北山 丈二

Solitary metastasis of a malignancy to the spleen is rare. We herein describe a case of splenic metastasis from early gastric cancer. A 76-year-old man underwent an endoscopic mucosal resection (EMR) for early gastric carcinoma in the cardia. Pathologically, the tumor showed invasion into the submucosal layer, and the stump of the surgical specimen appeared to be positive for malignant cells. He thus underwent a proximal gastrectomy with nodal dissection. One year later, serum carcinoembryonic antigen was elevated, and a splenic mass was detected by computed tomography and ultrasonography. Because the tumor increased in size very gradually and no metastatic lesions were detected at the other sites, we performed a splenectomy. The lesion was pathologically diagnosed as metastasis from the previous gastric carcinoma, and the patient remains healthy to date without recurrence, more than 2 years after the splenectomy. When solitary metastasis to the spleen is suspected during the postoperative follow-up of a patient with gastric cancer, a splenectomy is a potentially effective treatment.

Malignant ascites caused by gastric cancer are chemotherapy resistant and carry a poor prognosis. The efficacy of a regimen including intraperitoneal paclitaxel (PTX) was evaluated in 33 gastric cancer patients with ascetic fluid in the peritoneal cavity diagnosed with computed tomography (CT) scanning. Synchronous administration of intravenous (50 mg/m(2)) and intraperitoneal (20 mg/m(2)) PTX was performed via a subcutaneously placed intraperitoneal catheter on days 1 and 8, and S-1 was administered twice daily at 80 mg/m(2) /day for 14 consecutive days from day 1 to day 14, followed by 7 days of rest. The ascitic fluid volume was calculated with NIH Image J software using continuous CT images. After 2-4 treatment cycles, 23 (70%) patients showed reductions in their ascitic volumes of > 50%. Ascites disappeared completely in 8 patients and were markedly reduced (to <3% of the original volume) in 4 of the 9 patients (44%) who initially had massive (>2,500 ml) ascites. Median overall survival was significantly better in patients with ascitic reduction. Weekly intravenous and intraperitoneal PTX combined with S-1 was highly effective in gastric cancer with malignant ascites. The change in ascitic fluid volumes determined by CT image measurements is a useful predictor of outcome in these patients. Copyright (C) 2010 S. Karger AG, Basel

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

Currently, surgical treatment for colorectal hepatic metastasis is performed with low mortality and morbidity rates. However, there is no definitive marker that predicts patient outcome. The aim of this study is to identify the molecular predictor of survival along with its clinical properties. Fifty-six patients were surgically treated for colorectal cancer and synchronous hepatic metastasis from January 1994 to December 2004. Clinicopathologic and molecular factors were reviewed in association with overall survival (OS) and disease-free survival (DFS). Chromosome 18q deletion in the primary tumor was a molecular predictor that affected OS (P = 0.021). Decreased expression of the Smad4 protein tended to affect the outcome; however, no statistical significance was observed (P = 0.29:OS, P = 0.45:DFS). Preoperative carcinoembryonic antigen (P = 0.013) and carbohydrate antigen 19-9 (CA19-9) (P<0.0001) levels were poor clinical predictors of OS. The number of primary lymph nodes was the only pathologic factor that affected DFS (P = 0.0052). The number and diameter of hepatic metastasis had no influence on survival. In conclusion, we demonstrated that chromosome 18q deletion, in conjunction with high carcinoembryonic antigen and CA19-9 levels, is an unfavorable prognostic factor. This novel Molecular predictor is helpful in identifying patients who would benefit from surgical resection.

PURPOSE: The value of positive peritoneal cytology in colorectal cancer has been controversial. In this study, we aimed to clarify the prognostic significance of peritoneal cytology and the impact of the combination of peritoneal dissemination and peritoneal cytology on the prognostic evaluation of colorectal cancer. METHODS: From January 1997 to December 2005, intraoperative peritoneal cytology was performed on 410 patients who had at least serosal invasion. RESULTS: Thirty-one patients (7.6%) had positive peritoneal cytology. Patients with negative cytology showed a significantly better survival rate at five years than those with positive cytology (negative cytology, 68.0%; positive cytology, 20.6%; P < 0.0001). Multivariate analysis revealed that peritoneal cytology is one of the significant prognostic factors. Sixty percent of patients with positive cytology and 30.4% of patients with negative cytology recurred (P = 0.08). Regarding the recurrence site, patients with positive cytology showed a significantly higher recurrence rate of peritoneal dissemination than those with negative cytology (P = 0.0038). Some patients with positive cytology but without evident peritoneal dissemination achieved long-term survival. Additionally, some patients with macroscopic peritoneal dissemination and negative peritoneal cytology also achieved long-term survival. But for those patients with both positive cytology and evident macroscopic peritoneal dissemination, the five-year survival rate was zero. CONCLUSIONS: Patients with negative peritoneal cytology had a significantly better five-year survival rate than those with positive peritoneal cytology. In some cases in which either peritoneal cytology or peritoneal dissemination was negative, long-term survival could be achieved.

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 phosphorylcholineand n-butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effct 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. (Cancer Sci 2009; 100: 1979-1985).

P>Anastomotic leakage after radical esophagectomy is mostly caused by the hypoxia and high tension at the esophagogastric anastomotic site. Here, we introduce a new surgical technique, 'Angleplasty,' to enable the tensionless anastomosis at a highly oxygenic site of gastric conduit. In short, the seromuscular layer is cut for a perpendicular direction against a lesser curvature at a gastric angle and the gastric wall is carefully divided between the muscular and submucosal layers for longitudinal direction for 4-5 cm in length. Then, the wound is closed with seromuscular sutures for longitudinal direction. With this maneuver, the lesser curvature of the gastric roll is significantly elongated and the anastomosis site of the gastric conduit can be moved more distal on the greater curvature of the stomach where it is expected to receive more oxygen supply. This technique takes only several minutes, but provides highly favorable conditions for esophagogastric anastomosis and thus is clinically useful to reduce the risk of anastomotic leakage after esophagectomy.

Purpose. Paclitaxel is considered to be suitable for disseminated cancer in the peritoneal cavity because of its high molecular weight and lipophilic characteristics. However, the difference in pharmacokinetics of paclitaxel after intraperitoneal (i.p.) and intravenous (i.v.) administration is not fully defined. Here, we investigated the tissue concentration of paclitaxel in various organs at various time points after i.p. or i.v. administration. Methods. Paclitaxel (5 mg/kg) was administrated in an ear vein or in the abdominal cavity of rabbits. At 0.5, 6, 24, and 48 h after administration, the rabbits were sacrificed, and organs as well as peripheral blood were harvested. The serum and tissue concentrations of paclitaxel were measured by HPLC procedure. Result. The concentration of paclitaxel was high in the i.v. group at 0.5 h, whereas it was significantly higher in the i.p. group at 6 and 24 h. The AUC (area under the curve) was markedly higher in the omentum, mesenteric lymph nodes as well as ovary and stomach in the i.p. group. Conclusion. Compared with i.v. administration, paclitaxel concentration was maintained at a high level in the whole body by i.p. administration. Repeated i.p. paclitaxel can produce more marked clinical effects than i.v. administration for metastatic lymph nodes and primary lesions as well as peritoneal dissemination. (C) 2009 Elsevier Inc. All rights reserved.

Orally applicable Delta 9-tetrahydrocannabinol and its synthetic derivatives have been used as antiemetic drugs during chemotherapy in cancer patients. However, it is not well known how cannabinoids influence the effects of chemotherapeutic agents on malignant tumors. In this study, we investigated how the endogenous cannabinoid anandamide (AEA) changes the effect of paclitaxel on gastric cancer cell lines. In the human gastric cancer cell line, HGC-27, which express cannabinoid receptor 1 (CB1), AEA stimulated proliferation at concentrations under 1 mu M, while it strongly suppressed proliferation through the induction of apoptosis at 10 mu M. This bimodal effect was reproduced by a selective CB1 agonist, arachidonyl-2-chloroethylamide, although the effects were less marked. When AEA was used with paclitaxel, AEA at 10 mu M synergistically enhanced the cytotoxic effect of paclitaxel, whereas it showed no significant effect at lower concentrations. Flow cytometric analysis revealed that addition of 10 mu M AEA synergistically enhanced paclitaxel-induced apoptosis, possibly through the activation of caspase-3, -8, and -9. Our results suggest that cannabinoids could be a good palliative agent for cancer patients receiving paclitaxel. Crown Copyright (C) 2009 Published by Elsevier Inc. All rights reserved.

Perioperative blood transfusion has been shown to be associated with poor outcome in various types of malignancy. However, the relationship between the amount of blood loss and specific types of cancer recurrence has not been documented. We retrospectively examined the amount of intraoperative blood loss and the recurrence pattern in 146 patients who underwent curative gastrectomy for advanced gastric cancer and assessed the possible correlation between intraoperative blood loss and peritoneal, locoregional, and hematogenous recurrences. The amount of intraoperative blood loss in patients who developed peritoneal recurrence was significantly greater than that in patients without peritoneal recurrence, irrespective of blood transfusion. In contrast, the blood loss was not associated with nodal or hematogenous recurrence. Multivariate analysis demonstrated that large blood loss as well as operative curability B and adjuvant chemotherapy were independent risk factors for peritoneal recurrence and a worse outcome in advanced gastric cancer. Intraoperative blood loss in curative gastrectomy for advanced gastric cancer may have a specific association with the development of peritoneal recurrence. Surgeons must remember that clean and dry surgery may lessen not only 30-day mortality and morbidity but long-term peritoneal recurrence in gastric cancer.

Disorders in the blood coagulation system are often associated with malignancy. Patients with colorectal cancer (CRC) have been shown to have abnormal data for various coagulation tests. We retrospectively analyzed the relation between the preoperative plasma fibrinogen level and tumor recurrence in 569 patients with CRC who underwent curative surgical resection and were followed up without adjuvant chemotherapy. The plasma fibrinogen level showed a positive association with tumor recurrence, age, sex, T stage, and TNM classification. When divided with the median value, hyperfibrinogenemia is positively correlated with tumor recurrence, although it lost independence in the multivariate analysis. In the C-reactive protein (CRP)-negative population, hyperfibrinogenemia is independently correlated with tumor recurrence and recurrence-free survival. In contrast, hyperfibrinogenemia has no effect on recurrence in CRP-positive patients. Hyperfibrinogenemia is clinically relevant in tumor recurrence before a systemic inflammatory response and thus can be a useful predictor of recurrence in the preinflammatory stage of CRC.

We report a case of sigmoido-vesical fistula due to sigmoid diverticulitis. Magnetic resonance imaging enabled us to visualize the fistula itself in the bladder wall. Magnetic resonance imaging was highly effective in making a precise diagnosis and also provided important additional information for the preoperative work-up of the patient.

Appendiceal cancer is rare and associated with a poor prognosis because it is usually found at an advanced stage. We report a case of appendiceal adenocarcinoma manifesting as a colonic obstruction with a lower abdominal mass. Laparotomy revealed bilateral ovarian tumors and a small appendiceal tumor with peritoneal metastases. We performed ileocecal resection, colectomy, and oophorectomy, following which a histological diagnosis of signet ring cell carcinoma was made. Immunohistochemical analysis revealed positive expression of cytokeratin 7 and 20, and mucin core protein 2 (MUC2), compatible with appendiceal cancer and Kruckenberg metastases. When a patient is found to have disseminated pelvic signet ring cell carcinoma of unknown origin, the appendix should be considered as a possible primary site.

Sulforaphane (SUL) is an isothiocyanate naturally present in widely consumed vegetables, particularly in broccoli. SUL has recently been focused as a result of its inhibitory effects on tumor cell growth in vitro and in vivo. We used endothelial progenitor cells (EPCs) as an in vitro model to investigate the effect of SUL on the various steps of vasculogenesis and angiogenesis. Peripheral blood mononuclear cells from blood of normal human volunteers were plated on fibronectin-coated 100 mm dishes and incubated for 7 days. The viability of EPCs, treated with SUL at different doses, was assessed by MTS assay. Cell apoptosis was analyzed by flow cytometry. To determine the relative contributions of caspase-8 and caspase-9 pathways to SUL-induced apoptosis, the effect of caspase inhibitors was determined. The expression of apoptosis-related proteins (Bax, Bcl-2) was investigated by Western blot test. Finally, the effect of SUL on the ability of EPCs to form vascular-like structures on Matrigel was investigated. We clearly demonstrated that SUL induced the dose-dependent inhibition of EPCs' viability by induction of apoptosis. All caspases (caspase-3, -8, and -9) were activated during apoptosis induction by SUL, but the effect of caspase-9 was more prominent than that of caspase-8. Also, the expression of Bax was upregulated by SUL treatment. In addition to apoptosis induction, SUL dose-dependently inhibited the tube-like formation by EPCs on Matrigel. The present results demonstrate the antivasculogenic/antiangiogenic activity of SUL in vitro and open premise for the use of SUL as a multipotent anticancer agent that targets both cancer cells and the angiogenic endothelium.

Background. Zoledronic acid (ZOL) is clinically available for the treatment of skeletal complications. In preclinical studies, strong anti-cancer activities against breast cancer, prostate cancer, and leukemia were reported. It also inhibited the proliferation of cultured human endothelial cells, suggestive of an anti-angiogenic activity. Since ZOL has the tendency to accumulate in bone, we investigated the effect of ZOL on endothelial progenitor cells (EPCs), which originate from the bone marrow, and play important roles in angiogenesis. Materials and methods. Human peripheral blood mononuclear cells were cultured for 7 d to differentiate into EPCs. Cells were treated without/with ZOL or with geranylgeraniol (GGOH). Their endothelial phenotype was confirmed by the expression of CD144 and vascular endothelial growth factor receptor 2 and the tube-like formation ability on Matrigel (Becton Dickinson, Bedford, MA). Annexin V/propidium iodide staining was used to analyze apoptosis. Results. ZOL treatment, even at low doses, from d 2 to 7 of culture resulted in impaired EPC differentiation and could be restored by co-treatment with GGOH. On the other hand, treatment of putative EPCs with ZOL at concentrations higher than 10 gm resulted in induction of apoptosis. Conclusion. ZOL dose-dependently inhibited the differentiation of EPCs, the effect being observed even at low drug levels. At high concentrations, ZOL also induced the apoptotic death of putative EPCs. Since GGOH restored the inhibitory effect of ZOL on EPCs differentiation, the effect of ZOL appears to be dependent on the inhibition of prenylation of small-G-proteins. From these findings, we conclude that ZOL could be a potential anticancer agent by inhibiting angiogenesis. (C) 2009 Elsevier Inc. All rights reserved.

Recent epidemiologic studies have shown a positive association between obesity and certain cancers. Our retrospective studies show that hypertriglyceridemia is an independent risk factor for the development of colonic adenoma and nodal metastasis in early gastric and esophageal cancer in men. High-fat condition may be favorable for the growth of malignant cells. Serum level of adiponectin is reduced in patients with advanced gastric cancer, which may be associated with the positive link between adiposity and cancer. In early gastric cancer, patients with undifferentiated type have lower fat volume than those with differentiated type. Adiposity appears to be closely related with various aspects in pathophysiology of gastrointestinal malignancy. Copyright (c) 2009 S. Karger AG, Basel

Objectives: A dose-escalation study of weekly intraperitoneal paclitaxel (PTX) combined with S-1 and intravenous PTX was performed to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Patients and Methods: Nine gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered intravenously on days 1 and 8 at a fixed dose of 50 mg/m(2), and intraperitoneally with an initial dose of 20 mg/m(2), stepped up to 30 or 40 mg/m(2). S-1 was administered at a fixed dose of 80 mg/m(2)/day for 14 consecutive days, followed by 7 days of rest. A pharmacokinetic study of PTX was also performed. Results: The MTD was determined to be 30 mg/m(2), as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m(2). The intraperitoneal and serum PTX concentration remained effective for over 72 and 48 h, respectively. Conclusions: Combined chemotherapy of S-1 plus weekly intravenous and intraperitoneal PTX was shown to be a safe regimen that should be further explored in clinical trials. Copyright (C) 2009 S. Karger AG, Basel

Background and aim: Intra-peritoneal administration (i.p.) of Taxanes has recently been reported to be effective for the treatment of peritoneal dissemination, presumably because extremely high concentration of the drug is achievable onto the disseminated nodules as compared to intra-venous administration. Here, we aimed to investigate the ability of non-animal stabilized hyaluronic acid (NASHA) to retain the anti-cancer drugs in the peritoneal cavity, and, consequently, improve the efficacy of i.p. administration of paclitaxel. Methods: Mice were inoculated i.p. with MKN45P gastric cancer cells. The mice received i.p. administrations of paclitaxel, without or with NASHA, once a week for 3 consecutive weeks, and the intra-peritoneal nodules were counted after 4 weeks. The ability of NASHA to retain the i.p. administered liquid and paclitaxel in abdominal cavity was also investigated. Finally, the concentration of paclitaxel in metastatic nodule was measured with HPLC. Results: In the group receiving paclitaxel with NASHA, the number of disseminated nodules were significantly smaller than in those receiving paclitaxel without NASHA. The fluid volumes and concentration of paclitaxel recovered from the abdominal cavity as well as the concentrations of paclitaxel in metastatic nodule were significantly increased by the addition of NASHA. Conclusion: Our results indicate that NASHA improves the exposure time of i.p. administrated paclitaxel to disseminated nodules by retaining the drug in the abdominal cavity. Since the material is used in cosmetic surgery with few adverse effects, NASHA can be clinically used as the vehicle for the i.p. administration of anti-cancer agents for advanced gastric cancer with peritoneal dissemination. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

Excessive fat mass is a risk factor for postmenopausal breast cancer. Leptin, a fat cell-derived peptide hormone, elicits a growth-stimulating effect in breast cancer cells with leptin receptor expression, although the leptin-induced signal in malignant cells is not fully understood. Here, we found that exogenous leptin induced tyrosine phosphorylation of HER2 in SKBR3 cells, which showed marked overexpression of HER2. Phosphorylation of HER2 was detected at 2 min and continued up to 120 min after the start of stimulation. Leptin-induced HER2 phosphorylation was partially reduced by an epidermal growth factor receptor inhibitor, AG1478, or a Janus-activated kinase inhibitor, AG490. Leptin also induced phosphorylation of extracellular signal-regulated kinase 1/2, which was mostly abrogated by a HER2 tyrosine kinase inhibitor, AG825. In a proliferation assay, addition of 500 ng/mL leptin increased the proliferation of SKBR3, which was totally inhibited by AG825. Collectively, our data suggest that leptin can transactivate HER2 through both epidermal growth factor receptor and Janus-activated kinase 2 activation, which can cause the growth of breast cancer cells with HER2 overexpression. (c) 2008 Elsevier Inc. All rights reserved.

Background/Aims: Recurrence, which Occurs in about 20-30% of colorectal cancer patients after curative surgical treatment, is an important factor in determining prognosis. Therefore, early detection and prediction of recurrence is an Important issue in the treatment of the disease. Telomerase is a reverse transcriptase that synthesizes telomere DNA, thereby compensating for telomere loss that occurs with each replication cycle, and limits proliferation cells. Telomerase is expressed in the majority of primary human tumors and hTERT is considered one of the most important proteins affecting telomerase activity. We evaluated telomerase activity in mesenteric and peripheral blood samples in addition to hTERT expression in cancerous tissues by means of immunohistochemistry in 120 patients who underwent curative surgical treatment at our department. Methodology: We investigated the factors correlated with recurrence. Results: In univariate analysis, we found recurrence was significantly correlated with positive telomerase activity In the mesenteric vein (p=0.0021), positive telomerase activity in the peripheral vein (p=0.0032), histological type except well differentiated adenocarcinoma (p=0.0013), lymphatic infiltration (p=0.044), lymph node metastasis at surgery (p<0.0001), positive CEA (p=0.0004) and negative TERT immunoreactivity (p=0.012). In multivariate analysis, we found lymph node involvement at surgery (p=0.0045, hazard ratio: 6.21) and positive telomerase activity in peripheral vein (p=0.037, hazard ratio: 3.13) were significantly associated with the existence of recurrence. Conclusions: Our results show that measuring telomerase activity in peripheral blood samples is effective in predicting future recurrence to a degree greater than macroscopically examined tumor depth or other clinicopathological parameters.

Background and Aim: Epidemiological studies have suggested the positive correlation between hyperlipidemia and/or hyperglycemia and colorectal cancer risk. Methods: We retrospectively examined the association between fasting blood sugar (BS) or triglycerides (TG) and the presence of colorectal adenoma, carcinoma in situ and invasive cancer in 867 patients who received total colonoscopy by medical health check. Results: An increased TG level, but not a BS level, was significantly associated with the increased risk of adenoma, although with non-independent multivariate analysis. In contrast, an elevated BS level was identified as an independent risk factor for invasive cancer in 93 patients with carcinoma lesions with an odds ratio of 1.74 (P < 0.05). Conclusion: Our data suggest that hypertriglyceridemia and hyperglycemia may correlate with the development of adenoma and invasive cancer, respectively. The effectiveness of strict BS control in patients with hypertriglyceridemia for the prevention of the invasive colorectal carcinoma deserves further studies.

Background. Visceral obesity is known to be a risk factor for diabetes and cardiovascular disease. Cancer of the gastric cardia has been shown to have a close association with obesity in Western countries. In order to examine the possible relationship between fat volume and the development of gastric cancer (GC), we quantified visceral and subcutaneous fat areas of computed tomography (CT) images of patients with early GC. Methods. A total of 210 patients who underwent endoscopic resection or surgical gastrectomy and whose disease was pathologically diagnosed as early GC were investigated for total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) with Fat Scan software, using a CT slice at the umbilical level, and the relationships of these findings with clinical and pathological data were analyzed. The same analysis was performed in 147 patients with early colorectal cancer (CRC). Results. TFA, VFA, and SFA values in GC patients were not significantly different from the values in CRC patients. These values did not differ with the location of the GC. However, patients with undifferentiated-type GC had significantly smaller VFAs and SFAs than those with differentiated-type GC. Among the patients with undifferentiated GC, TFA and SFA values in the patients with submucosal cancer were significantly smaller than those in the patients with mucosal cancer. Conclusion. GC has different associations with adipose tissue volume according to its histological type. As compared with differentiated GC, lower adipose tissue volume may be a preferential environment for the development and progression of undifferentiated GC.

Background/Aims: The p38 mitogen-activated protein kinases. (p38 MAPKs) function in a wide variety,of signaling pathways. However, the role of p38s is cell type- and stimulus-dependent. The present study aimed to evaluate the effects of p38 MAPK inhibitor on human colon cancer cells. Methodology: The effect of p38 MAPK inhibitor, FR167653, on DLD-1 and SW480 was investigated related to cell proliferation, apoptosis induction and caspase activity. Additionally, the effect of FR167653 on colon cancer cell migration, MMPs production and ability to adhere to extracellular matrix was investigated. Results: Inhibitor of p38 MAPK dose-dependently suppressed the proliferative activity of both cell lines, and increased the induction of cell apoptosis. The caspase-3, 8, and 9 activities were accompanied in the pathway. Neither cell migration, MMPs production, nor the ability to adhere extracellular matrix were affected by FR167653. Conclusions: Inhibitor of p38 MAPK suppressed the proliferation of colon cancer cells by induction of cell apoptosis through the caspase activation. The present results suggest the pro-oncogenic role of p38 in colon cancer, and its inhibition would be a novel strategy for the prevention and treatment of colon cancer.

Vaccines targeting tumour angiogenesis were recently shown to inhibit tumour growth in animal models. However, there is still a lack of information about the clinical utility of anti-angiogenic vaccination. Therefore, here, we aimed to test the clinical effects of a vaccine using glutaraldehyde-fixed human umbilical vein endothelial cells (HUVECs). Six patients with recurrent malignant brain tumours and three patients with metastatic colorectal cancer received intradermal injections of 5 x 10(7) HUVECs/dose (in total 230 vaccinations). ELISA and flow cytometry revealed immunoglobulin response against HUVECs' membrane antigens. ELISPOT and chromium-release cytotoxicity assay revealed a specific cellular immune response against HUVECs, which were lysed in an effectors:targets ratio-dependent manner. Gadolinium-contrasted MRI showed partial or complete tumour responses in three malignant brain tumour patients. Except for a DTH-like skin reaction at the injection site, no adverse effect of vaccination could be observed. our results suggest that the endothelial vaccine can overcome peripheral tolerance of self-angiogenic antigens in clinical settings, and therefore should be useful for adjuvant immunotherapy of cancer. (c) 2007 Elsevier Ltd. All rights reserved

The prediction of the cellular direction of metabolic pathways toward either DNA synthesis or DNA methylation is crucial for determining the susceptibility of cancers to antimetabolites such as fluorouracil (5-FU). We genotyped the methylenetetrahydrofolate reductase (MTHFR) gene in NCI-60 cancer cell lines, and identified the methylation status of 24 tumor suppressor genes using methylation-specific multiplex ligation-dependent probe amplification. The susceptibility of the cancer cell lines to seven antimetabolites was then determined. Cells homozygous for CC at MTHFR-A1298C were significantly more sensitive to cyclocytidine, cytarabine (AraC) and floxuridine than those with AA or AC (p=0.0215, p=0.0166, and p=0.0323, respectively), and carried more methylated tumor suppressor genes (p=0.0313). Among the 12 tumor suppressor genes which were methylated in >25% of cancer cell lines, the methylation status of TIMP3, APC and IGSF4 significantly correlated with sensitivity to pyrimidine synthesis inhibitors. In particular, cells with methylated TIMP3 had reduced mRNA levels and were significantly more sensitive to aphidicolin-glycinate, AraC and 5-FU than cells with unmethylated TIMP3. We speculate that MTHFR-A1298C homozygous CC might direct the methylation rather than the synthesis of DNA, and result in the methylation of several tumor suppressor genes such as TIMP3. These genes could be useful biological markers for predicting the efficacy of antimetabolites.

Background: Epigallocatechin gallate (EGCG), a component of green tea catechin with the strongest biological activity, has been focused in recent years because of its anti-inflammatory and immunomodulatory activities. Dendritic cells (DCs) are professional antigen-presenting cells, capable of priming naive T cells, and play the key roles in the activation of T-cell-mediated immune responses. Objective: We aimed to investigate the effect of EGCG on human monocyte-derived DCs (MODCs) and, consequently, on the T-cell-mediated immune response. Methods: The induction of apoptosis, and the detailed phenotypic and functional changes of MODCs, generated by culture of peripheral blood monocytes in the presence of GM-CSF and IL-4, induced by EGCG was investigated and compared with the effects of dexamethasone. Results: Epigallocatechin gallate induced apoptosis and affected the phenotype of the developing DCs. The expressions of CD83, CD80, CD11c, and MHC class II, which are molecules essential for antigen presentation by DCs, were downregulated by EGCG. EGCG also suppressed the endocytotic ability of immature DCs, whereas dexamethasone-treated DCs had higher endocytotic ability than control DCs. Most importantly, mature DCs treated with EGCG inhibited stimulatory activity toward allogeneic T cells while secreting high amounts of IL-10. Conclusion: Epigallocatechin gallate induces immunosuppressive alterations on human MODCs, both by induction of apoptosis and suppression of cell surface molecules and antigen presentation.

Background: HER family is an attractive target for the treatment of esophageal cancer. The clinical relevance of HER-4 has not been yet characterized. Methods: The expression of HER-4 was immunohistochemically examined in 61 surgically resected esophageal squamous cell carcinomas (ESCC), and the prognostic significance of HER-4 in ESCC was evaluated. Results: HER-4 was positive in the cytoplasm and cell membrane of 51 (84%) tumors, with variable intensity and a heterogeneous distribution, with preferential expression in well or moderately differentiated tumors. Nuclear staining of HER-4 was observed in 37 (61%) cases as well. The membranous/cytoplasmic, but not nuclear, expression of HER-4 was positively correlated with the expression of HER-2 and HER-3. Survival of the HER-4-positive group was significantly better than that of the HER-4-negative group (P < 0.05). Multivariate analysis revealed that I extranuclear expression of HER-4 was independently correlated with increased survival. In contrast, nuclear staining of HER-4 was correlated r with increased T stage, which resulted in a significant reduction in survival in the HER-4 positive group (P < 0.05). Conclusion: Extranuclear HER-4 may have negative effects on the progression of ESCC, whereas nuclear translocation of HER-4 may elicit a tumor-promoting property. Inummohistochemical detection of HER-4 localization is clinically useful to predict the survival of the patients with ESCC.

Aim: Historically, cancer therapy directly targeting tumor cells have yielded suboptimal clinical results, and therefore anti-angiogenic therapy that targets tumor cells indirectly through impairing tumor vasculature is now considered to be one of the novel approaches potentially effective against various types of cancer. In this study, we evaluated whether lysates of endothelium could be effectively pulsed in dendritic cells (DCs), to enhance their anti-tumor effects. Methods: For this purpose, we prepared DCs of BALB/c mouse, incubated them with lysates of autologous or xenogeneic endothelium, and tested their anti-tumor effects in two syngeneic models of colon cancer. Results: DCs pulsed with the respective endothelium lysates significantly inhibited the growth of subcutaneous tumors as well as pulmonary metastases in mice, and their anti-tumor effect was superior to that of unpulsed DCs. Immunohistopathological analysis showed significant decrease in the mean vascular density of tumors, correlating well with the extent of tumor inhibition. In vitro analysis of splenocytes isolated from immunized mice revealed an induction of cytotoxic T lymphocytes and activation of natural killer cells, with a lytic activity against activated endothelium but not tumor cells. In addition, antibodies reacting with activated endothelium, but not tumor cells, were detected in murine sera by ELISA, and their function was confirmed by complement-dependent cytotoxicity assay. Conclusions: Our present results suggest that lysates of endothelium can be effectively pulsed in DCs and enhance their anti-tumor effects through induction of anti-angiogenesis, and therefore should have important clinical implications for adjuvant cancer therapy. (c) 2007 Elsevier Ltd. All rights reserved.