming to remove disease completely with a single procedure. Peritonectomy combined with perioperative chemotherapy may achieve long-term survival in a selected group of patients with PC. The higher mortality rate underlines this necessarily strict selection that should be reserved to experienced institutions.

Safety and efficacy of bidirectional chemotherapy for treatment of patients with peritoneal dissemination from gastric cancer: Selection for cytoreductive surgery.

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. New bidirectional chemotherapy (neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)) was developed. The aim of the present study was to assess the safety and efficacy of NIPS and to show the selection for cytoreductive surgery on PC from gastric cancer. Seventy-nine patients with PC from gastric cancer were treated with NIPS. A peritoneal port system was introduced into the abdominal cavity. The peritoneal wash cytological examination through a port was done before and after NIPS. The patients were treated with oral TS-1 twice a daily for 21 days, followed by a 1-week rest. On day 1, 8, and 15 from the start of oral TS-1 administration, 30 mg/m(2) of Docetaxel and 30 mg/m(2) of cisplatinum with 500 ml of saline were introduced into the peritoneal cavity through the port. A median course of oral TS-1 was 2.1 course and a median time of IP chemoterapy was 5.8. Peritoneal free cancer cells (PFCCs) had been detected in 65 (82.2%) patients before NIPS, and the positive cytology changed to be negative in 41 (63.0%) patients after NIPS. After NIPS, 41 patients underwent laparotomy, and complete cytoreduction was done in 32 (78%) patients. Complete cytoreduction was done in 27 (51.9%) of 52 patients with negative cytology but in only 4 (14.8%) of 27 patients with positive cytology (P < 0.001). Patients with negative cytology after NIPS survived significantly longer than those with positive cytology. The adverse effects after NIPS were mild and there was no treatment-related deaths. The grade 3/4 hematological adverse effects were found in 2 (2.6%) patients. Grade 3 renal toxicity and port site infection was found in three patients, respectively. NIPS using a port system is a safe and effective treatment for PC. Peritoneal wash cytology through a port system is a good indicator to select the patients to perform cytoreductive surgery.

[Long-term results of peritonectomy on the patients with peritoneal carcinomatosis].

Peritonectomy was done for 125 patients with peritoneal carcinomatosis (PC): 19-pseudomyxomaperitonei (PMP), 15-appendiceal carcinoma (AC), 20-colorectal cancer, 67-gastric cancer, 2-small bowel cancer and 2-peritoneal mesothelioma. Cytoreduction by the standard techniques was done in 130 patients with PC. Complete cytoreduction (CC-0) was achieved in 85 of 125 (68%) patients, who have undergone peritonectomy, but was performed only in 28 of 130 (21%) by the standard surgical techniques. CC-0 could be done to patients with peritoneal cancer indices (PCI) of less than 14. A Cox model showed that significant prognostic factors are CC-0, and the patients were younger than 66 years old. Accordingly, peritonectomy increased the incidence of CC-0, and may have improved the prognosis of patients with PC. Peritonectomy is recommended for patients with PMP, AC and colorectal cancer. In gastric cancer, it is indicated for patients with PCI less than 14.

Evaluation of lymphatic invasion in primary gastric cancer by a new monoclonal antibody, D2-40.

Lymphatic invasion is known as an independent predictor of lymph node metastasis in gastric cancer. However, the diagnosis of lymphatic invasion is sometimes difficult by hematoxylin-eosin (H&E) staining. Immunostaining using D2-40 was performed to study the distribution of lymphatic vessel and lymphatic invasion in a series of 78 primary gastric cancers. D2-40 showed specific staining for the lymphatic vessels, but not for blood vessels. The lymphatic invasion was most frequently found in the upper half of submucosal layer. Positive rate of lymphatic invasion by H&E staining was 27% (21/78), and that by D2-40 was 44% (34/78). Lymphatic invasion on H&E staining was diagnosed as false negative in 17 (21.8%) of 78 primary gastric cancers and false positive in 4 (5.1%) of 78 primary gastric cancers. Sensitivity for lymph node metastasis by the lymphatic invasion diagnosed by D2-40 was significantly higher (89%, 24/27) than by H&E staining (41%, 11/27). These results suggest that the diagnosis of lymphatic invasion by D2-40 is more sensitive than H&E staining. Sensitivity for the prediction of lymph node metastasis from the lymphatic invasion status in primary tumor by D2-40 was significantly higher than by H&E staining. Based on our results, we recommend the use of D2-40 immunoreactions for the routine evaluation of lymphatic invasion in gastric cancer.

[Effect of intraperitoneal chemotherapy on experimental peritoneal dissemination of gastric cancer].

In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA, CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.

Effect of intraperitoneal administration of docetaxel on peritoneal dissemination of gastric cancer.

The effect of intraperitoneal (i.p.) administration of docetaxel was evaluated for preclinical evidence of anticancer activity in athymic mice bearing a gastric cancer cell line, MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice. Nude mice were inoculated i.p. with 10(7) MKN-45-P cells. On days 2, 5, 9, 12, 16 and 19 after tumor inoculation, mice were treated with i.p. injection of docetaxel. Treatment doses of docetaxel were 8 mg/kg (N = 7) 2 mg/kg (N = 7) and 0.5 mg/kg (N = 7). Intraperitoneal carcinoembryonic antigen (CEA) levels, animal body weight, mortality and survival were determined. All control mice developed ascites and died within 19-40 days. The median survival time in the control group was 32 days, while those of mice treated with 8, 2 and 0.5 mg/kg were 90, 63 and 49.5 days, respectively. One of seven mice treated with 8 mg/kg of docetaxel died of toxicity on day 12. Four mice were tumor-free on day 90, but two had tumors in the abdomen when autopsied on day 90. One mouse treated with 2 mg/kg was ascertained to be tumor-free on day 90. All seven mice treated with 0.5 mg/kg of docetaxel died of peritoneal dissemination within 71 days. The results suggest the potential of intraperitoneal docetaxel administration for the treatment of peritoneal dissemination of 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 surgeon's 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.

REG gene expression is associated with the infiltrating growth of gastric carcinoma.

BACKGROUND: The Reg gene is known to be involved in the growth of not only pancreatic B-cells, but also epithelial cells of the gastrointestinal tract and carcinoma of its lineage. METHODS: Because, to the authors' knowledge, no studies have been reported regarding REG expression in gastric carcinoma, the authors investigated REG mRNA and REG protein expression using reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot analysis, and immunohistochemical study and correlated the results with the clinical features of gastric carcinoma. RESULTS: Using RT-PCR and Western blot analyses, reg mRNA and 16-kilodalton REG proteins were detected in two of eight human gastric carcinoma cell lines. Cytoplasmic localization of REG proteins in the cell lines was confirmed by fluorescent immunocytochemistry. The RT-PCR analysis revealed the presence of REG mRNA in as many as 77% (87 of 112 tumors) of primary gastric carcinoma tumors. Screening of a total of 195 patients with primary gastric carcinoma using immunoperoxidase staining revealed positive REG immunoreactivity in 60 of the 195 primary tumors (31%). REG expression in infiltrating tumors was found to be significantly higher compared with localized tumors (P < 0.05). Strong REG expression was noted in the cytoplasm of signet ring cell carcinoma tumors at a significantly higher incidence than in nonsignet ring cell tumors. Moreover, patients with REG-negative differentiated adenocarcinoma were found to have a significantly better prognosis compared with patients with REG-positive tumors. The incidence of venous invasion of REG-positive tumors was significantly higher than that of REG-negative tumors. CONCLUSIONS: The results of the current study suggest that the expression of the REG gene is closely related to the infiltrating property of gastric carcinoma, and may be a prognostic indicator of differentiated adenocarcinoma of the stomach.

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

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.

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.