Dissemination Of Gastric Cancer Research Articles

Inhibition of nuclear factor‐kappaB suppresses peritoneal dissemination of gastric cancer by blocking cancer cell adhesion

Currently, patients with peritoneal dissemination of gastric cancer must accept a poor prognosis because there is no standard effective therapy. To inhibit peritoneal dissemination it is important to inhibit interactions between extracellular matrices (ECM) and cell surface integrins, which are important for cancer cell adhesion. Although nuclear factor-kappa B (NF-κB) is involved in various processes in cancer progression, its involvement in the expression of integrins has not been elucidated. We used a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), to study whether NF-κB blocks cancer cell adhesion via integrins in a gastric cancer dissemination model in mice and found that DHMEQ is a potent suppressor of cancer cell dissemination. Dehydroxymethylepoxyquinomicin suppressed the NF-κB activity of human gastric cancer cells NUGC-4 and 44As3Luc and blocked the adhesion of cancer cells to ECM when compared with the control. Dehydroxymethylepoxyquinomicin also inhibited expression of integrin (α2, α3, β1) in in vitro studies. In the in vivo model, we injected 44As3Luc cells pretreated with DHMEQ into the peritoneal cavity of mice and performed peritoneal lavage after the injection of cancer cells. Viable cancer cells in the peritoneal cavities were evaluated sequentially by in vivo imaging. In mice injected with DHMEQ-pretreated cells and lavaged, live cancer cells in the peritoneum were significantly reduced compared with the control, and these mice survived longer. These results indicate that DHMEQ could inhibit cancer cell adhesion to the peritoneum possibly by suppressing integrin expression. Nuclear factor-kappa B inhibition may be a new therapeutic option for suppressing postoperative cancer dissemination.

The Metastasis-Associated microRNA miR-516a-3p Is a Novel Therapeutic Target for Inhibiting Peritoneal Dissemination of Human Scirrhous Gastric Cancer

Although aberrant microRNA (miRNA) is expressed in different types of human cancer tissues, its pathophysiologic role and the relevance of tumorigenesis and metastasis are still largely unknown. Here, we defined miRNAs involved in cancer metastasis (metastamirs) using an established mouse model for peritoneal dissemination of human scirrhous gastric carcinoma cells. Highly metastatic derivatives (44As3 cells) were derived from the parental cells originally isolated from patients (HSC-44PE cells). Using microarray analysis to identify differentially expressed miRNAs in 44As3 and HSC-44PE cells, we focused on miR-516a-3p as a candidate antimetastatic miRNA (antimetastamir) whose functions in cancer had not been studied. We confirmed attenuated expression of miR-516a-3p in 44As3 cells compared with HSC-44PE cells by Northern blot analysis and quantitative reverse transcriptase PCR. Stable ectopic overexpression in 44As3-miR-516a-3p cells permitted identification of sulfatase 1 as a direct target of the miRNA, through use of the isobaric tagging reagent iTRAQ and the QSTAR Elite Hybrid LC-MS/MS system. Sulfatase 1 is known to remove 6-O-sulfates from heparan sulfate proteoglycans on the cell surface, causing release of membrane-bound Wnt ligands from cells. Consistent with this function, Western blot analyses revealed high levels of Wnt3a, Wnt5a, and nuclear β-catenin accumulation in 44As3 cells but relatively reduced levels in 44As3-miR-516a-3p cells. Notably, orthotopic inoculation of nude mice with 44As3-miR-516a-3p cells yielded significantly longer survival periods compared with mice inoculated with control 44As3 cells. Through atelocollagen-mediated delivery of an miR-516a-3p expression vector into orthotopic 44As3 tumors, we documented its feasibility as a treatment agent. Our findings define the miRNA miR-516-3p as an antimetastamir with potential therapeutic applications in blocking metastatic dissemination of gastric cancers.

Effect of changes in the glycolytic metabolism on tumor progression and dissemination in gastric cancer.

47 Background: Metastases are a frequent finding in gastric cancer patients and are associated with a poor prognosis. Recent data indicate that there might be a link between metabolic changes in the glycolytic system and dissemination in gastric cancer. The enhanced expression of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and its signalling targets CXCR4 and CXCL12 seem to play a crucial role in enabling gastric tumours to develop dissemination. Methods: Microarray analysis was conducted investigating human specimens from consecutive gastric cancer patients with dissemination versus gastric cancer patients without dissemination. Subsequently siRNA-knock- down concerning PGK1 and CXCR4 and transfection (overexpression) of PGK1 was performed. Further, our thesis was investigated in a metastatic nude mouse model simulating human gastric cancer behavior by orthotopic tumour implantation. Tumour growth was detected by PET-MR-imaging and section of the animals. Results: Microarray analysis revealed a significant overexpression of PGK1, CXCR4 and CXCL12 in gastric cancer specimens with dissemination. Further siRNA-knock-down of PGK1 and CXCR4 showed a significant co-regulation on expression and protein level in vitro. The transfection (overexpression) of PGK1 also revealed a significant upregulation of its signalling targets CXCR4 and CXCL12 on expression and protein level. In addition the transfected cells showed a 50-fold distinctive property in the invasion assay compared to cancer cells without PGK1 overexpression. The in-vivo results obtained in the mouse model showed that elevated PGK1 expression increased invasive and metastatic behavior of implanted gastric tumours significantly and PET-MR-imaging and section correlated very well comparing tumour growth and metastasis. Conclusions: The overexpression of the glycolytic enzyme PGK1 and its signalling targets in gastric cancer might be a promising regulation-pathway promoting dissemination. This data may provide new prognostic markers and/or potential therapeutic targets to prevent migration of gastric carcinoma cells and has intriguing connection to an old hypothesis advocated by Otto Warburg for tumour metabolism. No significant financial relationships to disclose.

Analysis of pO2 in malignant ascites of patients with peritoneal dissemination of gastric cancer.

63 Background: Peritoneal metastasis is considered to develop from carcinoma cells detached from the serosal surface of the primary site and dispersed in the peritoneal cavity. And oxygen is one of the most important environmental factors for tumor development. To investigate the oxygenation condition in the abdominal cavity, that is largely unknown, we collected ascitic fluid from patients with peritoneal dissemination of gastric cancer and measured pO2 of it. Methods: In 19 patients with peritoneal dissemination of gastric cancer, who had a considerable amount of ascites and was receiving systemic and/or intraperitoneal chemotherapy, ascitic fluid was collected at the bedside in room air, and its pH, pCO2 and pO2 were measured using a blood gas analyzer immediately. Results: In 19 patients, pH of malignant ascites was significantly lower than that of arterial blood (7.39 ± 0.069 vs 7.44 ± 0.025 mmHg, p < 0.05). pCO2 tended to be higher in ascites than in arterial blood. Unexpectedly, pO2 in malignant ascites showed relatively high values (85.47 ± 23.31 mmHg), which were mostly the same as that of arterial blood (97.19 ± 10.40 mmHg, p = 0.149), and appeared to be higher than that in solid tumor tissue. Conclusions: Malignant ascites in gastric cancer patients showed an unexpectedly high oxygen tension, which was almost the same as that of arterial blood. The hyperpermeability condition may enable efficient oxygen delivery to peritoneal fluid via the microvessels lining the peritoneal cavity. Since the oxygen level critically affects the sensitivity of tumor cells to chemotherapeutic agents through metabolic transformation, aerobic conditions may be beneficial for the progression of peritoneal metastasis and also clinically important in considering the efficacy of chemotherapy. No significant financial relationships to disclose.

Therapeutic Effects of Ca2+ on Peritoneal Dissemination of Gastric Carcinoma in Vivo

It is well known that oral calcium supplementation has inhibited the gastric carcinogenesis in animals treated with chemical carcinogen and sodium chloride. However, the therapeutic effects of calcium ion (Ca2+) for peritoneal dissemination of gastric carcinoma in vivo remain unknown. Here, we showed that Ca2+ could be effective for inhibiting the peritoneal metastasis of gastric carcinoma MKN-45 cells along with apoptosis in vivo. Significantly prolonged survival was obtained for the peritoneal dissemination mouse models of MKN-45 cells after the intraperitoneal injection (i.p.) of Ca2+. These results suggest that Ca2+ could be a new candidate i.p. drug against peritoneal dissemination of gastric cancer in human.

Human peritoneal mesothelial cell transformation into myofibroblasts in response to TGF-ß1 in vitro

Peritoneal dissemination is one of the leading causes of death in gastric cancer patients. The interaction between carcinoma cells and the peritoneal lining may play a key role in tumor peritoneal dissemination. Human peritoneal mesothelial cells are a monolayer of squamous epithelial cells covering the peritoneal cavity and forming serosal membranes. The precise role of mesothelial cells in the peritoneal dissemination of gastric cancer remains to be identified. Expression of TGF-ß1, a cytokine known for its capacity to induce proliferative and transformative changes in cells, has been correlated with peritoneal metastasis and TNM stages of gastric cancer. High levels of TGF-ß1 in the subperitoneal milieu may play a key role in the transition of normal mesothelial cells to myofibroblasts. Here, we demonstrate that mesothelial cells activated by TGF-ß1 undergo epithelial-mesenchymal transition (EMT) and that the transition of mesothelial cells to myofibroblasts is dependent on Smad2 signaling. EMT of mesothelial cells was marked by up-regulation of α-smooth muscle actin and vimentin expression. Cytokeratin and E-cadherin expression decreased over time in transformed mesothelial cells. Knockdown of Smad2 gene by siRNA silencing significantly suppressed the transition of mesothelial cells to myofibroblasts. We conclude that when exposed to TGF-ß1 mesothelial cells undergo EMT which involves Smad2 signaling. Furthermore, mesothelial cells may be the possible source of myofibroblasts in peritoneal fibrosis and provide a favorable environment for the dissemination of gastric cancer.

Induction of gastric cancer cell adhesion through transforming growth factor-beta1-mediated peritoneal fibrosis

BackgroundPeritoneal dissemination is one of the main causes of death in gastric cancer patients. Transforming growth factor-beta1 (TGF-β1), one of the most potent fibrotic stimuli for mesothelial cells, may play a key role in this processing. The purpose of this study is to elucidate the effects of TGF-β1 on regulation of gastric cancer adhesion to mesothelial cells.MethodsPeritoneal tissues and peritoneal wash fluid were obtained for hematoxylin and eosin staining or ELISA to measure fibrosis and TGF-β1 levels, respectively. The peritoneal mesothelial cell line, HMrSV5, was used to determine the role of TGF-β1 in regulation of gastric cancer cell adhesion to mesothelial cells and expression of collagen, fibronectin, and Smad 2/3 by using adhesion assay, western blot, and RT-PCR.ResultsThe data showed that TGF-β1 treatment was able to induce collagen III and fibronectin expression in the mesothelial cells, which was associated with an increased adhesion ability of gastric cancer cells, but knockdown of minimal sites of cell binding domain of extracellular matrix can partially inhibit these effects.ConclusionPeritoneal fibrosis induced by TGF-β1 may provide a favorable environment for the dissemination of gastric cancer.

Type IV collagen levels are elevated in the serum of patients with peritoneal dissemination of gastric cancer

Type III procollagen (amino-terminal propeptide of procollagen type III) and type IV collagen are considered to be reliable serum markers for monitoring the progression of liver fibrosis. The peritoneal dissemination of gastric cancer is also characterised by abundant collagen deposition in the peritoneum. The present study was performed to investigate the potential of serum type III procollagen and IV collagen as biomarkers for peritoneal dissemination in gastric cancer. The study population consisted of 117 patients with gastric cancer: 32 patients had peritoneal dissemination which was pathologically diagnosed by laparotomy or laparoscopic examination, while 85 patients (45/40, early/advanced gastric cancer) had no peritoneal dissemination. We measured the serum levels of type III procollagen and type IV collagen in comparison to the commonly accepted tumor markers carcinoembryonic (CEA), carbohydrate antigen (CA)19-9 and CA125. The median type III procollagen levels showed no significant differences between the two groups, whereas the median type IV collagen levels were significantly (201 ng/ml) higher in patients with than in those without peritoneal dissemination (early/advanced gastric cancer, 124/136 ng/ml) (P<0.05). In receiver operating characteristic (ROC) curve analysis, type IV collagen had the largest area under the curve (0.83), followed by CA125 (0.72), CA19-9 (0.64), CEA (0.59) and type III procollagen (0.48). Type IV collagen was an independent marker (P<0.0001, odds ratio 15.7) for predicting peritoneal dissemination along with CA125 (P=0.0086, odds ratio 9.4) based on multivariate logistic regression. In conclusion, serum type IV collagen levels may be significant in the early detection and management of patients with peritoneal dissemination of gastric cancer.

Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer

Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate-generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and beta-catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study, the influence of PGK1 on CXCR4 and beta-catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study, we found that PGK1 regulates the expression of CXCR4 and beta-catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid-mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness suggesting that, PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and beta-catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum.

Ureteral metastasis as the first and sole manifestation of gastric cancer dissemination

BackgroundIsolated ureteral metastasis from gastric cancer is extremely rare.Case reportWe describe a 50 year old man with a history of subtotal gastrectomy who presented 4 years later with an ureteral metastasis. He was asymptomatic and diagnostic tests were performed due to the elevated creatinine level disclosed incidentally. The partial resection of distal right ureter as well as the resection of the right ureterovesical junction was performed with the implantation of double J stent. Histopathology revealed a metastasis of the adenocarcinoma that matched perfectly a tumour specimen from the gastric cancer surgery. It was first and isolated manifestation of gastric cancer dissemination.ConclusionsAlthough rare, the ureteral metastasis from gastric cancer can be the first, sole and asymptomatic manifestation of gastric cancer dissemination after a period of time.

The Knack of Surgical Intervention for Malignant Bowel Obstruction Due to Gastric Cancer Dissemination

The Knack of Surgical Intervention for Malignant Bowel Obstruction Due to Gastric Cancer Dissemination

Talaporfin-mediated photodynamic therapy for peritoneal metastasis of gastric cancer in an in vivo mouse model: Drug distribution and efficacy studies

Photodynamic therapy (PDT) is a potential treatment for the peritoneal dissemination of gastric cancer, because its cytotoxicity is limited to superficial lesions. We examined the accumulation of talaporfin in peritoneal metastatic nodules and determined the optimal laser condition for these nodules. We also evaluated the pathological response after therapy. We created a peritoneal metastasis model in nude mice using the MKN-45 EGFP cell line. We evaluated the accumulation of talaporfin in peritoneal metastatic nodules and normal organs by spectrophotometric analysis 2-8 h after i.p. talaporfin. To determine optimal PDT conditions, we treated metastatic nodules and the small intestine using multiple laser doses (2, 5, and 10 J/cm2, respectively). Accumulation of talaporfin was detected in metastatic nodules in higher intensities than in the small intestine. The fluorescent intensity of the peritoneal metastatic nodules gradually decreased dependent on the time interval between the laser treatment and talaporfin administration. Fluorescent intensity in the small intestine decreased more than in the metastatic nodules. The pathological response rates by dose were 52.5% at 2 J/cm2, 43.2% at 5 J/cm2, and 64.4% at 10 J/cm2, respectively, when the laser treatment was used 2 h after talaporfin administration, whereas at 4 h, they were 20.8, 25.5, and 26.2%, respectively. Finally, the recommended treatment conditions were considered to be a 2 J/cm2 laser dose and a 4-h interval in terms of toxicity. Talaporfin-mediated PDT may be an effective treatment modality for patients with advanced gastric adenocarcinoma and metastatic peritoneal nodules.

Adenoviral Oncolytic Suicide Gene Therapy for a Peritoneal Dissemination Model of Gastric Cancer in Mice

Peritoneal dissemination of gastric cancer is often refractory to systemic therapies. Although adenoviral gene therapy has been reported to be a potentially useful therapeutic modality, the adenovirus itself has a dose-limiting toxicity. A novel system was constructed using adenoviral oncolytic suicide gene therapy targeting carcinoembryonic antigen (CEA), and its therapeutic effect and the possibility to reduce the total viral dose while still preserving the antitumor effect were assessed. Three types of adenoviruses were prepared for this novel system: (A) Ad/CEA-Cre, (B) Ad/lox-CD::UPRT for a Cre/loxP system, and (C) Ad/CEA-E1 for conditionally replicating adenovirus. The antitumor effect of the oncolytic suicide gene therapy (A + B + C) was then evaluated in vitro. Mice bearing peritoneal dissemination of human gastric cancer were treated with either this system (A + B + C) or with a tenfold viral dose of suicide gene therapy (A + B). The adverse effects in terms of hepatotoxicity were then evaluated between the two groups. The current system (A + B + C) demonstrated significantly better cytotoxic effect for CEA-producing cell lines than did suicide gene therapy (A + B) at the same viral dose in vitro. The effect of oncolytic suicide gene therapy was almost equal to that of the tenfold viral dose of suicide gene therapy in vivo. The hepatotoxicity of the two treated groups was also found to be equivalent. It was possible to reduce the total adenoviral dose of oncolytic suicide gene therapy while still preserving the antitumor effect.

Suppression of gastric cancer dissemination by ephrin‐B1‐derived peptide

Interaction of the Eph family of receptor protein tyrosine kinases and their ligands, ephrin family members, induces bidirectional signaling through cell-cell contacts. High expression of B-type ephrin is associated with high invasion potential of tumors, and we previously observed that signaling through the C-terminus of ephrin-B1 mediates the migration and invasion of cells, and is involved in the promotion of carcinomatous peritonitis in vivo. Here we show that the intracellular introduction of a synthetic peptide derived from ephrin-B1 C-terminus blocks ephrin-B1 mediated signaling in scirrhous gastric cancer cells. Treatment of cancer cells with a fusion peptide consisting of HIV-TAT and amino acids 331-346 of ephrin-B1 (PTD-EFNB1-C) suppressed the activation of RhoA, mediated by the association of ephrin-B1 with an adaptor protein Dishevelled, and also inhibited extracellular secretion of metalloproteinase. Moreover, injection of PTD-EFNB1-C peptide into the peritoneal cavity of nude mice suppressed carcinomatous peritonitis of intraperitoneally transplanted scirrhous gastric cancer cells. These results indicate the possible application of ephrin-B1 C-terminal peptide to develop novel protein therapy for scirrhous gastric carcinoma, especially in the stage of tumor progression, including peritoneal dissemination.

Efficacy of sequential methotrexate and 5-fluorouracil (MTX/5FU) in improving oral intake in patients with advanced gastric cancer with severe peritoneal dissemination

Although peritoneal dissemination of gastric cancer is common and often causes deterioration of the patient's condition and quality of life (QOL), these patients are usually excluded from clinical trials. We retrospectively investigated the clinical benefit and toxicity of sequential methotrexate and 5-fluorouracil (MTX/5FU) therapy for patients with peritoneal dissemination. The subjects were 31 patients with severe peritoneal dissemination of gastric cancer who were treated with MTX/5FU. The treatment schedule comprised weekly administration of MTX (100 mg/m(2)) followed by 5FU (600 mg/m(2)). Leucovorin (10 mg/m(2)) was administered six times, every 6 h, starting 24 h after MTX administration. The median survival time was 255 days, and the median progression-free survival was 127 days. Of the 21 patients with measurable lesions, 4 (19%) patients achieved a partial response. Ascites volume decreased markedly in 14 (54%) of the 26 patients with ascites. Seventeen patients had adequate oral intake, but the other 14 patients had required nutritional support before treatment. The median dripinfusion free survival was 100 days in the former 17 patients, and oral intake improved in 3 (21%) of the latter 14 patients. Grade 3 or 4 neutropenia was observed in 26% of the patients and anemia was observed in 45%. The grade 3 nonhematological toxicities were vomiting (6%) and fatigue (10%). Early death, within 30 days of the last administration of MTX/5FU, occurred due to disease progression in 2 patients, but there were no treatment-related deaths. MTX/5FU chemotherapy may be effective in treating peritoneal dissemination of gastric cancer and might improve the patient's condition in terms of reducing ascites and improving oral intake.

Intraperitoneal administration of paclitaxel solubilized with poly(2‐methacryloxyethyl phosphorylcholine‐co n‐butyl methacrylate) for peritoneal dissemination of gastric cancer

Intraperitoneal (i.p.) administration of paclitaxel (PTX) is a hopeful therapeutic strategy for peritoneal malignancy. Intravenously (i.v.) injected nanoparticle anticancer drugs are known to be retained in the blood stream for a long time and favorably extravasated from vessels into the interstitium of tumor tissue. In this study, we evaluated the effect of i.p. injection of PTX (PTX-30W), which was prepared by solubulization with water-soluble amphiphilic polymer composed of PMB-30W, a co-polymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effect of i.p. administration of PTX-30W was compared with conventional PTX dissolved in Cremophor EL (PTX-Cre). The drug accumulation in peritoneal nodules was evaluated with intratumor PTX concentration and fluorescence microscopic observation. PTX-30W reduced the number of metastatic nodules and tumor volume significantly more than did conventional PTX dissolved in Cremophor EL (PTX-Cre), and prolonged the survival time (P < 0.05). PTX concentration in disseminated tumors measured by HPLC was higher in the PTX-30W than in the PTX-Cre group up to 24 h after i.p. injection. Oregon green-conjugated PTX-30W, i.p. administered, preferentially accumulated in relatively hypovascular areas in the peripheral part of disseminated nodules, which was significantly greater than the accumulation of PTX-Cre. I.p. administration of PTX-30W may be a promising strategy for peritoneal dissemination, due to its superior characteristics to accumulate in peritoneal lesions.

A foreign body granuloma after gastric perforation mimicking peritoneal dissemination of gastric cancer: Report of a case

This report presents the case of a 58-year-old man who was found to have foreign body granulomas (FBGs) that mimicked disseminated gastric cancer. The patient presented with a severe attack of acute upper abdominal pain, was admitted to the hospital, and thereafter underwent an immediate laparotomy due to a diagnosis of an upper gastrointestinal perforation. Follow-up endoscopy revealed an ulcer scar measuring 2 cm in size in the anterior wall of the middle stomach. The pathological examination of biopsy specimens taken around the scar revealed well to poorly differentiated adenocarcinoma. At the time of reoperation performed 2 months after the first operation, many small white granulomas were observed which were thought to be the result of peritoneal dissemination of the gastric cancer. However, both the cytology of the Douglas washing and pathological examination of frozen section specimens were negative for carcinoma, and therefore a distal gastrectomy was performed. The pathological examination revealed the presence of FBGs. In this rare case, the FBGs formed shortly after surgery and were difficult to distinguish from disseminated cancer.

6635 A novel NF-kB inhibitor DHMEQ could suppress peritoneal dissemination of gastric cancer by anti-tumor/-adhesive effects in mice

6635 A novel NF-kB inhibitor DHMEQ could suppress peritoneal dissemination of gastric cancer by anti-tumor/-adhesive effects in mice

Combined chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 for malignant ascites due to advanced gastric cancer with peritoneal dissemination

e15524 Background: Malignant ascites caused by peritoneal metastasis the most life-threatening mode of metastasis and recurrence and seriously impair the quality of life in patients with gastric cancer. However, none of the treatment protocols have proved satisfactory clinical outcome. Methods: Twenty one patients with malignant ascites due to the peritoneal dissemination of gastric cancer were enrolled. Intraperitoneal catheter with infusing port was placed subcutaneously in all patients, and Paclitaxel was administered intraperitoneally at 20 mg/m2, together with intravenously at 50 mg/m2, on days 1 and 8. S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. The change of the ascetic volume was prospectively investigated as the primary endopoint of the response rate. The volume of malignant ascites was objectively measured with the calculation of the consecutive computed tomography (CT) images using NIH image J software. Peritoneal cytology and mRNA of CEA in acitic fluid were also evaluated in 17 and 16 cases, respectively. Results: The volume of malignant ascites before the treatment was more than 500ml in 8 patients and less than 300ml in 13 patients. The average course of the treatment was 9 (2–19). The ascetic volume was markedly (more than 33%) reduced in 8 patients and totally disappeared in 5 cases with CT image, and thus the response rate was 62%. Malignant cells in peritoneal cytology disappeared in 13 cases while CEA mRNA became negative only in 2 cases. The one year overall survival was 71% in all patients and 85% in patients with reduced ascites. Conclusions: Combined chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 was a useful protocol for malignant ascites caused by peritoneal dissemination of gastric cancer. No significant financial relationships to disclose.

Regional administration of oncolytic Echovirus 1 as a novel therapy for the peritoneal dissemination of gastric cancer

The dissemination of malignant gastric cells to the peritoneum occurs frequently, usually as an early event in disease, and results in poor patient prognosis. Surgery and chemotherapy offer limited therapeutic success. The low-pathogenic human enterovirus, Echovirus 1 (EV1), is an oncolytic virus that selectively targets and destroys malignant prostate and ovarian cancer xenografts in vivo. Lytic EV1 infection requires the cell surface expression of alpha(2)beta(1), an integrin involved in the dissemination of gastric cancer cells to the peritoneum. Herein, we evaluated the capacity of EV1 for anti-neoplastic cell action in gastric peritoneal carcinomatosis. Flow cytometric analysis demonstrated that alpha(2)beta(1) was abundantly surface expressed on a panel of gastric cancer cell lines, rendering the majority of lines highly susceptible to in vitro lytic EV1 infection and supportive of efficient viral progeny production. A bioluminescent MKN-45-Luc SCID mouse model of peritoneal dissemination was developed to allow real-time non-invasive monitoring of peritoneal tumor burden. Employing this mouse model, we demonstrated a therapeutic dose-response for escalating oncolytic EV1 doses. Taken together, these results emphasize the exciting potential for EV1 as a single or adjunct therapy for the control of the peritoneal dissemination of gastric cancer.