Adjuvant immunochemotherapy with protein-bound polysaccharide K for colon cancer in relation to oncogenic beta-catenin activation.

Purpose: Protein-bound polysaccharide K is an immunotherapeutic agent that promotes apoptosis by inhibiting nuclear factor-kappaB activation in cancer cells. We previously showed that oncogenic beta-catenin activates nuclear factor-kappaB and inhibits apoptosis by up-regulating beta-transducin repeat-containing protein. We investigated whether the activation state of beta-catenin in the primary tumor is associated with differences in survival rates of patients with colon cancer undergoing immunochemotherapy with 5-fluorouracil plus polysaccharide K vs.

Meningeal carcinomatosis preceded by a rapid increase in serum CA19-9 levels in a patient with breast cancer.

We report a patient with breast cancer who developed meningeal carcinomatosis that was preceded by a rapid increase in the serum level of carbohydrate antigen (CA) 19-9. A 60-year-old woman was admitted for primary breast cancer with multiple metastases to the vertebrae. She received cyclophosphamide 400 mg/m(2), epirubicin 40 mg/m(2), and 5-fluorouracil (5-FU) 400 mg/m(2) (CEF) chemotherapy every 3 weeks.

Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation.

Glycogen synthase kinase 3beta (GSK3beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappaB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3beta expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of beta-catenin oncoprotein in the tumor cells.

Chemotherapy under cachectic conditions and the possibility of cachexia-controlled chemotherapy.

We studied the role of chemotherapy in cancer cachexia, which is well known to lower QOL and responsiveness to chemotherapy. In BALB/c mice we used two clones derived from the murine colon 26 adenocarcinoma cell line; clone 5, a non-cachexigenic tumor and clone 20, a cachexigenic tumor, in which IL-6 mRNA was selectively detected. While maximum tolerated dose (MTD) of CPM and CPT-11 showed significantly smaller tumor weight and higher survival than 1/2 MTD in both drug groups with clone 5, the results were reversed with clone 20.

Preoperative CEA and PPD values as prognostic factors for immunochemotherapy using PSK and 5-FU.

Purpose: Immunochemotherapy using PSK used as postoperative adjuvant chemotherapy for colorectal cancer in Japan, is a treatment that depends on the immunocompetence of the host. Therefore, we analyzed the data of Hokuriku district conducted by the CIP study group to compare the long-term survival for preoperative CEA level and PPD reaction.

Patients And Methods: Between February 1991 and March 1993, 87 patients with primary colon cancer and macroscopic lymph node metastasis (macroscopic Dukes' C) underwent macroscopic curative resection.

A pilot study of individualized maximum repeatable dose (iMRD), a new dose finding system, of weekly gemcitabine for patients with metastatic pancreas cancer.

Objectives: We developed and established a new dose-finding system, the individualized maximum repeatable dose (iMRD), suitable to induce prolonged TTP rather than tumor shrinkage.

Methods: We applied this system in weekly gemcitabine therapy for 18 metastatic pancreas cancer patients. We determined the iMRD at the 5th week, after weekly dose adjustments.

[A randomized phase II clinical trial of tailored CPT-11 + TS-1 vs TS-1 in patients with advanced or recurrent gastric carcinoma as the first-line chemotherapy (JFMC31-0301)].

The Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) has designed and initiated a randomized Phase II clinical trial planned as a first-line of chemotherapy for advanced or recurrent gastric cancer. The trial focuses on two groups and selecting the better of two regimens. The first group was given tailored CPT-11, adjusting individual optimal dosage using toxicity-based grading as an index in combination with TS-1, and the second group was given standard TS-1 treatment.

Oral administration of uracil-tegafur (UFT) inhibits liver micrometastasis of human colon cancer in an orthotopic nude mouse model and its early detection system.

Purpose: To evaluate the effect of UFT (an oral antineoplastic drug combining uracil and tegafur) as an adjuvant chemotherapy.

Methods: We examined whether UFT inhibits micrometastasis of the liver from colon cancer implanted into the cecum of nude mice in an orthotopic model. Moreover, we studied whether our early detection system using a polymerase chain reaction (PCR) of the human beta-globin gene would be useful in this model.

A randomized phase II clinical trial of tailored CPT-11 + S-1 vs S-1 in patients with advanced or recurrent gastric carcinoma as the first line chemotherapy.

A randomized phase II clinical trial has been designed and started in the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) to select the better regimen between tailored CPT-11 + S-1 and the standard S-1 treatment for advanced or recurrent gastric cancer as the first line chemotherapy. Selection of the better treatment for general clinical practice in this clinical trial will lead to a more precise assignment of a promising regimen for a future phase III randomized trial, placing continuous 5-FU infusion as the reference arm. In this trial, subsidiary pharmacokinetic analysis for the tailored dose arm is also proposed.

Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer.

Background: The ubiquitin-proteasome pathway is important in regulating protein signaling pathways that are involved in tumorigenesis. beta-transducin repeat-containing proteins (beta-TrCP) are components of the ubiquitin ligase complex targeting beta-catenin and IkappaBalpha for proteasomal degradation and are thus a negative regulator of Wnt/beta-catenin signaling and a positive regulator of NF-kappaB signaling. We analyzed expression of beta-TrCP in colorectal cancers and its association with types of beta-catenin subcellular localization, an indirect measure of activation.

Angiogenesis of AFP producing gastric carcinoma: correlation with frequent liver metastasis and its inhibition by anti-AFP antibody.

We studied roles of angiogenesis in patients with alpha-fetoprotein (AFP)-producing gastric carcinoma (APGC), which is well known to have a poor prognosis and frequent liver metastases. Immunohistochemical analyses were conducted using antibodies against alpha-fetoprotein, factor VIII (endothelial cells) and vascular endothelial growth factor (VEGF). Archival specimens of APGC (n=25) and non-APGC (n=68) were studied.

Pilot study of low-dose, divided maximum tolerated dose of CPT-11 in 21 consecutive patients with metastatic colorectal or gastric cancer.

Purpose: We devised a new treatment regimen, delivering a frequent low dose of CPT-11, calculated by dividing the maximum tolerated dose (MTD) to reduce its toxicity without impairing its efficacy.

Methods: CPI-11, 25 mg/m2, determined by dividing the MTD dose per month by 12, was given on days 1, 2, and 3 of every week, to 21 consecutive patients; 12 with metastatic colon cancer and 9 with metastatic gastric cancers.

Results: The total delivered dose of CPI-11 per patient was more than 1,000 mg in 17 (80.

The usefulness of CEA and/or CA19-9 in monitoring for recurrence in gastric cancer patients: a prospective clinical study.

Background: Many studies on postoperative carcinoembryonic antigen (CEA) and/or carbohydrate antigen (CA)19-9 monitoring after operation for gastric cancer have been reported, but most have been retrospective.

Methods: A nationwide observational study was implemented in 135 leading institutions in Japan to evaluate the significance of CEA and/or CA19-9 in postoperative monitoring for recurrence in patients with advanced gastric cancer. Three hundred and twenty-one patients examined in this analysis underwent radical gastrectomy at one of Japan's leading institutions between November 1993 and March 1996 and had been followed up for at least 5 years.

Long-term effect of 5-fluorouracil enhanced by intermittent administration of polysaccharide K after curative resection of colon cancer. A randomized controlled trial for 7-year follow-up.

Background And Aims: The efficacy of a biological response modifier polysaccharide K in adjuvant immunochemotherapy was evaluated in primary colon cancer patients with macroscopic Dukes' C after curative resection.

Patients And Methods: Employing the minimization method using three factors (lymph node metastases, preoperative serum CEA level, and institution), 446 patients were allocated into groups P and C. Group P received immunochemotherapy, oral PSK (3 g per day) followed by oral 5-FU (200 mg/body per day), while group C received only intermittent chemotherapy, oral 5-FU (200 mg per day) followed by 4-week rest.

beta-Catenin and ras oncogenes detect most human colorectal cancer.

Unlabelled: PURPOSE AND STUDY DESIGN: Recent studies have shown that beta-catenin translocated into the cell nucleus functions like an oncogene. Accumulating evidence suggests that activation of the beta-catenin oncogenic signaling cascade along with its twin, the K-ras cascade, may exert syngeneic or synergistic effects on tumor development and progression. In the study reported here, we analyzed oncogenic beta-catenin activation on the basis of its nuclear accumulation (NA) and compared the results with those of mutational activation of K-ras in 74 patients with colorectal cancer to determine whether the two oncogene-mediated signaling cascades interact.

Irinotecan enhances IL-12 production by OK-432-activated murine macrophages.

Background: Our previous study showed that the combination of irinotecan (CPT-11) and OK-432 had an additive antitumor effect. The purpose of this study was to analyze the mechanism by which this combined treatment had an effect on immunity.

Materials And Methods: To investigate the immune effects of murine splenocytes stimulated by SN-38 (the active form of CPT-11) and OK-432, endogenous interleukin (IL)-12 p70 production was assayed by ELISA and flow cytometry.

Thymidylate synthase expression as a predictor of the prognosis of curatively resected colon carcinoma in patients registered in an adjuvant immunochemotherapy clinical trial.

The expression levels of thymidylate synthase (TS) affect the sensitivity of tumor cells to fluorinated pyrimidine cytotoxic agents and determine the response of patients with colorectal cancer to fluorinated-pyrimidine-based chemotherapy. The correlation between the expression of TS and the prognosis of patients with colorectal cancer was examined in a prospective study. Evaluation of biomarkers including TS expression was performed using tumor specimens from 229 colorectal cancer patients.

Abnormal expression of E-cadherin, beta-catenin, and c-erbB-2 in advanced gastric cancer: its association with liver metastasis.

Background And Aims: We investigated expression of E-cadherin, beta-catenin, and c-erbB-2 in gastric cancer to identify molecular factor(s) relevant to development of liver metastasis, which is a frequent cause of mortality in gastric cancer patients.

Patients And Methods: We analyzed by immunohistochemistry and compared expression patterns of E-cadherin, beta-catenin, and c-erbB-2 in the tumor between 40 cases of gastric cancer (GC) without (GC-H(-)) and 16 with concurrent liver metastasis (GC-H(+)).

Results: Loss of E-cadherin expression in the primary tumor was found in 18% of GC-H(-) and in 19% of GC-H(+).

The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion.

We previously reported that vessel count, vascular endothelial growth factor (VEGF) and platelet derived endothelial cell growth factor (PD-ECGF) expression are associated with metastasis formation in human colon cancer. This study was done to determine a stage of colon cancer progression where induction of these factors occurred (i.e.

Detection of oncogenes in the diagnosis of cancers with active oncogenic signaling.

Releasing individuals from susceptibility to and anxiety about the development of cancer is an eventual goal of cancer research. This owes much to rapid progress in molecular oncology that is supported by advances in technology. Cancers of the colon and rectum, pancreas and lung that share certain clinical and molecular oncological characteristics represent timely and important target of this field.

Multiparametric in situ mRNA hybridization analysis of gastric biopsies predicts lymph node metastasis in patients with gastric carcinoma.

We examined the expression level of several genes that regulate different steps in metastasis formation in formalin-fixed, paraffin-embedded biopsies of 189 primary human gastric carcinomas prior to surgical resection in patients in whom lymph node metastasis was not evident by endoscopic ultrasound or computed tomography (CT) scan. The expressions of epidermal growth factor receptor (EGF-R), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and E-cadherin were examined by a colorimetric in situ mRNA hybridization technique. The integrity of the mRNAs was verified, leaving 161 (85.

Essential roles of tumor necrosis factor receptor p55 in liver metastasis of intrasplenic administration of colon 26 cells.

Intrasplenic administration of a colon adenocarcinoma cell line, colon 26, induced tumor necrosis factor (TNF) alpha protein expression around the central and portal veins of the liver at 3 days, and liver metastases by 24 days after the tumor injection, in 90% of wild-type (WT) mice. To explore the roles of TNF-alpha in the process, we administered colon 26 cells into tumor necrosis factor receptor p55 (TNF-Rp55) knockout (KO) mice. Less than 50% of TNF-Rp55 KO mice developed liver metastasis with significantly lower liver weights and the volumes of metastatic foci.

Evaluation of intraoperative intraperitoneal cytology for advanced gastric carcinoma.

Objective: We evaluated intraperitoneal cytology during surgery as a significant predictor of survival and tried to establish strategies for preventing peritoneal carcinomatosis.

Methods: The study included 236 patients with gastric carcinoma macroscopically invading the serosa who underwent intraperitoneal cytological examination during surgery. In the 215 resected patients, the relationship between cytological positivity for cancer cells and various clinicopathologic features was analyzed.