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A 16-year-old boy was diagnosed with Crohn's disease. Treatment with oral mesalazine was started at 3 g per day; however, he complained of high fever, a nonproductive cough, and left shoulder pain after 2 weeks. His chest radiography and chest computed tomography showed cardiomegaly and left pleural effusion, while an echocardiogram revealed pericardial effusion. Because no infection was detected by thoracentesis and the drug lymphocyte stimulation tests for mesalazine were positive, the patient was diagnosed with mesalazine-induced pleuropericarditis. After the cessation of mesalazine, the clinical symptoms and laboratory findings quickly improved.

Intraperitoneal (IP) chemotherapy for peritoneal carcinomatosis (PC) from gastrointestinal cancer has been investigated and applied clinically for several decades. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy have been considered to be the optimal treatment options for selected patients with colorectal and gastric cancers with PC. Accumulating evidence suggests that the administration of IP paclitaxel for patients with PC from gastric cancer may improve the patient survival. The pharmacokinetics of such treatment should be considered to optimize IP chemotherapy. In addition, newly emerging molecular-targeted therapies and research into new drug delivery systems, such as nanomedicine or controlled absorption/release methods, are essential to improve the effects of IP chemotherapy. This review summarizes the current status and future prospects of IP chemotherapy for the treatment of gastrointestinal cancer.

This study reviewed 1059 patients with colorectal cancers (CRCs) to evaluate the age-related changes in the clinicopathologic features, according to the gender. The presence of concomitant adenoma was the only independent age-related factor in men (P = .0044), whereas the presence of right-sided CRC was the only one in women (P < .0001). The results suggest the oncologic background difference between men and women among the elderly. Introduction: Although several reports have documented the increased incidence of right-sided colorectal cancer (CRC) in the elderly, especially in women, the gender-specific, age-related changes in the characteristics of CRCs, especially related to the cancer localization, have not been fully investigated. This study evaluated the age-related changes in the clinicopathologic features of CRCs, according to the gender. Materials and Methods: A total of 1059 consecutive patients with CRCs who were admitted to the authors' surgical department between February 2005 and June 2012 were retrospectively reviewed. The patients were divided into male (n = 632) and female (n = 427) groups and then according to the age group, and the correlation between the age group and the other clinicopathologic features was analyzed by univariate and multivariate analysis. Results: The number of concomitant adenomas found was significantly increased along with increasing age in men, and the presence of concomitant adenoma was the only independent age-related factor of male CRC in the multivariate analysis (P = .0044). In contrast, in women, the location of the CRC progressively shifted to the right side (proximal colon) with increasing age, and the presence of right-sided CRC was the only independent factor of female CRC in the multivariate analysis (P < .0001). Conclusion: There was a significant gender-specific difference in the age-related changes in the characteristics of CRC. Increasing the number of concomitant adenomas and the shift of CRC localization to the proximal colon were the gender-specific characteristics of male and female CRC, respectively.

Introduction: We report a rare case of delayed abdominal wall abscess after abdominoperineal resection (APR) for rectal cancer. Case description: A 63-year-old woman was diagnosed with rectal cancer and received chemo-radiotherapy, followed by APR. One year after surgery, the patient complained of pain and skin redness in the lower abdomen. A low-density mass lesion with 5.9-cm diameter was found in the lower abdominal wall by computed tomography, which showed high uptake on positron-emission tomography. These findings suggested the possibilities of either delayed abscess formation or abdominal wall recurrence of rectal cancer with central necrosis. Percutaneous drainage was performed. The content was a purulent exudate, without neoplastic cells in the cytology. The lesion quickly disappeared after the drainage, and no recurrence of the tumor was observed for more than 2 years. Discussion and evaluation: In this case, the un-absorbable yarn, such as silk, has not been used during the operation, no foreign body was retained in the abdominal wall, and there was no associated inflammatory bowel disease. Use of neoadjuvant chemoradiotherapy was the only possible cause of delayed abscess formation in this case. Conclusion: In case local recurrence is suspected by imaging modalities in the postoperative of colorectal cancer, especially those with precedent chemoradiotherapy or radiotherapy, although rare, the possibility of a delayed abscess formation should also be considered.

Background: Lysophosphatidylserine (lysoPS) is a type of lysophospholipid mediator, which is involved in allergic conditions and tumor progression. We investigated the physiological function of lysoPS on colorectal cancer (CRC) cell lines, as well as the involved receptor and signaling pathways. Materials and Methods: Expression of lysoPS receptors on six cell lines was examined by reverse transcription-polymerase chain reaction (RT-PCR). The physiological functions of lysoPS were investigated, and experiments using small interfering RNA (siRNA) or inhibitors of the signaling pathways were conducted. Results: Among the three lysoPS receptors, GPR34 was highly expressed on all cell lines. LysoPS stimulated the chemotactic migratory ability. Wortmannin inhibited the migratory ability, as well as the GPR34 knock-down, strongly suggestive of the involvement of this receptor in the PI3K/Akt pathway. Conclusion: The involved receptor and pathways in the migratory ability in response to lysoPS was demonstrated, which opens premises for targeting as a new strategy for prevention and treatment of colorectal cancer.

Background. Retrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer with unresectable metastasis (mCRC). Prognostic significance of lymph node dissection (LND) in mCRC has not been examined previously. The aim of this study was to investigate the prognostic impact of primary tumor resection and LND in mCRC. Methods. A total of 1,982 patients with mCRC from January 1997 to December 2007 were retrospectively studied. The impact of primary tumor resection and LND on overall survival (OS) was analyzed using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Covariates in the models for propensity scores included treatment period, institution, age, sex, carcinoembryonic antigen, tumor location, histology, depth, lymph node metastasis, lymphovascular invasion, and number of metastatic organs. Results. In a multivariate analysis, primary tumor resection and treatment in the latter period were associated with an improved OS, and age over 70 years, female sex, lymph node metastasis, and multiple organ metastasis were associated with a decreased OS. In the propensity-matched cohort, patients treated with primary tumor resection showed a significantly better OS than those without tumor resection (median OS 13.8 vs. 6.3 months; p = 0.0001). Furthermore, among patients treated with primary tumor resection, patients treated with D3 LND showed a significantly better OS than those with less extensive LND (median OS 17.2 vs. 13.7 months; p < 0.0001). Conclusions. It was suggested that primary tumor resection with D3 LND improves the survival of patients with mCRC.

Colon cast passage, which is the spontaneous passage of a full-thickness, infarcted colonic segment per rectum, is a rare occurrence. The main cause is acute ischemic colitis resulting from a circulation compromise. Most of the colon cast cases reported were secondary to abdominal aortic aneurysm repairs or colorectal surgery. We report a case of an 80-year-old woman with ischemic colitis who excreted a 20-cm colon cast. In most cases that involve a colon cast containing a muscle layer component, invasive therapy is required owing to colonic obstruction or stenosis. However, in the present case, the colon cast consisted only of a mucosa layer and was not associated with severe stenosis or obstruction; therefore, it was successfully treated by conservative therapy. Histologic examination of the colon segment may be crucial in determining the appropriate treatment.

The importance of Notch signaling in colorectal cancer (CRC) tumorigenesis has been recently recognized. However, the significance of Notch3 expression and its association with Notch1 expression in CRC is unclear. In the present study, we investigated Notch1 and Notch3 expression in Stage II and III CRC to assess their association with clinicopathological characteristics. The protein expression of Notch1 and Notch3 was examined using immunohistochemistry in 305 CRC specimens. Nuclear expression of Notch1 and Notch3 and their associations with clinicopathological characteristics and distant relapse-free survival (dRFS) were evaluated. Nuclear Notch1 was overexpressed in 37 % of specimen, and nuclear Notch3 in 38 %. Nuclear Notch3 expression correlated with tumor differentiation status (P = 0.0099). Nuclear expression of Notch1 and Notch3 was associated with tumor recurrence (P = 0.0311 and P = 0.0053, respectively). In multivariate analysis, nuclear Notch3 expression [hazard ratio (HR) = 1.71; 95 % confidence interval (CI), 1.06-2.78; P = 0.0271), lymph node metastasis, and venous involvement were independently correlated with dRFS. In subgroup analysis, nuclear Notch3 expression was strongly associated with dRFS in Stage II CRC (HR = 3.47; 95 % CI 1.44-9.22; P = 0.0055). Both nuclear Notch1 and Notch3 were positive in 67 specimens (22 %) and both were negative in 144 specimens (47 %). Coexpression of nuclear Notch1 and Notch3 had an additive effect toward poorer dRFS compared with a negative subtype (HR = 2.48; 95 % CI, 1.41-4.40; P = 0.0019). Nuclear Notch3 expression might be a novel predictive marker for recurrence in Stage II and III CRC.

BACKGROUND: Preoperative chemoradiotherapy has been widely used for the prevention of local recurrence of locally advanced rectal cancer, and the effect of chemoradiotherapy is known to be associated with overall survival. OBJECTIVE: We aimed to evaluate the association of the pathologic response grade with tumor recurrence rate after chemoradiotherapy, using radiographic analysis and the Response Evaluation Criteria in Solid Tumors as the parameters. DESIGN: This study was conducted at a single tertiary care institution in Japan. SETTING: This was a retrospective cohort study of patients undergoing preoperative chemoradiotherapy. PATIENTS: A total of 101 low rectal cancer patients receiving preoperative chemoradiotherapy from July 2004 to August 2012 were enrolled. MAIN OUTCOME MEASURES: The tumor reduction rate was measured with the use of traditional Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry, and the correlation between the reduction rate and the pathologic response grade was examined. RESULTS: The tumor reduction rate assessed according to Response Evaluation Criteria in Solid Tumors showed no association with the pathologic response grade (p =0.61). In contrast, the radiographic response rate by both barium enema and CT volumetry strongly correlated with the pathologic response grade (p < 0.0001 and p = 0.001). In terms of local tumor recurrence, those diagnosed as high responders by the pathologic response grade, Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry had a lower recurrence rate (p =0.03, p =0.03, p =0.0002, and p =0.001). The difference between high responders and low responders was especially prominent by barium enema and CT volumetry. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSIONS: Double-contrast barium enema and CT volumetry were superior to Response Evaluation Criteria in Solid Tumors in evaluating the effect of chemoradiotherapy and predicting the likelihood of tumor recurrence.

To develop a drug-delivery system for the prolonged retention of intraperitoneally (i.p.) administered cisplatin (CDDP) to deliver intraperitoneal chemotherapy against peritoneal carcinomatosis effectively. CDDP was encapsulated inside an in situ cross-linkable hyaluronic acid (HA)-based hydrogel. The gelation and degradation kinetics of the hydrogel and the release kinetics of CDDP were investigated in vitro, and the antitumor effect was investigated in a mouse model of peritoneal dissemination of human gastric cancer. The gelation time varied according to the concentration of two polymers: HA-adipic dihydrazide and HA-aldehyde. CDDP was released from the hydrogel for more than 4 days. A cell proliferation assay showed that the polymers themselves were not cytotoxic toward MKN45P, a human gastric cancer cell line. By mixing the two polymers in the peritoneum, in situ gelation was achieved. The weight of peritoneal nodules decreased in the hydrogel-conjugated CDDP group, whereas no significant antitumor effect was observed in the free CDDP group. In situ cross-linkable HA hydrogels represent a promising biomaterial to prolong the retention and sustain the release of intraperitoneally administered CDDP in the peritoneal cavity and to enhance its antitumor effects against peritoneal dissemination.

Published reports concerning internal hernias after extraperitoneal stoma construction are scarce. In our present report, we describe the case of a 56-year-old man who was referred to our hospital for the treatment of rectal cancer. He underwent abdominoperineal resection of the rectum with sigmoidostomy using an extraperitoneal route. On the ninth postoperative day, the patient experienced sudden and intense abdominal pain and was diagnosed with strangulation of the small intestine due to a stoma-associated internal hernia. Therefore, an emergency laparotomy was performed. The surgical findings showed that the small intestine protruded through the space between the sigmoid colon loop and the abdominal wall in a cranial-to-caudal direction. The strangulated portion of the small intestine was recovered, and the orifice of herniation was closed. No recurrence of internal herniation was observed during the follow-up period.

Intraperitoneal (IP) administration of paclitaxel (PTX) can enable direct infiltrate of high amount of PTX into peritoneal nodules and elicit remarkable clinical responses against peritoneal metastases. In this study, we examined the mechanisms leading to tumor shrinkage after IP PTX. We compared the microscopic features of peritoneal metastases before and after IP PTX in surgically removed human samples, as well as in a murine xenograft model using immunohistochemistry. We found that many microvessels exist in the peripheral areas of metastatic nodules in human samples before treatment. However, peripheral vessels were greatly reduced in number, and luminal obstructions were observed in lesions showing complete response after chemotherapy including IP PTX. Similar changes were observed in peripheral vessels of peritoneal tumors in MKN45-inoculated nude mice treated with IP-PTX. Moreover, pimonidazole staining revealed that highly hypoxic regions were produced by IP PTX at the tumor periphery. These findings strongly suggest that the remarkable efficacy of IP PTX in the treatment of peritoneal metastases is, at least in part, dependent on the destruction of peripheral microvessels by exposure to infiltrated PTX.

In this study, we analyzed intraperitoneal cells recovered from human samples and found that CD90(+)CD45(-) cells exist as a minor population but vigorously grow in culture, showing the morphological features of mesothelial cells (MC). Interestingly, the MC highly expressed arginase I and markedly suppressed T cell proliferation with the reduction of CD3 chain expression in T cells stimulated by coated anti-CD3 mAb. The addition of nor-NOHA (500 mu M), or L-arginine (1 mM) mostly restored the inhibitory effect of MC on T cell proliferation as well as the reduced expression of CD3 zeta chain. The expression level of CD3 zeta chain in T cells in the peritoneal cavity was significantly down-regulated from circulating T cells. These results suggest that intraperitoneal free MC have immunomodulatory functions through the control of L-arginine level, and thus may play significant roles in the pathogenesis of various diseases in the peritoneal cavity. (c) 2014 Elsevier Inc. All rights reserved.

Background. Peritoneal metastasis of gastric cancer has extremely poor clinical outcomes. Recently, we developed a combination chemotherapy that used intraperitoneal (IP) paclitaxel (PTX) and produced excellent antitumor effects against peritoneal lesions. However, no information is available about the benefit of gastrectomy in cases with malignant ascites. Methods. A total of 64 patients with severe peritoneal metastasis and ascites received IP PTX at 20 mg/m(2) via implanted subcutaneous peritoneal access ports as well as intravenous (IV) PTX at 50 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2) day for 14 consecutive days, followed by 7 days of rest. In all patients, investigative laparoscopy was performed around the combination chemotherapy, and gastrectomy was performed on patients who showed apparent shrinkage of their peritoneal nodules as well as negative peritoneal cytology at the second laparoscopy. Results. Gastrectomy was performed in 34 patients. The median course of chemotherapy before surgery was 5 courses (range 2-16). R0 operation was achieved in 22 patients (65 %), and grade 2 and 3 histological responses were obtained in 7 (21 %) and 1 (3 %) patient(s), respectively. The median survival time and 1-year overall survival of the gastrectomized patients were 26.4 months and 82 %, and those of the 30 patients who did not receive gastrectomy were 12.1 months and 26 %, respectively. Morbidity was minimal, and there was no mortality. Conclusions. Salvage gastrectomy after chemotherapy of S-1 with IV and IP PTX is promising, even for patients with highly advanced gastric cancer and severe peritoneal metastasis and malignant ascites.

BackgroundPeritoneal metastasis (PM) is the most life-threatening type of metastasis in abdominal malignancy. To improve the diagnostic accuracy of cytologic detection (CY) of free tumor cells (FTC) in the peritoneal cavity, we tried to quantify the FTC to leukocyte ratio using flow cytometry in patients with peritoneal metastasis. MethodsCells were recovered from ascites or peritoneal lavages from 106 patients who underwent abdominal surgery and additional 89 samples which were obtained from peritoneal catheter or access port in patients with PM (+) gastric cancer. The cells were immunostained with monoclonal antibodies to CD45 and to CD326 (EpCAM). Using flow cytometry, CD326 (+) and CD45 (+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated. ResultsIn 106 samples obtained by laparotomy, Median (M) of the TLR of PM (+) patients was 1.39% (0-807.87%) which was significantly higher than PM (-) patients (M=0%, 0-2.14%, P<0.001). In PM (+) patients, 86 CY (+) samples showed higher TLR than 61 CY (-) samples (M=2.81%, 0.02-1868.44% vs. M=0%, 0-3.45%, p<0.0001). In all of the 24 patients who were monitored for TLR before and after intraperitoneal (IP) chemotherapy, the TLR was reduced which was more dramatic than the results of the change in cytology. ConclusionsTLR measured with FACS is an excellent reflection of the tumor spread in the peritoneal cavity and could be a reliable diagnostic biomarker to determine the severity of PM as well as effectiveness of IP chemotherapy. (c) 2013 International Clinical Cytometry Society

The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(2) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, alpha-smooth muscle actin and fibroblast activated protein-a by the stimulation with TGF-beta, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies.

Background: Intraperitoneal administration of paclitaxel (PTX) can elicit a marked clinical response in peritoneal metastases of gastric cancer. Methods: In this study, we retrospectively analyzed the clinical outcome of 17 patients who underwent R0 resection with D2 dissection for advanced gastric cancer with macroscopic serosal exposure and received intraperitoneal PTX as adjuvant therapy. Results: A pathological study revealed that the depth of invasion of the primary tumor was pT4a or pT4b in 10 cases, and that the pN stage was more than pN2 in 8 cases. Genetic analysis of peritoneal lavage fluid was performed in 14 cases, all of which were positive for carcinoembryonic antigen mRNA. In these patients, PTX was intraperitoneally administered at 20-60 mg/m2 with oral S-1 for 3-36 months after surgery. In a median follow-up period of 66 months, recurrence occurred in the liver and peritoneum in 2 (11.7%) and 1 (5.9%) patients, respectively, and no nodal recurrence was observed. Five-year overall survival and disease-free survival were 88.2 and 82.3%, respectively. Conclusion: Since these patients are considered to be a high-risk group for peritoneal recurrence, this result strongly suggests that adjuvant chemotherapy including intraperitoneal PTX is a promising protocol to improve the outcome of patients with advanced gastric cancer with serosal exposure. © 2014 S. Karger AG, Basel.

Background: Right-sided colon cancer is considered to be biologically different from left-sided colon cancer; however, conflicting results have been reported regarding differences in prognosis. We aimed to clarify the prognostic impact of tumor location in stage IV colon cancer. Methods: Stage IV colon cancer treated from January 1997 to December 2007 (n = 2208) were retrospectively studied. Clinical and pathological features were compared between right-sided colon cancer (cecum, ascending, and transverse colon) and left-sided colon cancer (descending, sigmoid, and rectosigmoid colon). The impact of tumor location on cancer-specific survival (CSS) was analyzed in a multivariate analysis and propensity score analysis to mitigate the differences in background features. Results: Right-sided colon cancer was associated with older age, female sex, larger tumor size, poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma, a more advanced state within stage IV disease, and a worse CSS. In the cohort matched by propensity scores for background clinicopathological features, tumor location in the right-sided colon was associated with a significantly worse CSS (hazard ratio 1.2, 95% confidence interval 1.1-1.4, p = 0.008) in patients treated with palliative primary tumor resection, but not in those treated with R0 resection or no resection. Conclusion: Right-sided colon cancer were diagnosed at a more advanced state within stage IV disease and showed a significantly worse prognosis than left-sided colon cancer, suggesting that stage IV right-sided colon cancer is oncologically more aggressive than left-sided colon cancer. (C) 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Background: The identification of responders is an important issue in chemotherapy for metastatic colorectal cancer (mCRC). 'Deepness of response' (DpR), defined as the maximum rate of reduction from the initial tumor burden, was recently proposed as a novel hypothetical parameter associated with overall survival (OS) in first-line chemotherapy plus cetuximab for mCRC. We determined whether this concept was universally applicable to diverse standard chemotherapeutic regimens for mCRC. Methods: We reviewed mCRC patients who received the first-line systemic chemotherapy regimens FOLFOX, CapeOX or FOLFIRI (with biologics) at our department between June 2005 and March 2015. Data such as clinicopathological parameters, metastasized organs, chemotherapeutic regimens, the best response by RECIST v1.1, progression-free survival (PFS) and OS were retrospectively retrieved for patients who exhibited tumor shrinkage. DpR was calculated as the uni-dimensional maximum reduction rate of measurable tumors. We addressed the association between DpR and survival. Results: Of the 156 patients receiving first-line chemotherapy regimens, tumor shrinkage was observed in 63 (41 of whom were men; median age 62 years). Complete remission was achieved in 6 patients, partial remission in 42 and stable disease in 15. The median DpR was 44.2% and was employed as the cutoff, in line with previous reports. DpR >= 45% (31 patients) was correlated with longer PFS (median 16.4 vs. 8.1 months for DpR <45%, p = 0.006) and OS (median 58.6 vs. 30.9 months for DpR <45%, p = 0.041). There was basically no difference in the subsequent chemotherapy between the DpR >= 45% and DpR <45% groups. Conclusion: DpR correlated with OS in various first-line systemic upfront chemotherapy regimens for mCRC. (C) 2015 S. Karger AG, Basel

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. (c) 2013 American Cancer Society.

Background and Aim: Gastrointestinal (GI) luminal obstruction or malignant biliary obstruction (MBO) is not a rare condition in gastric cancer patients with peritoneal metastasis. The role of endoscopic or percutaneous interventions is not fully elucidated in this setting. Methods: A total of 123 patients with unresectable or recurrent gastric adenocarcinoma with peritoneal metastasis receiving intravenous and intraperitoneal paclitaxel combined with S-1 were retrospectively studied. Safety and efficacy of interventions for GI luminal obstruction and MBO were evaluated. Results: A total of 27 patients (22%) underwent GI luminal and/or biliary interventions; GI luminal alone in 10, biliary alone in 10 and both in seven, with a technical success rate of 100%. Clinical success rate was 65% in self-expandable metallic stents (SEMS) placement for GI luminal obstruction. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was prognostic of clinical success in GI luminal stenting (100% in PS of 1 vs 14% in PS of 23, P?<?0.001). Biliary drainage (endoscopic SEMS placement in four and percutaneous transhepatic biliary drainage in 12) relieved obstructive jaundice in 94%. Six complications were observed: four after GI luminal stenting (two occlusion and one aspiration pneumonia) and two after biliary stenting (one cholangitis and one cholecystitis). Median survival after the initial intervention was 5.7?months. PS at interventions was prognostic of survival after interventions (12.3?months in PS of 1 vs 2.2?months in PS of 2 or 3, P?<?0.001). Conclusion: Endoscopic or percutaneous interventions for GI luminal obstruction or MBO were feasible and effective in gastric cancer patients with peritoneal dissemination receiving combination chemotherapy.

The efficacy of intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis has been verified by clinical trials. To perform intraperitoneal chemotherapy safely and effectively, the appropriate management of intraperitoneal access ports is essential. The aim of this study was to investigate the occurrence of port complications during cyclically repeated intraperitoneal chemotherapy. The medical records of 131 gastric cancer patients with peritoneal metastases who received intraperitoneal paclitaxel between 2005 and 2011 were retrospectively analyzed. The median period of intraperitoneal chemotherapy using a port system was 12.9 months (range: 0.861.5 months), and a total of 27 (20.6) patients experienced port complications. Inflow obstruction (7.6) and infection (6.9) were the main complications, followed by reflux (3.1), subcutaneous masses (1.5) and fistulae (1.5). The median interval between port implantation and port complication was 5.4 months (range: 0.340.9 months). Complications were controllable and chemotherapy was not terminated by complications. Survival was not affected by the presence or absence of port complications (median survival time: 22.5 vs. 17.2 months, respectively; P 0.65). Intraperitoneal chemotherapy for gastric cancer using a port is safe and feasible under appropriate management.

The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel-incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX-Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX-Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX-Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX-Cre group (P<0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX-Cre. Serum paclitaxel concentrations 6, 12, 24, and 48h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX-Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX-Cre group (24100 +/- 3560 vs 108 +/- 25 similar to ng/mL, respectively; P<0.001), as was the area under the concentrationtime curve from 0 to 48h (191000 +/- 32100 vs 1500 +/- 108ng center dot h/mL, respectively; P<0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation. (Cancer Sci 2012; 103: 13041310)

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. 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. 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. 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 detected 7 cases of leptomeningeal carcinomatosis in 126 patients with peritoneal dissemination of gastric cancer who received combined systemic and intraperitoneal chemotherapy. Leptomeningeal carcinomatosis was diagnosed 79-1540 days after the diagnosis of the primary gastric cancer. Patients presenting with various neurological symptoms were diagnosed by cerebrospinal fluid (CSF) cytology and radiological imaging. Irradiation to the whole brain and spine was performed in 4 patients, and provided palliation and increased survival for 1 patient. Intrathecal chemotherapy and drainage of CSF was performed in 1 patient each, but produced no significant clinical benefit in either of them. Survival after the diagnosis of leptomeningeal carcinomatosis was between 3 and 155 days. As patients with peritoneal dissemination of gastric cancer are living longer because of improved chemotherapy, clinicians must recognize the possibility of leptomeningeal carcinomatosis when patients complain of neurological symptoms.

Intraperitoneal (i.p.) administration of paclitaxel nanoparticles (PTX-30W) prepared by solubulization with the amphiphilic copolymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate can efficiently suppress the growth of peritoneal metastasis. In this study, we characterized the drug distribution of i.p. injected PTX-30W in peritoneal tumor and liver in a mouse model using MKN45, human gastric cancer cells. Oregon green-conjugated PTX-30W showed perivascular accumulation in MKN45 tumor in the peritoneum at 24 h after intravenous (i.v.) injection; however, the amount of PTX in tumor was markedly less than that in liver. In contrast, a larger amount of PTX accumulated in the peripheral area of disseminated nodules at 1 h after i.p. injection and the area gradually enlarged. The depth of PTX infiltration reached 1 mm from the tumor surface at 48 h after i.p. injection, and the fluorescence intensity was markedly greater than that in liver. Interestingly, i.p. injected PTX preferentially accumulated in relatively hypovascular areas, and many tumor cells in the vicinity of PTX accumulation showed apoptosis. This unique accumulation pattern and lesser washout in hypovascular areas are thought to be attributable to the superior penetrating activity of PTX-30W, and thus, PTX-30W is considered to be highly suitable for i.p. chemotherapy for peritoneal dissemination. (Cancer Sci 2011; 102: 200-205).

The aim of this study was to elucidate the possible effects of short-term exposure to a 1439-MHz electromagnetic field (EMF) employing time division multiple access (TDMA), which is the basis of the Japanese Personal Digital Cellular system, on estrogenic activity in rats. Sixty-four ovariectomized female Sprague-Dawley rats were divided into four groups: EMF exposure (EM), sham exposure, cage control, and 17 beta-estradiol injected (E2). The EM group was exposed, for 4 h per day on three consecutive days, to the 1439-MHz TDMA signal that produced 5.5-6.1 and 0.88-0.99 W/kg average specific absorption rates in the brain and the whole body, respectively. The uterine wet mass and serum estradiol level significantly increased in the E2 group, while there were no differences among the other three groups. Although negative effects of long-term EMF exposure must be thoroughly investigated before a final conclusion can be reached, our results do not support the assumption that the high frequency EMF used in cellular phones exerts estrogenic activity. Bioelectromagnetics 31: 573-575, 2010. (C) 2010 Wiley-Liss, Inc.

Objective: Oxygen is one of the most important environmental factors for tumor development. In this study, we examined pO2 in malignant ascites in patients with peritoneal carcinomatosis. Methods: In 21 patients with peritoneal dissemination of gastric cancer, ascitic fluid was collected and its pH, pCO2 and pO2 were determined using a blood gas analyzer. Results: In 21 patients, pH of malignant ascites was significantly lower than that of arterial blood (7.39 ± 0.07, 7.44 ± 0.02, p &lt 0.05). Accordingly, pCO2 tended to be higher in ascites than in arterial blood. Unexpectedly, pO2 in malignant ascites showed relatively high values (90.4 ± 27.72 mm Hg), which were mostly the same as those of arterial blood (97.09 ± 10.33 mm Hg, p = 0.858). Even in 19 patients whose samples were collected at bedside in room air, pO2 of malignant ascites was 85.94 ± 23.94 mm Hg, which was patently higher than that in venous blood or in solid tumor tissues. Conclusion: Since the oxygen level critically affects the sensitivity of tumor cells to chemotherapeutic agents through metabolic transformation, the oxygenic condition in the peritoneal cavity may be beneficial for the progression of peritoneal metastasis, and also clinically important in considering the efficacy of chemotherapy. © 2010 S. Karger AG, Basel.

A 47-year-old man with acute abdominal pain in the right lower quadrant underwent an appendectomy via McBurney's incision. Postoperative histology revealed a moderately differentiated adenocarcinoma in the appendix that invaded the submucosa along with lymphatic involvement. Forty-three days later, an ileocecal resection with radical lymph node dissection was performed through a midline incision. Three of the 30 resected lymph nodes were found to have adenocarcinoma metastasis. Five years later, an isolated abdominal wall recurrence occurred within the wound scar of the midline incision. A complete excision of the tumor and the invaded portion of the ileum was performed. To date, the patient has been well, with no evidence of recurrence for 5 years since the resection. The mechanism of abdominal wound recurrence is considered the leakage of carcinoma cells from transected lymph vessels during lymph node dissection, followed by the implantation of these cells into the abdominal wound. © 2010 Elsevier Inc. All rights reserved.

We experienced 3 cases of recurrent breast cancer treated with S-1 therapy, delaying tumor progression and improving their quality of life (QOL). All the patients had been previously treated with both anthracyclines and/or taxanes prior to S-1 chemotherapy. All patients almost completed the full dose through the whole course of treatment, and the drug showed good tolerability. Long-term (more than 12 weeks) therapeutic efficacy and the patients' QOL have been maintained for all patients. No major side effects were seen. It is thought that less toxicity enabled patient 3 to undergo long-term therapy. It is especially important that one patient had therapeutic efficacy and QOL improvement from treatment with S-1 and aromatase inhibitor for over 3 years, after being treated with anthracyclines, taxanes and vinorelbine. We conclude that S-1 is effective and well tolerated in patients with metastatic breast cancer, and will accommodate a long-time progression with respect to efficacy and maintaining the patients' QOL. Further evaluation of S-1 is necessary to elucidate its clinical role in breast cancer treatment.

Objectives: A phase I study of biweekly intravenous (IV) paclitaxel (PTX) plus intraperitoneal (IP) cisplatin (CDDP) and PTX was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Methods: Nine gastric cancer patients with peritoneal metastasis were enrolled. PTX was administered intravenously at a dose of 100 mg/m(2) and intraperitoneally with an initial dose of 20 mg/m(2) (level 1), stepped up to 30 or 40 mg/m(2) depending on observed toxicity. CDDP was administered intraperitoneally at a dose of 30 mg/m(2) over 24 h. PTX and CDDP were administered on days 1 and 15 in 4-week cycles. Results: The MTD was determined to be dose level 1, as 2 of 3 patients experienced dose-limiting toxicities (DLTs), grade 4 leukopenia and grade 3 vomiting. Therefore, the doses of IV PTX, IP CDDP and IP PTX were reduced to 80, 25 and 20 mg/m2, respectively (level 0). Consequently, the RD was determined to be dose level 0, as only 1 of 6 patients experienced DLT, grade 3 nausea. Conclusions: Combination chemotherapy of IV PTX plus IP CDDP and PTX was shown to be a safe regimen that should be further explored in clinical trials. Copyright (C) 2011 S. Karger AG, Basel

We report the case of a 52-year-old woman with occult breast cancer who presented with a hard metastatic nodule in the left axilla. Although histology identified a metastatic adenocarcinoma in the lymph nodes, numerous tests failed to detect the primary tumor. Immunohistochemistry showed that the resected lymph node was positive for both estrogen and progesterone receptors, suggesting the breast as the site of the primary tumor. Left modified radical mastectomy was performed. Pathology revealed an invasive ductal carcinoma (1.5 x 1 mm in size) with extensive lymphatic involvement, which strongly expressed both vascular endothetial growth factor-C (VEGF-C) and VEGF-D. (c) 2005 Elsevier Ltd. All rights reserved.

Massive postoperative polyuria is rare, except in neurosurgery patients. Here we report excessive polyuria in a 59-year-old woman following total gastrectomy for advanced gastric cancer. The etiology of the patient's polyuria was unknown. Urine output was measured hourly and replaced with Ringer's lactate solution at 80% of measured volume. The rate of urine output during 9 postoperative days ranged from 900 to 2700 ml·h-1. Several administrations of an antidiuretic hormone (ADH) analogue were ineffective in reducing urine output, suggesting a possible relationship of the massive polyuria to nephrogenic diabetes insipidus. Following oral administration of a thiazide diuretic, known to exert an antidiuretic action in nephrogenic diabetes insipidus, urine output was dramatically reduced. We conclude that this case of massive polyuria probably resulted from postoperative nephrogenic diabetes insipidus. © JSA 2006.

Introduction. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid, derived from activated platelet, that is known to induce diverse cellular responses through at least five G-protein-coupled receptors on various cell types. Abnormal platelet and coagulation activation is often seen in patients with gastric cancer. However, neither the effects of this platelet-derived mediator S1P nor the distribution of S1P receptors on the gastric cancer cell are fully understood. The aim of this study was to examine the possible role of S1P and its receptors in the progression of gastric cancer. Materials and methods. We characterized the expression profiles of S1P receptors in nine human gastric cancer cell lines and evaluated the relationship between the responses to S1P and its receptor expression on cell migration by modified Boyden chamber and cell proliferation by MTS assay. Results. Northern blotting analysis has revealed that S1P2 was expressed in all gastric cancer cell lines to varying degrees, and S1P3 was expressed in four cell lines. S1P1 expression was weak, and no significant expression of either S1P4 or S1P5 was detected. The addition of S1P markedly stimulated the migration of MKN1 and HCG-27 that dominantly expressed S1P3, and the effect was potently inhibited by pertussis toxin or wortmannin. In contrast, S1P significantly inhibited the migration of AZ-521 that expressed S1P2 exclusively. This indicates that the balance between S1P2- and S1P3-mediated signals might be critical in determining the metastatic response of gastric cancer cells to S1P. S1P elicited weak but significant antiproliferative effects on all of the three cell lines, although the effects were not major. In these cells, S1P induced extracellular signal-regulated kinase (ERK) phosphorylation with transient Akt dephosphorylation that may cause the weak effects on proliferation. Conclusions. Our results suggest that the S1P receptor expression may critically determine the biological behavior of gastric cancers and thus therapeutic interventions directed at each S1P receptor might be clinically effective in preventing metastasis in gastric cancer. (c) 2006 Elsevier Inc. All rights reserved.

AIM: To examine whether lysophosphatidic acid (LPA) induces phosphorylation of c-Met and epidermal growth factor receptor (EGFR), both of which have been proposed as prognostic markers of colorectal cancer, and whether LPA induces cyclooxygenase-2 (COX-2) expression in human colon cancer cells. METHODS: Using a human colon cancer cell line, LoVo cells, we performed immunoprecipitation analysis, followed by Western blot analysis. We also examined whether LPA induced COX-2 expression, by Western blot analysis. RESULTS: Immunoprecipitation analysis revealed that 10 mu mol/L LPA induced tyrosine phosphorylation of c-Met and EGFR in LoVo cells within a few minutes. We found that c-Met tyrosine phosphorylation induced by LPA was not attenuated by pertussis toxin or a matrix metalloproteinase inhibitor, in marked contrast to the results for EGFR. In addition, 0.2-40 mu mol/L LPA induced COX-2 expression in a dose-dependent manner. CONCLUSION: Our results suggest that LPA acts upstream of various receptor tyrosine kinases (RTKs) and COX-2, and thus may act as a potent stimulator of colorectal cancer. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.

The ligand-less receptor HER2/neu (erbB-2) has been proposed as a prognostic marker of gastric cancer that correlates with poor clinical outcome, indicating that HER2 signals play an important role in gastric cancer progression. This study demonstrated that two Major natural lysophospholipids, lysophosphatidic acid (LPA) and sphingosine I-phosphate (SIP), induce rapid and transient phosphorylation of HER2 in two human gastric cancer cell lines, MKN28 and MKN74 cells. We also revealed that tyrosine phosphorylation of HER2 induced by both lysophospholipids was significantly attenuated by two inhibitors, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This suggests that the pathway of HER2 transactivation induced by these lysophospholipids is dependent on the proteolytically released EGFR ligands. Our results indicate that LPA and SIP act upstream of HER2 in gastric cancer cells, and thus may act as potent stimulators of gastric cancer. (C) 2004 Elsevier Inc. All rights reserved.

The widespread use of the mobile phone has initiated many studies on the possible adverse effects of a high frequency electromagnetic field (EMF), which is used in mobile phones. A low frequency EMF is reported to suppress melatonin synthesis. The aim of this study was to clarify the effects on melatonin synthesis in rats after short term exposure to a 1439 MHz time division multiple access (TDMA) EMF. The average specific absorption ratio (SAR) of the brain was 7.5 W/kg, and the average SARs of the whole body were 1.9 and 2.0 W/kg for male and female rats, respectively. A total of 208 male and female rats were investigated. After acclimatization to a 12 h light-dark (LD) cycle, serum and pineal melatonin levels together with pineal serotonin level under a dark condition (less than I lux) were examined by radioimmunoassay. No significant differences in melatonin and serotonin levels were observed between the exposure, sham, and cage control groups. These results suggest that short term exposure to a 1439 MHz TDMA EMF, which is about four times stronger than that emitted by mobile phones, does not alter melatonin and serotonin synthesis in rats. Further investigations on the effects of long term exposure are warranted. (C) 2004 Wiley-Liss, Inc.

Lysophosphatidic acid (LPA), which interacts with at least three G protein-coupled receptors (GPCRs), LPA I /Edg-2, LPA2/Edg-4, and LPA3/Edg-7, is a lipid mediator with diverse effects on various cells. Here, we investigated the expression profiles of LPA receptors and patterns of LPA-induced migration in gastric cancer cells. Northern blot analysis revealed that various gastric cancer cells expressed variable levels of LPA1, LPA2, and LPA3 without a consistent pattern. Using a Boyden chamber assay, LPA markedly increased cell migration of LPA1-expressing cells, the effects of which were almost totally abrogated by Kil6425, anLPA antagonist against LPA1 and LPA3. In contrast, LPA by itself did not significantly induce migration in MKN28 and MKN74 cells, which exclusively expressed LPA2. However, when hepatocyte growth factor (HGF) was placed with LPA in the lower chamber, LPA induced migration of these cells in a dose-dependent manner. Inummoprecipitation analysis revealed that LPA induced transient tyrosine phosphorylation of c-Met in LPA2-expressing cells, which suggests that the transactivation of c-Met by LPA causes a cooperative migratory response with HGF to these cells. Our results indicate that LPA regulates the migration of gastric cancer cells in a receptor-specific manner and suggest that the expression pattern of LPA receptors may affect the metastatic behavior of gastric cancer. (C) 2004 Elsevier Inc. All rights reserved.

Receptor tyrosine kinases (RTKs) are transactivated by the stimulation of G protein-coupled receptors (GPCRs). Sphingosine I-phosphate (SIP), a ligand of GPCR, is known as a tumor-promoting lipid, but its signaling pathways are not fully understood. We here demonstrated that SIP induces rapid and transient tyrosine phosphorylation of epidermal growth factor receptor (EGFR) and c-Met in gastric cancer cells, both of which have been proposed as prognostic markers of gastric cancers. The pathway of SIP-induced c-Met transactivation is Gi-independent and matrix metalloproteinase-independent, which differs from that of EGFR transactivation. Our results indicate that SIP acts upstream of various RTKs and thus may act as a potent stimulator of gastric cancer. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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; P<0.05), and LPA2 mRNA at a significantly higher level (three-fold; P<0.05), 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.

Although peritoneal metastasis is an important factor determining the prognosis of patients with gastrointestinal cancer, the mechanisms have not yet been clearly defined. Human peritoneal mesothelial cells (HPMC) are the first line against disseminated tumor cells. Recent reports have shown that mesothelial cells are capable of secreting various cytokines and growth factors. In this study, we isolated human mesothelial cells from surgically resected omental tissue and examined the production and interaction of two major angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2). Quiescent HPMC produced a considerable amount of VEGF at almost the same level as tumor cells. Interestingly, addition of FGF-2 to the culture significantly increased the mRNA synthesis and protein secretion of VEGF in a dose-dependent manner, as determined by Northern blot and ELISA. The addition of 0.5 ng/mL FGF-2 was enough to stimulate VEGF production, and the effect reached a plateau at 5 ng/mL. Reverse-transcribed polymerase chain reaction (RT-PCR) method clarified that the HPMC-derived VEGF consisted mostly of VEGF(121) and VEGF(165), which are both predominantly soluble forms. These data suggest that HPMC contribute to the development of metastases and the accumulation of malignant ascites due to the production of VEGF, especially in cancers that do not express enough amount of VEGF. (C) 2003 Elsevier Inc. All rights reserved.

Background/Aims: The EDG-2 (endothelial cell differentiation gene-2) has been characterized as one of the high-affinity receptors of lysophosphatidic acid: an extracellular lipid mediator which can induce tumor progression. Recent studies have revealed that EDG-2 plays an important role in various pathological events including cell proliferation and tumor development. The investigation of EDG-2 is thus considered important for eliciting the mechanism of tumorigenesis. However, in colorectal tissue, the clinical significance of EDG-2 expression remains unclear. In the current study, we examined the immunohistochemical expression of EDG-2 in colorectal mucosa and adenoma, and clarified its relation with the clinicopathological features. Methodology: One hundred and sixty-one colorectal polyps were resected endoscopically or surgically at our institute from 2000 to 2001. According to the degree of dysplasia, adenomas were grouped into two categories: low-grade (mild or moderate dysplasia) and high-grade (severe dysplasia or carcinoma in situ). We investigated EDG-2 expression by immunohistochemistry. Results: EDG-2 was expressed almost exclusively in the cytoplasm in colorectal normal mucosa and adenoma. EDG-2 expression in normal mucosa and adenoma was 8% and 76%, respectively. EDG-2 expression was increased in low-grade adenoma compared with that in normal mucosa (P < 0.001). EDG-2 expression was significantly greater in adenomas with larger diameters (P < 0.001). Conclusions: We demonstrated that EDG-2 expression was increased in the early stage of adenoma. A significant correlation between EDG-2 expression and the size - of the adenomas suggests that EDG-2 may play an important role in the growth of these adenomas.

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. S1P(1)/Edg1 (endothelial differentiation gene) and S1P(1)/Edg5 respectively, when each of the S1P receptor subtypes is expressed in CHO (Chinese-hamster ovary) cells. In B16F10 mouse melanoma cells, in which S1P(2), 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 S1P, in the melanoma cells resulted in potentiation of S1P inhibition of both Rac and cell migration. In contrast, overexpression of S1P(1) 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 S1P(2) greatly potentiated the inhibition of metastasis by S1P, whereas that of S1P(1) resulted in aggravation of metastasis. Suppression of cellular Rac activity by adenovirus-transduced expression of N(17)Rac, but not N(19)RhoA, 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.

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 ligand dependent 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.

This study sought to clarify the effects of exposure to electromagnetic waves (EMW) used in cellular phones on learning and memory processes. Sprague-Dawley rats were exposed for either 1 h daily for 4 days or for 4 weeks to a pulsed 1439 MHz time division multiple access (TDMA) field in a carousel type exposure system. At the brain, average specific absorption rate (SAR) was 7.5 W/kg, and the whole body average SAR was 1.7 W/kg. Other subjects were exposed at the brain average SAR of 25 W/kg and the whole body average SAR of 5.7 W/kg for 45 min daily for 4 days. Learning and memory were evaluated by reversal learning in a food rewarded T-maze, in which rats learned the location of food (right or left) by using environmental cues. The animals exposed to EMW with the brain average SAR of 25 W/kg for 4 days showed statistically significant decreases in the transition in number of correct choices in the reversal task, compared to sham exposed or cage control animals. However, rats exposed to the brain average SAR of 7.5 W/kg for either 4 days or for 4 weeks showed no T-maze performance impairments. Intraperitoneal temperatures, as measured by a fiber optic thermometer, increased in the rats exposed to the brain average SAR of 25 W/kg but remained the same for the brain average SAR of 7.5 W/kg. The SAR of a standard cellular phone is restricted to a maximum of 2 W/kg averaged over 10 g tissue. These results suggest that the exposure to a TDMA field at levels about four times stronger than emitted by cellular phones does not affect the learning and memory processes when there are no thermal effects.

Lysophosphatidic acid (LPA) is a lipid mediator with diverse effects on various cells. Here, we investigated the effects of LPA on human colon carcinoma DLD1 cells. Northern blot analysis revealed that DLD1 highly expressed LPA1/Edg-2 but showed only low expression of LPA2/Edg-4 and no expression of LPA3/Edg-7 at the mRNA level. Western blot analysis revealed that DLD1 cells highly expressed LPA1 at the protein level. Using the Boyden chamber assay, LPA markedly increased DLD1 cell migration at concentrations as low as 10 nm, with maximum stimulation at 100 nm (3.6-fold increase). Checkerboard analysis indicated that LPA stimulated both the chemotactic and chemokinetic migration of DLD1 cells. LPA induced a dose-dependent increase in the proliferation of DLD1 cells (3.2-fold increase at 20 mum). Furthermore, LPA stimulated DLD1 cell adhesion to collagen type I (2.0-fold increase at 10 mum) and also stimulated the secretion of both vascular endothelial growth factor (1.4-fold increase at 20 mum) and interleukin 8 (19-fold increase at 20 mum) by ELISA. In contrast, as for matrix metalloproteinase, LPA had no significant effect on pro-matrix metalloproteinase-2 secretion and its activation, as measured by Western blot analysis. Thus, LPA, at concentrations that are present physiologically, enhanced DLD1 cell migration, proliferation, adhesion, and secretion of angiogenic factors, all of which are crucial for cancer metastasis. In comparison, other human colon carcinoma cells (HT29 and WiDR) exclusively expressed LPA2. LPA enhanced their proliferation and secretion of angiogenic factors, whereas LPA did not enhance migration or adhesion. Our results suggest that LPA acts as a potent stimulator of colon cancer progression, although the binding to LPA1 and LPA2 induces slightly different responses.