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Purpose Intraperitoneal paclitaxel plus systemic chemotherapy demonstrated promising clinical effects in patients with gastric cancer with peritoneal metastasis. We aimed to verify its superiority over standard systemic chemotherapy in overall survival. Patients and Methods This randomized phase III trial enrolled patients with gastric cancer with peritoneal metastasis who had received no or short-term (< 2 months) chemotherapy. Patients were randomly assigned at a two-to-one ratio to receive intraperitoneal and intravenous paclitaxel plus S-1 (IP; intraperitoneal paclitaxel 20 mg/m and intravenous paclitaxel 50 mg/m on days 1 and 8 plus S-1 80 mg/m per day on days 1 to 14 for a 3-week cycle) or S-1 plus cisplatin (SP; S-1 80 mg/m per day on days 1 to 21 plus cisplatin 60 mg/m on day 8 for a 5-week cycle), stratified by center, previous chemotherapy, and extent of peritoneal metastasis. The primary end point was overall survival. Secondary end points were response rate, 3-year overall survival rate, and safety. Results We enrolled 183 patients and performed efficacy analyses in 164 eligible patients. Baseline characteristics were balanced between the arms, except that patients in the IP arm had significantly more ascites. The median survival times for the IP and SP arms were 17.7 and 15.2 months, respectively (hazard ratio, 0.72; 95% CI, 0.49 to 1.04; stratified log-rank P = .080). In the sensitivity analysis adjusted for baseline ascites, the hazard ratio was 0.59 (95% CI, 0.39 to 0.87; P = .008). The 3-year overall survival rate was 21.9% (95% CI, 14.9% to 29.9%) in the IP arm and 6.0% (95% CI, 1.6% to 14.9%) in the SP arm. Both regimens were well tolerated. Conclusion This trial failed to show statistical superiority of intraperitoneal paclitaxel plus systemic chemotherapy. However, the exploratory analyses suggested possible clinical benefits of intraperitoneal paclitaxel for gastric cancer.

Lysophosphatidic acid (LPA) is a simple bioactive phospholipid with diverse effects on various cells, that interacts with three G protein-coupled transmembrane receptors, LPA1, LPA2, and LPA3. The expression pattern and functions of these LPA receptors in various tumors have not been fully examined, except in ovarian cancer. To evaluate the LPA receptor expression profile in human colorectal cancer and in normal mucosa, we used real-time reverse transcription-polymerase chain reaction (RT-PCR) and measured the expression levels of LPA1, LPA2, and LPA3 messenger RNA (mRNA) in 26 colorectal cancers and 16 corresponding normal tissue samples. Normal epithelium expressed both LPA1 and LPA2 mRNA at similar levels. In comparison, colorectal cancers expressed LPA1 mRNA at a significantly lower level (0.3-fold; Po0.05), and LPA2 mRNA at a significantly higher level (three-fold; Po0.05), as compared with normal tissues. Thus, the ratio of LPA2/LPA1 increased markedly during malignant transformation (18-fold increase). LPA3 mRNA was expressed at only a low level in both normal and cancer tissues. We also assessed LPA2 expression immunohistochemically using a rat anti-LPA2 monoclonal antibody, and confirmed high expression of LPA2 in colorectal cancer at the protein level. As for LPA1, we examined Western blot analysis for 16 matched normal and cancer tissues. It revealed a significant decrease in the expression of LPA1 protein in cancer tissues compared to normal mucosa in nine of 16 cases, and in the remaining seven cases the expression levels was much the same. These results suggested that alteration of LPA receptor expression might be an important event in the development of colorectal cancer, and therefore, LPA and its receptors could be a chemopreventive target against colorectal cancer. Keywords: aberrant expression of LPA2; carcinogenesis; colorectal cancer; LPA receptor; lysophosphatidic acid; phospholipid Lysophosphatidic acid (LPA, 1-or 2-acyl-sn-glycero-3-phosphate), the simplest glycerophospholipid, mediates a broad range of cellular responses, including smooth muscle cell contraction, platelet aggregation, neurite retraction/cell rounding, regulation of cell proliferation, protection from apoptosis, modulation of chemotaxis, and transcellular migration.

We investigated mechanisms for inhibition of B16 melanoma cell migration and invasion by sphingosine-1-phosphate (S1P), which is the ligand for the Edg family G protein-coupled receptors and also implicated as an intracellular second messenger. S1P, dihydro-S1P, and sphingosylphosphorylcholine inhibited B16 cell migration and invasion with the relative potencies expected as S1P 2 receptor agonists. The S1P 2 -selective antagonist JTE013 completely abolished the responses to these agonists. In addition, JTE013 abrogated the inhibition by sphingosine, which is the S1P precursor but not an agonist for S1P receptors, indicating that the sphingosine effects were mediated via S1P 2 stimulation, most likely by S1P that was converted from sphingosine. S1P induced inhibition and activation, respectively, of Rac and RhoA in B16 cells, which were abrogated by JTE013. Adenovirus-mediated expression of N 17 Rac mimicked S1P inhibition of migration, whereas C3 toxin pretreatment, but not Rho kinase inhibitors, reversed the S1P inhibition. Overexpression of S1P 2 sensitized, and that of either S1P 1 or S1P 3 desensitized, B16 cells to S1P inhibition of Rac and migration. In JTE013-pretreated, S1P 3 -overexpressing B16 cells, S1P stimulated cellular RhoA but failed to inhibit either Rac or migration, indicating that RhoA stimulation itself is not sufficient for inhibition of migration. These results provide compelling evidence that endogenously expressed S1P 2 negatively regulates cell motility and invasion through liganddependent reciprocal regulation of cellular Rac and RhoA activities. In the presence of JTE013, S1P instead stimulated Rac and migration in B16 cells that overexpress either S1P 1 or S1P 3 , unveiling counteractions between S1P 2 and S1P 1 or S1P 3 chemotactic receptor.Sphingosine-1-phosphate (S1P) 1 is a pleiotropic lysophospholipid mediator present in plasma and is released in a large amount from activated platelets. It is now widely accepted that many of the actions of S1P are mediated through the Edg family G protein-coupled S1P receptors, which include ubiquitously expressed isotypes S1P 1 /Edg1, S1P 2 /Edg5/AGR16, and S1P 3 /Edg3, and additional members S1P 4 /Edg6 and S1P 5 / Edg8, whose expression patterns are more tissue-specific (for a review, see Refs. 1-6). It is also demonstrated that lysophosphatidic acid (LPA), a classical serum-derived lysophospholipid mediator that shares a number of biological activities with S1P, acts on distinct members of the Edg family, including LPA 1 / Edg2, LPA 2 /Edg4, and LPA 3 /Edg7 (4, 5, 7).Previous studies have demonstrated that S1P regulates cell motility in either a positive or negative direction, in a manner apparently dependent upon cell type tested. Thus, Sadahira et al. (8) first reported that S1P inhibits trans-well migration as well as invasion across a Matrigel layer of B16 mouse melanoma cells and other types of tumor cells. S1P also inhibits chemotaxis of human arterial smooth muscle cells (9, 10) and human neutrophils (11) toward platelet-derived growt...

Background Serum tumor markers have been shown to correlate with the clinical status of patients with advanced gastric cancer. However, the clinical significance of each tumor marker in patients with peritoneal dissemination has not been fully verified. Methods Four serum markers, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, CA125, and CA72-4, were periodically measured in 102 patients with peritoneal dissemination who received combination intravenous and intraperitoneal chemotherapy. The initial values at diagnosis and after treatment were analyzed in association with clinicopathological factors, response to chemotherapy, and overall survival. Results The sensitivities of CEA, CA19-9, CA125, and CA72-4 for peritoneal metastasis at the initial diagnosis were 19, 36, 46, and 45%, respectively. The CA125 level was significantly correlated with the degree of peritoneal dissemination and the existence of malignant ascites. Patients with ovarian metastasis showed significantly higher levels of CA72-4. The median survival time of patients with an elevated CA125 level was significantly shorter than that of patients with a normal CA125 level (36.7 vs. 16.6 months, p \ 0.001). Multivariate analysis showed that the degree of peritoneal metastasis and an elevated CA125 level were independent prognostic factors. Normalization of the CA125 level after 3 courses of chemotherapy was correlated with reduced ascites and improved survival.Conclusions Serum CA125 and CA72-4 are clinically useful markers in diagnosis, evaluating the efficacy of chemotherapy, and predicting the prognosis of patients with peritoneal dissemination. From an academic point of view, periodic measurements of these markers are warranted in gastric cancer patients with possible peritoneal dissemination.

We have recently reported that S1P (sphingosine-1-phosphate) differentially regulates cellular Rac activity and cell migration in either a positive or a negative direction via distinct G-protein-coupled receptor subtypes, i.e. S1P1/Edg1 (endothelial differentiation gene) and S1P2/Edg5 respectively, when each of the S1P receptor subtypes is expressed in CHO (Chinese-hamster ovary) cells. In B16F10 mouse melanoma cells, in which S1P2, but not the other S1P receptor subtypes, is endogenously expressed, S1P inhibited cell migration with concomitant inhibition of Rac and stimulation of RhoA in dose-dependent manners. Overexpression of S1P2 in the melanoma cells resulted in potentiation of S1P inhibition of both Rac and cell migration. In contrast, overexpression of S1P1 led to stimulation of cell migration, particularly at the lower S1P concentrations. Treatment of B16F10 cells with S1P inhibited lung metastasis 3 weeks after injection into mouse tail veins. Intriguingly, overexpression of S1P2 greatly potentiated the inhibition of metastasis by S1P, whereas that of S1P1 resulted in aggravation of metastasis. Suppression of cellular Rac activity by adenovirus-transduced expression of N17Rac, but not N19RhoA, strongly inhibited cell migration in vitro and lung metastasis in vivo. These results provide the first evidence that G-protein-coupled receptors could participate in the regulation of metastasis, in which ligand-dependent, subtype-specific regulation of the cellular Rac activity is probably critically involved as a mechanism.

BACKGROUND:The prognosis of patients with gastric cancer with peritoneal metastasis is extremely poor. This phase 2 study evaluated the benefits and tolerability of weekly intravenous and intraperitoneal paclitaxel (PTX) treatment combined with oral S-1 in patients with gastric cancer who had macroscopic peritoneal metastasis. METHODS: Patients with gastric cancer who had primary tumors with macroscopic peritoneal metastasis were enrolled. PTX was administered intravenously at 50 mg/m 2 and intraperitoneally at 20 mg/m 2 on days 1 and 8, respectively. S-1 was administered at 80 mg/m 2 per day for 14 consecutive days, followed by 7 days of rest. The primary endpoint was the 1-year overall survival (OS) rate. The secondary endpoints were the response rate, efficacy against malignant ascites, and safety. RESULTS: Thirty-five patients were enrolled. The median number of treatment courses was 11 (range, 2-35). The 1-year OS rate was 77.1% (95% confidence interval, 60.5-88.1). The overall response rate was 71% in 7 patients with target lesions. Malignant ascites disappeared or decreased in 15 of 22 (68%) patients. The frequent grade 3/4 toxic effects were neutropenia (34%), leukopenia (23%), and anemia (9%). CONCLUSIONS: Combination chemotherapy consisting of intravenous and intraperitoneal PTX with S-1 is well-tolerated and effective in patients with gastric cancer who have macroscopic peritoneal metastasis. Cancer 2013;119:3354-8. V C 2013 American Cancer Society.KEYWORDS: phase 2 study; paclitaxel; S-1; gastric cancer; peritoneal metastasis; intraperitoneal chemotherapy. INTRODUCTIONGastric cancer is the fourth most common cancer worldwide and the second leading cause of cancer-related deaths. 1 Multimodal therapy combined with systemic chemotherapy, radiation therapy, and surgery has been developed in the treatment of advanced gastric cancer. 2 Even for noncurable gastric cancer, many clinical trials have been conducted using various newly developed anticancer drugs. In a phase 3 study using docetaxel (DTX), cisplatin, and fluorouracil for recurrent or metastatic gastric cancer patients, the 1-year overall survival (OS) rate and median survival time (MST) were 40% and 9.2 months, respectively. 3 In another phase 3 study using S-1 and cisplatin for unresectable or recurrent gastric cancer, the 1-year OS rate and MST were 54.1% and 13.0 months, respectively. 4 Among patients with noncurable gastric cancer, the prognosis of patients with peritoneal metastasis is extremely poor, 5 and no standard treatment for peritoneal metastasis has been established.One potential treatment approach is the introduction of paclitaxel (PTX), which has been shown to produce a high response rate (29%-36%) for undifferentiated-type adenocarcinoma 6,7 and can be expected to show high efficacy for peritoneal dissemination. The intraperitoneal (IP) administration of PTX was developed to reinforce the drug's effect on peritoneal metastasis. This would be accomplished by making the drug act directly on the nodules at a high concentration. In ...

BackgroundCurative resection of sigmoid colon and rectal cancer includes “high tie” of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate, and it is unclear whether this confers a survival advantage. Accordingly, the IMA may be ligated at a point just below the origin of the left colic artery (LCA) “low tie” combined with lymph node dissection (LND) around the origin of the IMA (low tie with LND). However, no study has investigated the detailed prognostic results between “high tie” and “low tie with LND.” The aim of this study was to assess the utility of “low tie with LND” on survival in patients with sigmoid colon or rectal cancer.MethodsA total of 189 sigmoid colon or rectal cancer patients who underwent curative operation from 1997 to 2007 were enrolled in this study. The patient’s medical records were reviewed to obtain clinicopathological information. Overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method, with differences assessed using log-rank test.ResultsForty-two and 147 patients were ligated at the origin of the IMA (high tie) and just below the origin of the LCA combined with LND around the origin of the IMA (low tie with LND), respectively. No significant differences were observed in the complication rate and OS and RFS rates in the two groups. Further, no significant difference was observed in the OS and RFS rates in the lymph node-positive cases in the two groups.Conclusions“Low tie with LND” is anatomically less invasive and is not inferior to “high tie” with prognostic point of view.