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The patient was a 66-year-old woman who underwent upper gastrointestinal endoscopy as part of a detailed examination because of loss of appetite and anemia, and type 2 gastric cancer was detected on the greater curvature in the pyloric area. Abdominal ultrasonography and CT revealed lymph node enlargement around the pyloric area and multiple liver metastases in both lobes of the liver. Curative resection was judged to be impossible, and oral S-1 therapy was started. However, no efficacy was observed even after the completion of three courses, and especially because of the rapid increase in the size of the liver metastases, treatment was switched to combination therapy consisting of a continuous hepatic artery infusion of 5-FU+Leucovorin (day 1-7) and weekly PTX for 3 consecutive weeks (day 8, 15, 22) followed by a 1-week rest. The tumor marker levels decreased rapidly, and at the end of 4 courses marked regression of the primary tumor and lymph node metastases as well as of the metastatic foci in the liver was observed. Adverse events have been mild, and at present, 6 months after the switch in treatment, good QOL has been maintained, and treatment is continuing. This method appears to be an effective treatment strategy for unresectable advanced gastric cancer complicated by liver metastasis.

Gastrointestinal stromal tumors (GISTs) in the small intestine are relatively rare. We present a case of GIST arising from the small intestine, which could be resected under laparoscopic assistance. A 60-year-old male visited another hospital due to massive anal bleeding. Blood examination showed severe anemia. Although anemia improved after conservative treatment, the bleeding site was not identified and he was referred to our hospital for close examination. Abdominal CT showed a well-defined mass with homogeneous internal density in the left upper abdomen. On abdominal angiography, selective enhancement of the second jejunal artery revealed a tumor stain. Due to suspected GIST in the small intestine, laparoscopic-assisted resection of the jejunum was performed. Histopathological examination demonstrated low-grade malignant GIST. The laparoscopic procedure is considered to be useful as minimally invasive surgery for diagnosis and treatment of selected cases with GISTs in the small intestine.

Objective: The study was a non-randomized, parallel-group comparison to evaluate the efficacy of a community-based weight reduction program with exercise and diet modification for overweight adults using existing community health services., Methods: The study population consisted of 1,115 community-dwelling people who underwent annual health checkups in 2002 and were screened by exclusion criteria (age> 65, body mass index (BMI) < 24.2). They received a mail request to select one of two courses; a usual single-session health instruction course (control group) or a 9-month weight management course (intervention group). Forty six patients registered in the intervention group, and fifty patients in the control group. The analyzed sample consisted of 76 participants (9 males and 67 females) excluding dropouts from November 2002 to July 2003. Intervention included monthly classes (2 hours per class, 9 classes) consisting of an individual support program for behavioral change and a community support program for continuation after the class. The control group participants received conventional instructions based on their health status., Results: No significant inter-group differences were observed at baseline, except in age and height of females. The mean BMI decreased from 27.2 (SD = 2.8) kg m(-2) to 25.3(3.1) kg m(-2) in the intervention group, and 26.4 (1.7) kg m(-2) to 26.1(1.7) kg m(-2) in the control group. Repeated measures analysis of variance showed significant time and group interaction adjusted for gender and age. The proportion showing maintenance and action in stage of exercise behavior increased in the intervention group (31% to 60%), but remained stable in the control group (45% to 48%) . The proportion showing maintenance and action in stage of diet behavior increased in the intervention group (24% to 80%), but remained stable in the control group (29% to 26%)., Conclusion: Community-based weight reduction programs may be effective to facilitate change in exercise and diet behavior for body weight reduction in overweight adults.

(2S)-1-(4-Amino-2,3,5-trimethylphenoxy)-3-{4-[4-(4-fluorobenzyl) phenyl]-1-piperazinyl}-2-propanol dimethanesulfonate (SUN N8075) is a novel antioxidant with neuroprotective properties. We examined whether SUN N8075 inhibited the neuronal damage resulting from permanent focal cerebral ischemia, and examined its neuroprotective properties in vivo and in vitro mechanism. Focal cerebral ischemia was induced by permanent middle cerebral artery occlusion in mice, and the resulting infarction, brain swelling, and neurological deficits were evaluated after 24 h or 72 h. Brain damage was assessed histochemically using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and antibody recognizing 4-hydroxynonenal histidine adduct (4-HNE). In the in vitro study, we examined the effects of SUN N8075 on 1) lipid peroxidation in mouse brain homogenates and 2) cell viability and caspase-3 protease activity under a hypoxic insult or FeSO(4) in rat cultured cerebrocortical neurons. SUN N8075 administered either 10 min before or at 1 h after the occlusion reduced both infarction size and neurological deficits. SUN N8075 reduced brain swelling when administered 10 min before, 1 h, or 3 h after occlusion. Furthermore, only pretreatment (administered 10 min before) decreased infarct volume and brain swelling at 72 h after middle cerebral artery occlusion. SUN N8075 reduced the number of TUNEL-positive cells and decreased the level of oxidative damage, as assessed by immunopositive staining to 4-HNE. SUN N8075 inhibited lipid peroxidation, leakage of lactate dehydrogenase, caspase-3 activation induced by in vitro hypoxia, and the neuronal damage induced by in vitro FeSO(4) exposure. These findings indicate that SUN N8075 has neuroprotective effects against acute ischemic neuronal damage in mice and may prove promising as a therapeutic drug for stroke.

In the present study, we experimentally examined the feasibility of two-colonoscope surgery using two types of forceps to achieve safe, reliable, and complete endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD) of large superficial tumors in the right colon. It was confirmed at all experimental sessions that the two pairs of forceps intersected with each other over a wide angle of at least 90 degrees in the cecum, and that the tips of the forceps could be moved by at least 180 degrees in the longitudinal and horizontal directions. In another experiment, a piece of tissue measuring 3x3 cm or larger could be safely resected from a chicken thigh as the pseudo-tumor. Based on these results, two-colonoscope surgery is considered clinically promising as a next-generation EMR/ESD technique for safe, reliable, and complete resection of superficial tumors of the right colon measuring 3 cm or more in diameter.

Objective: To evaluate the effectiveness of the Life Style Modification Program for Physical Activity and Diet (LiSM-PAN) in comparison to a conventional healthcare program., Method: Subjects with risk factor(s) for chronic disease were allocated as a cluster to the LiSM group (n=92) or the Control group (n=85). The LiSM-PAN program consisted of counseling plus social and environment support, and the Control program consisted of written feedback for changing physical activity and dietary practice. Intervention was conducted for 6 months during 2001-2002 and with data analysis during 2003-2004 in Tokyo, Japan. The main outcomes were leisure time exercise energy expenditure (L.E.E.E.), maximum oxygen uptake (VO2max), dietary habits, body mass index (BMI), blood pressure, blood glucose, and lipid parameters., Results: The LiSM group showed a significantly greater increase in L.E.E.E. than the Control group at the end of the intervention (mean inter-group difference: 400.6 kcal/week, 95% CI: 126.1, 675.0 kcal/week). No significant mean inter-group differences were observed in dietary habits. The LiSM group showed significantly greater decreases in BMI, systolic blood pressure, and LDL-cholesterol than the Control group., Conclusion: The LiSM-PAN program produced greater positive changes in L.E.E.E., dietary habits, and risk factors for cardiovascular diseases in high-risk middle-aged male workers compared to the Control program.

The endoplasmic reticulum (ER) plays an important role in ischemic neuronal cell death. ER stress-related markers [immunoglobulin binding protein (BiP)/glucose-regulated protein (GRP) 78, activating transcription factor-4 (ATF-4), and C/EBP-homologous protein (CHOP)] in the striatum and the cortex were investigated after permanent middle cerebral artery occlusion (MCAO) in mice. Using endoplasmic reticulum stress-activated indicator (ERAI) transgenic mice, which show splicing of X-box protein 1 (XBP-1) mRNA as green fluorescence, we monitored the regional changes in fluorescence after MCAO. BiP mRNA (by reverse-transcription polymerase chain reaction [RT-PCR] analysis) was increased in the cortex at 6 h. In immunohistochemical and/or Western blot analysis, the expressions of ER stress-related markers (BiP, ATF-4, and CHOP) were increased in the infarct region, more strongly in the cortex than in the striatum. ERAI fluorescence was observed in the ischemic area starting from 6 and 12 h, respectively, after MCAO, with the peaks at 1 day and the fluorescence co-localized with the 2,3,5-triphenyltetrazolium chloride (TTC)-visible extension of brain infarction. These findings suggest that permanent MCAO induces expression of ER-stress related genes mainly in the periphery of the MCA territory.

Reconstruction by pancreaticoenterostomy has generally been employed after medial pancreatectomy for tumor. As a less invasive procedure, here we report three patients who successfully underwent pancreatic end-to-end anastomosis after medial pancreatectomy. The subjects consisted of 2 patients with serous cystadenomas and 1 patient with an intraductal papillary mucinous tumor. These tumors were detected in the pancreatic neck or body, and the maximal tumor diameters ranged from 10 to 33mm. The pancreatic duct diameters were 2 mm in 2 patients and 4 mm in 1 patient. The procedure was carried out by ductal anastomosis and parenchymal anastomosis with interrupted sutures. A pancreatic tube was inserted for decompression at the anastomotic site in all patients. The mean operative time was 3 hours and 31 minutes, and the intraoperative blood loss was 428 mL. Although pancreatic fistula was observed in 2 patients with the normal pancreas, conservative therapy relieved this complication. Neither tumor relapse nor stenosis of the pancreatic duct at the anastomotic site was detected in any patient, with a follow-up of 4 to 27 months. Our experience confirmed that in selected cases, this reconstructive procedure was feasible and safe for physiological reconstruction without involvement of the digestive tract.

Nuclear factor-kappaB (NF-kappaB) activation promotes cell survival and growth. Reports show that chemotherapeutic agents and cytokines that are used for cancer therapy activate NF-kappaB expression in tumor cells and its suppression enhanced the antitumor activity. We hypothesized that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda7/IL-24) induces NF-kappaB expression and that inhibition of this expression results in enhanced tumor cell killing. Treatment of human lung tumor (H1299 and A549) cells with Ad-mda7 resulted in NF-kappaB activation in a dose- and time-dependent manner before activation of cell death pathways. To establish that inhibition of Ad-mda7-mediated NF-kappaB activation results in enhanced tumor cell killing, H1299 cells that overexpress the dominant-negative I kappa B alpha (dnI kappa B alpha) were treated with Ad-mda7 in vitro. An enhanced growth arrest and apoptosis was observed in Ad-mda7-treated H1299-dnI kappa B alpha compared with H1299-Neo cells. This Ad-mda7-mediated enhanced killing of H1299-dnI kappa B alpha cells involved cleavage of mitogen-activated protein kinase kinase kinase 1 (MEKK1) and caspase-3 in a feedback loop mechanism. The inhibition of MEKK1 or caspase-3 cleavage in H1299-dnI kappa B alpha cells resulted in reduced Ad-mda7-mediated cell killing. In vivo, the treatment of H1299-dnI kappa B alpha s.c. tumors with Ad-mda7 resulted in increased drug sensitivity and delayed the tumor growth rate compared with Ad-mda7-treated H1299-Neo tumors. Molecular analysis of Ad-mda7-treated H1299-dnI kappa B alpha tumors showed increased MEKK1 cleavage and activation of caspase-3 compared with Ad-mda7-treated H1299-Neo tumors. Our findings thus showed that the NF-kappaB activation induced by Ad-mda7 treatment of lung cancer cells is an intrinsic survival mechanism and that the inhibition of this NF-kappaB expression results in enhanced tumor cell killing.

We performed D2 low anterior resection in a patient with stage I rectal cancer [pathological diagnosis: proper muscle (pm) invasion, n0, lymphatic invasion (ly), (-); venous invasion (v), (-); anal margin, (-)]. The tumor recurred at the anastomotic site approximately one year later and was treated with Miles' operation [pm, n0, ly (+); v (-); deep border of the primary tumor (-)]. The tumor marker CEA increased to 50.4 ng/ml at four months after surgery and pelvic local recurrence was detected. Since then, the patient has been receiving chemoradiotherapy on an out-patient basis. Cytokeratin immunostaining of all the lymph nodes collected during the two operations showed clusters of occult neoplastic cells (ONCs) in the perinodal fat around the nodes harvested at the first operation. These findings suggest that the risk of local recurrence of rectal cancer is increased even in stage I disease if ONCs are found in the perinodal fat. Further studies are required to examine the relationship between local recurrence and extranodal ONCs in patients with primary rectal cancer.

Among 41 patients with synchronous liver metastases of colorectal cancer, 15 patients underwent synchronous resection of their liver metastases and achieved a median survival time (MST) of 1,441 days (versus 748 days for the 26 patients without resection, p=0.038), a median relapse-free survival time of 652 days (MST not reached), and a recurrence rate in the residual liver of 20% (3/15 patients). The alternating hepatic arterial infusion and systemic chemotherapy showed partial response (PR) in 6 cases, stable disease (SD) in 8 cases, and progressive disease (PD) in 1 case (n=15/26). They had an objective response rate of 40% (6/15), tumor control rate (>/= SD) of 93.3% (14/15), one-year progression-free survival rate of 35.7%, 50% time to progression of 270 days, one-year survival rate of 76.2%, and two-year survival rate of 50.8% (MST not reached). Grade 3 leucopenia was observed in 2/15 patients (13.3%). These results suggest that the present alternating therapy may become a standard regimen for patients in whom synchronous resection of liver metastases is impossible and patients who have stage IV colorectal cancer with a risk of recurrence in the remnant liver and/or at extrahepatic sites such as the lungs.

The calcium-binding protein, S100A4, with an inverse association of E-cadherin, is known to correlate with prognosis in various cancers. In this study, we investigated the expression of the S100A4 and E-cadherin status in relation to the clinicopathological parameters of pancreatic cancer. The expression status of these two proteins was examined in 72 specimens of primary pancreatic carcinoma with immunohistochemistry. Fifty-six of 72 (78%) surgical specimens of primary pancreatic cancer were positive for S100A4 according to immunohistochemistry. Thirty-one (43%) specimens of pancreatic cancer showed positive expression of E-cadherin. The inverse association of S100A4 and E-cadherin expression was significant in the cancers (p < 0.0001). The S100A4 expression correlated significantly with the pathological T stage and poorer prognosis (p = 0.024). The 41 E-cadherin-negative cases showed poorer prognoses and a higher incidence of liver metastasis (p = 0.0344, p = 0.027). The 10 cases with S100A4-negative/E-cadherin-positive cancers showed a significantly better prognosis than the others (p < 0.05). The histological grade (p = 0.004), nodal status (p < 0.0001) and S100A4-positive status (p = 0.048) were highly significant independent prognostic predictors (p < 0.05). These results suggest that S100A4 overexpression combined with reduced E-cadherin expression play important roles in tumor progression and metastasis in pancreatic cancer. The combined examination of these two molecules is useful in evaluating the outcome of pancreatic cancer patient.

A loss or reduced expression of E-cadherin, the main cell-to-cell adhesion molecule, correlates with distant metastasis in various cancers. Recent studies have reported a close correlation between the expression of E-cadherin and that of S100A4, calcium-binding protein. In this study, we investigated the expression of E-cadherin and S100A4 status in relation to the clinicopathological parameters of pulmonary adenocarcinoma. We finely and quantitatively examined the expression of E-cadherin and S100A4 using real-time polymerase chain reaction (PCR) in a total of 92 pulmonary adenocarcinomas obtained by surgical resection. All of the pulmonary adenocarcinomas showed significant expression of E-cadherin and S100A4. Real-time PCR showed lower E-cadherin expression in 21 adenocarcinomas, while 71 adenocarcinomas expressed a higher expression of E-cadherin. Of 21 adenocarcinomas with lower-expressing E-cadherin, 12 showed a higher expression of S100A4. These 12 cases significantly showed a poorer prognosis than others (p=0.047, Kaplan-Meier, log-rank test) and significantly showed more frequent venous involvement than others (p=0.042, chi2 test). These results suggested that reduced E-cadherin expression combined with higher S100A4 expression is related to a poor prognosis through hematogenous metastasis in pulmonary adenocarcinoma.

Hepatocellular carcinoma rarely metastasizes to the orbit. We report on a 72-year-old man with a past history of resection for hepatocellular carcinoma and recurrent HCC, who presented with diplopia and left painful proptosis. Head scans revealed a large and irregular mass in the left orbit that caused destruction of the orbital bone superiorly and posterolaterally. A biopsy specimens of the orbital tumor showed features of metastatic foci of hepatocellular carcinoma. The tumor was surgically excised and histological findings revealed moderately differentiated hepatocellular carcinoma, resembling hepatocytes with a tendency to form trabeculae. Immunohistochemically, the tumor cells showed positive reaction against low-molecular-weight keratin and α-fetoprotein. There have been only 12 previous cases of hepatocellular carcinoma metastatic to the orbit cited in the literature. We presented here a rare case of hepatocellular carcinoma metastatic to the orbit.

Despite recent advances in treatment strategies, the overall 5-year survival rate for patients with common epithelial cancers is poor largely because of the difficulty in treating metastatic cancers. Therefore, therapeutic agents are urgently needed that can effectively inhibit both primary epithelial tumors and their metastases. One such agent that has shown promise in preclinical studies is the tumor suppressor/cytokine, melanoma differentiation associated gene-7 also known as interleukin-24 (mda-7/IL-24). Preclinical studies from our and other laboratories have shown that overexpression of MDA-7/IL-24 causes a strong tumor- suppressive effect in many human cancer cells but spares normal cells. This gene therapy also enhances the tumor-suppressive activity of radiotherapy and chemotherapy. Secreted MDA-7 protein that is glycosylated also has been shown to have potent antiangiogenic activity both in vitro and in vivo. Studies examining the immune properties of mda-7 have shown that MDA-7/IL-24 unlike the related IL-10, functions as a Th1 cytokine. Recently, an MDA-7 protein-mediated "bystander effect" on tumor cells has been documented. Building on these findings we successfully completed a Phase I clinical trial of adenovirus-based mda-7 cancer therapy that confirmed the safety of this gene therapy. Phase II trials evaluating the efficacy of mda-7-based gene therapy are warranted. The outcome of such ongoing mda-7-based gene therapy trials will allow us to better understand this therapy's clinical utility.

Vascular endothelial growth factor A (VEGF-A) plays an essential role in tumor progression through stromal neovascularization in malignant solid tumors. Neuropilin (NRP) is considered to be the specific receptor for limited types of VEGF-A isoform, VEGF165. The clinicopathological implications of NRP are not well understood in colon cancer, while almost all colon cancers overexpressed VEGF-A. We examined the expression levels of NRP1 and NRP2 genes in 54 colon cancer cases and paired extraneoplastic tissue with quantitative real-time polymerase chain reaction. The gene expression levels of NRP1 in the tumor (0.431+/-0.583) were significantly decreased compared to those in the extraneoplastic tissue (0.754+/-0.799) (paired t-test, p=0.0208). On the other hand, the gene expression levels of NRP2 in the tumor (0.763+/-0.791) were not decreased compared to those in the extraneoplastic tissue (0.508+/-0.386) (paired t-test, p=0.0511). Twenty cases, with preserved expression of the NRP1 gene in the tumor, showed a better prognosis as compared to the 34 cases with decreased NRP1 expression (p=0.0258, log-rank test). No significant relationship was noted between NRP2 gene expression and prognosis. The results suggested that preserved NRP1 expression provides colon cancer patients with a better prognosis.

The GB-04-JCK xenograft line of human gallbladder small cell carcinoma was established in nude mice by serial transplantation. The xenotransplantability has been maintained for more than 20 years. The carcinoma cells grew in a solid-sheet pattern and were found to have hyperchromatic nuclei, finely dispersed chromatin and inconspicuous nucleoli in the primary gallbladder tumor, as well as in the established xenograft GB-04-JCK The carcinoma cells also had Grimelius argyrophil granules, electron-dense neuroendocrine granules bounded by a single membrane. The xenograft line retained histological and immunohistochemical characteristics of the primary gallbladder tumor and is the first reported xenotransplantable tumor of human gallbladder small cell carcinoma.

Tumor xenografts in immune-deficient mice (athymic nude mice and SCID mice) are well-established animal models for the study of human cancer. Several human melanoma cell lines were reported to metastasize in the immune-deficient mice models. However, metastatic rates were extremely low in spite of large numbers of injections of cancer cells, more than 1 x 10(6) cells/mouse. The NOD/SCID/gamma(C)(null) (NOG) mouse shows multiple immunological dysfunctions, including cytokine production capability, in addition to the functional incompetence of T, B and natural killer (NK) cells. However, the immune-deficient mice, with preserved NK cell activity, might interfere with engraftment efficiency. We examined the distant metastasis of the human melanoma cell lines (A2058, A375, G361 and HMY-1, 1 x 10(4) cells/mouse) in the 6 weeks after intravenous inoculation. All four melanoma cell lines showed metastasis in the NOG mice, while no metastatic lesions were observed in the NOD/SCID mice. Metastatic lesions were noted in the liver and lung of 6/6 (100%) mice at A2058, 8/9 (89%) at A375, 2/6 (33%) at G361 and 2/8 (25%) at HMY-1. A2058 and A375 cell lines with high metastatic potentials show increased gene expression of S100A4. Western blot assay confirmed the increased protein levels of S100A4 in the A2058 and A375 cell lines. E-cadherin gene expression was conversely inhibited in these cell lines. The increased expression of S100A4 combined with inhibited E-cadherin expression resulted in high metastatic potentials of the human melanoma cell lines in vivo.

Glutamate cysteine ligase (GCL) plays an important role in the intracellular detoxification of cisplatin (CDDP). GCL is composed of a modifier or light chain subunit (GCLM) and a catalytic or heavy chain subunit (GCLC). Previously, we showed that the GCL subunits enhanced CDDP-resistance in non-small cell lung cancer (NSCLC) xenografts. In small cell lung cancer (SCLC), it is unclear whether the GCL subunits are essential to CDDP-resistance. We examined the gene expression of GCLM and GCLC in four human SCLC xenografts with the real-time polymerase chain reaction (PCR). An in vivo drug sensitivity test with CDDP was performed on the SCLC xenografts. CDDP-resistance was examined as the growth ratio of the relative volume of the treated xenografts to the controls (T/C%). The expression level of GCLM gene in SCLC was significantly lower than that in NSCLC (p=0.0026, Welch's t-test). One of four SCLC xenografts showed 62% of T/C and this was evaluated as CDDP-resistance, while the other three xenografts were sensitive to CDDP in vivo (Mann-Whitney U-test, p<0.01, one-sided). The expression level of the GCLM gene was significantly correlated to T/C% (Fisher's test, p=0.0289, correlations = 0.975), while the GCLC gene expression level was not associated with T/C%. These results suggest that the overexpression of GCLM is correlated with CDDP-resistance in SCLC xenografts in vivo.

Hepatocellular carcinoma (HCC) is rarely metastasized to the pharyngeal region. We report the case of a 59-year-old man admitted to our hospital with a complaint of hematemesis. An endoscopic examination revealed a tumor located in the left piriform sinus. Histological examination showed metastasis from HCC. Subsequent abdominal examinations demonstrated mild liver cirrhosis due to chronic HCV infection and primary nodules in the lateral segment of the liver. The pharyngeal tumor was completely removed by endoscopic polypectomy after radical hepatectomy for HCC. The patient died of recurrence of HCC 8 months after the first admission. With the presentation of this case, we review the literature reported so far.

Certain pulmonary adenocarcinomas show gastrointestinal differentiation with the expression of various mucins. The CDX homeobox gene, an intestine-specific transcription factor, is related to gastric carcinogenesis with MUC2 and MUC6 expression. The intestinal mucin MUC2 is expressed in the normal lung, while the gastric mucin MUC6 is not. Previously, we have reported that the expressions of MUC2 and MUC6 were related to a poor prognosis in small adenocarcinomas of the lung. We estimated the expressions of the mucin (MUC2 and MUC6) and CDX (CDX1 and CDX2) to examine how CDX relates to the gastrointestinal mucin production in the pulmonary adenocarcinoma. Thirty-nine human non-small cell lung cancer (NSCLC) xenografts were examined (13 adenocarcinoma, 18 squamous cell carcinoma and 8 large cell carcinoma). Significant expression of the MUC6 gene was observed in 7 out of 39 (17.9%) NSCLC xenografts. The expressions of the MUC6 genes were noted in 6 out of 13 (46.2%) adenocarcinoma xenografts, but only in 1 of 18 (0.06%) squamous cell carcinoma xenografts. The adenocarcinoma xenografts significantly showed higher expression of the MUC6 gene than squamous cell carcinoma xenografts (t-test, p=0.0343). Four adenocarcinoma-xenografts co-expressed both the MUC2 and MUC6 genes, and the residual 2 adenocarcinoma-xenografts expressed only the MUC6 gene. One MUC6 overexpressing squamous cell carcinoma focally contained an adenocarcinoma component. The expression patterns of the gastrointestinal mucins were analogous to gastric cancer. The cellular morphology of these carcinoma xenografts was of the gastric cancer type. The proteins of the MUC2 and MUC6 were immunohistochemically confirmed in the xenografts. The expression of the MUC6 gene was significantly correlated with the expressions of the CDX1 and CDX2 genes in the xenografts (Fisher's test, p<0.0001 and p=0.0005, respectively), while there was no significant association between the expression of the MUC2 and CDX genes. These results suggest that the expression of CDX molecules in the pulmonary carcinogenesis pathway relates to gastric cancerous features of aberrant MUC6 expression.

Several studies have shown antitumor activities of the melanoma differentiation-associated gene 7 (mda-7) and the nonsteroidal anti-inflammatory drug sulindac when used as a monotherapies against a wide variety of human cancers. However, the combined effects of mda-7 and sulindac have not previously been tested. Therefore, we tested the antitumor activity of an adenoviral vector expressing mda-7 (Ad-mda7) in combination with sulindac against non-small cell lung cancer cells in vitro and in vivo. When treated with Ad-mda7 in combination with sulindac, human lung cancer cells (A549 and H1299) underwent growth suppression resulting in apoptosis. The growth inhibition induced by Ad-mda7 in combination with sulindac was significantly greater than that observed with Ad-mda7 or sulindac alone. Furthermore, the degree of growth inhibition induced using this combination was dose-dependent for sulindac. Treatment with Ad-mda7 in combination with sulindac had no growth inhibitory effects on human normal lung (CCD-16) fibroblasts. We then investigated the mechanism by which sulindac enhances Ad-mda7-mediated apoptosis. Sulindac increased expression of ectopic MDA-7 protein in tumor cells, thereby increasing the expression of downstream effectors RNA-dependent protein kinase, p38MAPK, caspase-9, and caspase-3 and enhancing apoptosis of non-small cell lung cancer cells. Pulse-chase experiments showed that the increased expression of MDA-7 protein in sulindac-treated cells was due to increased half-life of the MDA-7 protein. Finally, treatment of human lung tumor xenografts in nude mice with Ad-mda7 plus sulindac significantly suppressed growth (P = 0.001) compared with Ad-mda7 or sulindac alone. Our results show for the first time that combined treatment with Ad-mda7 plus sulindac enhances growth inhibition and apoptosis of human lung cancer cells. The increased antitumor activity observed with the combination treatment is a result of increased half-life of MDA-7 protein. Regulation of protein turnover is a heretofore-unrecognized mechanism of this nonsteroidal anti-inflammatory drug.

Objective: the effects of regular exercise over 5 years on mortality and ADL impairment were evaluated in elderly people., Design: intervention study., Setting: Tsuru City, Yamanashi Prefecture, Japan., Methods: the subjects of this study were 245 elderly people living at home. Of these individuals, 155 (56 males aged 76.5+/-4.2 years at the baseline level; 99 females aged 76.2+/-4.8 years) who voluntarily participated in our original health-promoting programme were regarded as an intervention group. The remaining 90 (29 males aged 77.6+/-5.2 years at the baseline level; 61 females aged 77.3+/-5.1 years) were regarded as a control group. The programme was a 5-year intervention consisting of collective sessions given six times a year every 2 months. The intervention was a combination of an exercise programme based on theories of exercise physiology and a support programme based on health education theories. The relative risks of death and ADL impairment adjusted for age, presence or absence of cardiovascular or musculo-skeletal disorders, and functional fitness level at the baseline were calculated using logistic regression analysis., Results: the rates of participant compliance per year were 67.7% in the first year of the intervention period and gradually decreased thereafter to 43.9% in the last year. Amongst female subjects the percentage of those who exercised habitually at the end of the study period was the same as that in the baseline in the intervention group but was significantly lower at the end of the study in the control group (chi2 = 10.576, P < 0.01). The relative risk of death in the intervention group was 1.0 (95% CI 0.22-4.51) amongst the males and 0.16 (95% CI 0.03-0.81) amongst the females. Relative risk of ADL impairment was 0.22 (95% CI 0.03-1.42) amongst the males and 0.36 (95% CI 0.13-1.02) amongst the females., Conclusion: These findings suggest that the improved mortality and state of independence in the female portion of the intervention group occurred as a result of increased physical exercise levels in daily life. However, validation of our results must await research that employs a randomized control trial to avoid various biases and confounding factors between the intervention and the control groups.

The tumor-suppressor gene PTEN encodes a multifunctional phosphatase that is mutated in a variety of human cancers. PTEN inhibits the phosphatidylinositol 3-kinase pathway and downstream functions, including activation of Akt/protein kinase B (PKB), cell survival, and cell proliferation in tumor cells carrying mutant- or deletion-type PTEN. In such tumor cells, enforced expression of PTEN decreases cell proliferation through cell-cycle arrest at G1 phase accompanied, in some cases, by induction of apoptosis. More recently, the tumor-suppressive effect of PTEN has been reported in ovarian and thyroid tumors that are wild type for PTEN. In the present study, we examined the tumor-suppressive effect of PTEN in human colorectal cancer cells that are wild type for PTEN. Adenoviral-mediated transfer of PTEN (Ad-PTEN) suppressed cell growth and induced apoptosis significantly in colorectal cancer cells (DLD-1, HT29, and SW480) carrying wtPTEN than in normal colon fibroblast cells (CCD-18Co) carrying wtPTEN. This suppression was induced through downregulation of the Akt/PKB pathway, dephosphorylation of focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) and cell-cycle arrest at the G2/M phase, but not the G1 phase. Furthermore, treatment of human colorectal tumor xenografts (HT-29, and SW480) with Ad-PTEN resulted in significant (P=0.01) suppression of tumor growth. These results indicate that Ad-PTEN exerts its tumor-suppressive effect on colorectal cancer cells through inhibition of cell-cycle progression and induction of cell death. Thus Ad-PTEN may be a potential therapeutic for treatment of colorectal cancers.

We successfully saved a patient with appendicitis followed by necrotizing fascitis. A 77-year-old man with a history of ambulatory treatment for depression underwent an emergency operation because of severe abdominal pain. Laparotomy demonstrated that necrotizing appendicitis was massively extending over the abdominal cavity, involving the right paracolic sulcus and Douglas pouch and posterior surface of the right kidney. Irrespective of the emergency surgery, redness and swelling in the right chest and abdomen, which was noted at the time of admission, was not decreased. Successively, a retension incision was performed under the diagnosis of necrotizing fasciitis. Necrotizing fasciitis is an extremely rare complication of appendicitis, and there were only 10 cases documented. Once necrotizing fasciitis occurs, the mortality rate is high, so that correct diagnosis and prompt debridement are mandatory. Particularly for elderly patients with appendicitis, rapid and accurate diagnosis and treatment are required.

We measured functional fitness in older subjects and performed a follow-up survey for 6 years to clarify whether the level of functional fitness at a given point contributes to prediction of the subsequent occurrence of impairment of functions necessary for independent living. The longitudinal data were obtained for 391 persons aged 60 years or over, who were independently living in the community. Four items of functional fitness, i.e. the ability to perform standing/sitting movements, ability to perform traveling movements, ability to perform housekeeping movements, and ability to perform personal grooming activities, were assessed. The relationship between functional fitness and the risk of the occurrence of impairment of independence in daily living was evaluated using a binomial logistic regression model. In males, all the 4 items of functional fitness were significantly related to the risk of impairment of activities of daily living (ADL). In females, however, none of the items was significantly related to the risk of ADL impairment. In conclusion, functional fitness appears to be valid as a predictive parameter of future occurrence of ADL impairment in relatively healthy and independent elderly males. However, its validity in elderly females needs further evaluation.

Acute appendicitis is usually encountered clinically as acute abdomen. Typical cases are easy to diagnose, but it can sometimes be very difficult to make a diagnosis in atypical cases. We retrospectively studied patients who underwent ultrasonography for right-sided lower abdominal pain suggesting acute appendicitis, and assessed the accuracy of ultrasonic diagnosis. The subjects were 202 patients (100 males and 102 females) aged 6-89 years (mean: 33.3 years). From the ultrasonic findings, appendicitis was classified as follows: 1) catarrhal: a clear layer structure of the appendiceal wall and mucosal edema; 2) phlegmonous: an ill-defined layer structure of the appendiceal wall, moderate enlargement of the apendix, and maximum transverse dimension of > or = 10 mm; and 3) gangrenous: unidentifiable layer structure of the appendiceal wall and marked enlargement to form a mass. The appendix was visualized in 142 of the 202 patients (70.3 %). When the appendix was detected, the sensitivity, specificity and accuracy of ultrasound for making a diagnosis of appendicitis were 97.6%, 82.0 %, 91.5 %, respectively. With regard to assessment of the severity of inflammation, ultrasonic and histologic findings were concordant in 61.2 % of the patients. However, ultrasound was shown to possibly underestimate the extent of inflammation. On the other hand, 11 of the 60 patients with an undetectable appendix (18.3 %) were clinically diagnosed as having appendicitis. The pathologic diagnosis was catarrhal appendicitis in 3 patients and phlegmonous appendicitis in 8 patients. In patients with an undetectable appendix, the possibility of catarrhal or phlegmonous appendicitis should be kept in mind.

Pancreatic cancer is a malignant tumor with an extremely poor prognosis. The mechanisms of the aggressive growth and metastasis are not yet extensively understood. Over-expression of epidermal growth factor receptor (EGFR) was suggested to be associated with malignant transformation of pancreatic cancer. We examined EGFR expression in 77 cases of invasive ductal adenocarcinoma of the pancreas, and analyzed the relation between the EGFR expression pattern and clinicopathological factors. EGFR immunoreactivity was detected in 41.6% (32/77) of human pancreatic cancers; i.e. diffuse expression in 32.5% (25/77) and focal expression in 9.1% (7/77). The EGFR expression was associated with gender (p<0.05), histological differentiation (p<0.05) and metastatic status of TNM classification (p<0.01). The observations suggested that EGFR expression plays important roles in metastasis, especially liver metastasis and recurrence of human pancreatic cancer.

Pancreatic cancer is a malignant tumor with an extremely poor prognosis. Thrombospondin-1 (TSP-1) was suggested to be a potential regulator of tumor growth and metastasis. We examined TSP-1 expression in 77 cases of invasive ductal adenocarcinoma of the pancreas, and analyzed the correlation between the TSP-1 expression pattern and clinicopathological features in pancreatic cancer. TSP-1 immunoreactivity was detected in the cancer stroma. The diffusely positive and focally positive patterns of TSP-1 were found in 33 (42.9%) and 40 (51.9%) of 77 cases, respectively. The TSP-1 diffuse expression was significantly correlated with lymph node metastasis (p<0.01), neural invasion (p<0.05) and TNM stage (p<0.01). The prognostic significance of clinicopathological parameters were analyzed by univariate and multivariate analysis using the log-rank test and the Cox proportional hazards model. Based on the univariate analysis, histological differentiation (p<0.01), lymphatic invasion (p<0.01), venous invasion (p<0.05), neural invasion (p<0.01), TNM stage (p<0.01) and TSP-1 expression (p<0.01) were significant parameters. These observations suggested that TSP-1 plays important roles in cancer cell growth and metastasis of human pancreatic cancer, and that stromal TSP-1 immunoreactivity is a good prognostic predictor of patients with pancreatic cancer.

A patient was diagnosed as having subacute ileus due to advanced cancer of the descending colon with multiple liver metastases and was treated by palliative left hemicolectomy. He was considered to have Stage IV cancer based on the finding of extensive peritoneal dissemination. Histopathological examination showed that the tumor was moderately differentiated adenocarcinoma. Postoperative palliative chemotherapy was given with 5-FU and LV twice a month as 1 course, and he received a total of 3 courses. As a result, the multiple liver metastases were completely eliminated. However, his liver metastases recurred, so CPT-11 was added to 5-FU and LV for another 3 courses. When bilateral pleural effusions developed about 1 year postoperatively, CPT-11 was changed to CDGP. Jaundice and massive ascites eventually developed, and he died about 1 year and 5 months postoperatively.

The effective use of activated carbon as oral adsorbent in the primary treatment of acute acetaminophen poisoning was studied. The adsorption characteristics of acetaminophen onto activated carbons in presence of sorbitol were investigated in vitro. Both the equilibrium amount adsorbed and the removal rate of acetaminophen onto activated carbon were decreased with the increase of sorbitol concentration in solutions. The sorbitol concentration independency of the inhibition to the acetaminophen adsorption was recognized. It was concluded that the addition of sorbitol to the suspension of activated carbon inhibited the acetaminophen adsorption by activated carbon.

Case 1: a patient was diagnosed as having ascending colon cancer with right ovarian metastasis, and underwent palliative right hemicolectomy plus oophorectomy. The tumor was a well-differentiated adenocarcinoma with right ovarian metastasis, and the disease was classified as stage IV. Oral chemotherapy with UFT plus LV was performed for about 3 years, and the patient is still being followed up with no recurrence at 5 years postoperatively. Case 2: a patient was diagnosed as having incomplete large bowel obstruction caused by ascending colon cancer, and underwent curative right hemicolectomy. The tumor was a moderately differentiated adenocarcinoma, and the disease was classified as stage II. Since multiple liver metastases developed at 3 months postoperatively, oral chemotherapy with UFT plus LV was started. Imaging studies showed the complete elimination of liver metastases after 2 months. Subsequently, liver metastasis recurred about 10 months later. The patient died of unrelated cerebral infarction at 2 years and 6 months postoperatively.

A patient who had undergone radical gastrectomy for synchronous gastric cancer (T(1)N(0)M(0), stage I) and duodenal cancer (Tis, stage 0) in November 1987 was found to have esophageal cancer in November 1994, and underwent radical thoracolaparotomy at our hospital (T(1)N(0)M(0), stage I). After follow-up for about 3.5 years, renal cancer was detected in April 1998, and radical nephrectomy was performed (T(1)N(0)M(0), stage I). Two years later, in April 2000, the patient was found to have a polypoid lesion in the colonic conduit used for reconstruction after esophagectomy, and endoscopic mucosal resection was performed (Tis, stage 0). The patient remains under careful follow-up, including observation of the colonic conduit and the residual large intestine.

To test our hypothesis that somatosensory inputs would influence postural modulation of soleus H-reflex, eleven subjects were investigated under the head-out water immersion (HOWI) conditions. Subjects were supine or standing on a tilting bed in each condition. They were instructed to maintain an upright posture with both legs. The water was filled to the subject's neck level in a test tank to reduce 95% of the gravitational effect by buoyancy. Surface electromyography of the soleus and tibialis anterior was measured. The soleus H-reflex was elicited at a stimulation intensity of 1.05 times the motor threshold. The recruitment profile of the motor response was unchanged between the conditions. The background activities of the soleus and tibialis anterior were not detected in any condition. The peak-to-peak amplitude of the H-reflex was significantly different between the conditions while the stimulation intensity (small M size) was not different. The soleus H-reflex during standing was significantly decreased compared with being supine in the control condition, whereas it did not in the HOWI condition. It was concluded that somatosensory inputs due to gravity exert an influence on postural modulation of the soleus H-reflex to maintain static posture in humans.

To examine the association of level of functional fitness to demographic, health, and life behavioral or social factors, cross sectional data were obtained for 737 persons aged 60 years or older, and who were independently living in the community. Functional fitness was measured with a functional fitness test containing 4 task items: standing, walking, hand performance, and self-care performance. Among the demographic factors, statistically significant associations with functional fitness were found for age in both male and female and for the presence of spouse in male. Health status, previous or present history of circulatory diseases and musculo-skeletal diseases were significantly associated with lower levels of functional fitness in male, and previous or present history of musculo-skeletal diseases and presence of higher obesity associated with lower fitness level in female. With life behaviors, men who had habitual exercise activities and women who had no habitual nap but habitual exercise activities and frequent out-of-home activities showed significantly higher fitness level than their counterparts. These results suggest that level of functional fitness in independently living aged people in the community was significantly associated with the presence of spouse, history of circulatory and musculo-skeletal diseases, and habitual exercise activities in males; and with the history of musculo-skeletal diseases, obesity, and habitual exercise activities, napping, and frequent out-of-home activities in females.

A case of a 66-year-old Japanese woman with two synchronous urinary bladder tumors, namely verrucous carcinoma and poorly differentiated squamous cell carcinoma, is described. Both tumors were accompanied by widespread squamous metaplasia in the background and unassociated with bilharzial infection. The poorly differentiated squamous cell carcinoma, having a satellite tumor in its proximity, was large and in an advanced stage. The verrucous carcinoma was small with minimal invasion to the muscularis propria. The boundary between both tumors was well defined, suggesting colliding growth appearance. Immunoexpression of cytokeratins of verrucous carcinoma was similar to that of squamous metaplasia, and significant differences between verrucous carcinoma and poorly differentiated squamous cell carcinoma were demonstrated in their immunoexpression of cytokeratins.

A test of functional fitness defined as physical capacity to independently perform daily functional activities was developed for aged persons. The functional fitness test was composed of four physical capacity evaluation tasks representing physical abilities necessary to perform main activities of daily living; viz. sitting and standing up test, zig-zag walking test, hand working test with pegboard for dexterity evaluation, and rope working test for self-care evaluation. The reliability and feasibility of the test were examined with 765 aged persons living in the community. The distribution of measurement values in each item showed neither extreme skewness nor kurtosis. Retest reliabilities for each task were 0.857 to 0.942, but the second trial showed significantly reduced (p < 0.001) values than the first trial in test-retest. Significant relationships (r = 0.503 to 0.627) between measurement values in each items and chronological age were found in both male and female. Functional fitness test and physical fitness test scores were correlated 0.740. These results showed that the functional fitness test developed in the present study has a high reliability and feasibility to evaluate functional capacity of daily living in aged persons.

The life style of young adults has been receiving attention with a view to its improvement to prevent coronary heart diseases (CHD) later in life. In this study, to determining the influence of different life styles on the serum phospholipids level, we carried out experimental studies on the effects a high sugar diet and physical exercise on serum phospholipid levels. Considering the trend for young people to consume large quantities of carbonated drinks, in which most of the sugar is sucrose, we tested the effect of a high carbohydrate diet on one group of six healthy male subjects and did not find that it caused a significant increase in the serum phospholipids level. In another group of 108 healthy young female subjects, a mild exercise regimen results in a slight, but significant decrease in the serum phospholipid level (p < 0.01). The serum total cholesterol level of the group did not exhibit a significant change.