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Purpose: To clarify physician- and nurse-reported effects of intravenous hydration therapy on symptoms of terminally ill patients with cancer., Methods: A cross-sectional questionnaire survey of Japanese physicians and nurses. The respondents were requested to report their clinical observations about improvement or deterioration of seven symptoms of terminally ill patients with lung or gastric cancer receiving 0.5-1 L/d intravenous hydration therapy, 1.5-2 L/d intravenous hydration therapy, and reduction of intravenous hydration volume from 1.5-2 L/d to 0.5-1 L/d., Results: The responses from a total of 413 oncologists, 88 palliative care physicians, 2735 oncology nurses, and 593 palliative care nurses were analyzed (response rates, 53% in physicians and 83% in nurses). Fewer than 30% of the respondents in all specialties reported that they often or very often observed improvement of dehydration symptoms with 0.5-1 L/d or 1.5-2 L/d intravenous hydration therapy. Deterioration of fluid retention symptoms was reported by 5.8%-13% of the oncologists and 20%-50% of the other specialists with 0.5-1 L/d intravenous hydration therapy for patients with lung cancer, and by 9.3%-24% of the oncologists and 16%-68% of the other specialties with 1.5-2.0 L/d hydration for patients with gastric cancer. By reducing intravenous hydration volume, 20%-70% of the palliative care physicians and nurses reported that they often or very often observed improvement of fluid retention symptoms, while less than 7.0% of all specialists reported that they often or very often observed deterioration of dehydration symptoms., Conclusions: The physicians and nurses in both oncology and palliative care settings frequently observed deterioration of fluid retention symptoms with limited benefits in alleviating dehydration symptoms by intravenous hydration therapy for terminally ill patients with cancer. It is suggested that routine use of artificial hydration therapy should not be recommended, and individualized treatment policy based on the comprehensive assessment of each patient's needs is strongly required.

The epidermal growth factor receptor (EGFR) is a member of the family of transmembrane protein kinase receptors known as the erbB or HER receptor family. When activated, EGFR phosphorylates and activates other intracellular proteins that affect cell signaling pathways, cellular proliferation, control of apoptosis and angiogenesis. EGFR signaling is best thought of as a network of activating and inactivating proteins with EGFR as the entry point into the network. EGFR overexpression occurs in most GI malignancies and while data are not entirely consistent, EGFR overexpression often confers a poor prognosis in those GI malignancies that have been studied. It often correlates with poorly differentiated histology, more advanced stage and other known poor prognostic markers. The EGFR is a tempting target because of its presence and overexpression on so many tumor types. However, downstream of the EGFR are several proteins that may be activated without EGFR thus allowing blockade to be overcome. Therefore, while blocking the activity of the EGFR protein appears to be a promising anticancer strategy, a simplistic strategy of blocking only EGFR is likely to only impact a minority of patients. It is time for the laboratory and clinical researchers to work closely together to develop this treatment strategy, moving back and forth from clinical to laboratory to best understand how to block this network effectively enough to produce a broader antitumor effect. While multiple methods of targeting the EGFR pathway are under development, including the inhibition of downstream proteins, only two modalities have entered clinical trials in GI malignancies: small molecule inhibitors of the intracellular kinase domain of EGFR and antibodies designed to block the extracellular ligand-binding domain of EGFR. EGFR inhibitors are still experimental in every GI malignancy with the notable exception of cetuximab that is approved for second or third-line therapy of metastatic colorectal cancer, used either alone or in combination with irinotecan (Camptosar, Kalamazoo, Mich). Data on clinical applications of these agents in GI malignancies will be the focus of this paper.

Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney's triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.

Objectives: Prediction of perioperative cardiac events associated with noncardiac surgery remains difficult in patients whose functional capacity cannot be evaluated by exercise testing. Dobutamine stress echocardiography (DSE) has been used in these patients to improve risk stratification, but the results of standard DSE provide only a binary index of risk (positive or negative). Two new semiquantitative indices of DSE (semi-DSE) were retrospectively examined to determine the prediction of perioperative cardiac events compared to standard DSE., Methods and Results: Clinical assessment of cardiac risk factors and standard DSE were performed safely in 122 consecutive patients (73 men, 49 women) undergoing noncardiac surgery. Preoperative revascularization was performed in 12 patients. The perioperative cardiac events consisted of 2 deaths, 4 cases of heart failure, and 2 cases of angina pectoris. For the semi-DSE indices, the extent of ischemia was indexed as the number of wall segments (SEG) displaying biphasic or worsening segmental wall-motion score, and the severity of ischemia (SI) was indexed as the sum of the differences in wall-motion scores between peak stress and rest divided by the number of affected segments. The optimal cut-off values of these indices for predicting cardiac events were 4.0 for SEG and 1.0 for SI. The risk stratification was further refined by these indices (high-, moderate-, and low-risk groups). The diagnostic accuracy of the semi-DSE indices, evaluated by the area under the receiver operating characteristic curves, was better than that of standard DSE (p < 0.001)., Conclusions: Semi-DSE may improve cardiac-event risk stratification compared to standard DSE in patients undergoing noncardiac surgery whose functional capacity cannot be evaluated by exercise stress testing.

Gastrointestinal stromal tumors (GIST) are defined as c-KIT-positive mesenchymal neoplasias located in the gastrointestinal tract and abdomen, most of which present an activating KIT mutation, a fundamental step in the development of disease. However, recent studies reported a small subgroup of KIT-negative GIST, in which platelet-derived growth factor receptor A, protein kinase C-tau, and FLJ10261 expression was detected. Imatinib (Gleevec, Novartis) is an orally administered competitive inhibitor of the tyrosine kinase domain of receptors such as KIT, ABL, and BCR-ABL fusion proteins, and the platelet-derived growth factor receptor. Phase I-III clinical trials have demonstrated the efficacy of imatinib in the treatment of metastatic GIST. However, the optimal dose and role of imatinib in an adjuvant or neoadjuvant setting have yet to be defined. Therefore, further studies investigating the mechanism of resistance to imatinib in patients with GIST are warranted.

To date, dozens of melanoma-associated antigens (MAGEs) have been identified and classified into 2 subgroups, I and II. Subgroup I consists of antigens which expression is generally restricted to tumor or germ cells, also named as cancer/testis (CT) antigen. Proteins and peptides derived from some of these antigens have been utilized in promising clinical trials of immunotherapies for gastrointestinal carcinoma, esophageal carcinoma, pulmonary carcinoma and so on. Various MAGE family members play important physiological and pathological roles during embryogenesis, germ cell genesis, apoptosis, etc. However, little is known regarding the role of MAGE family members in cell activities. It is reasonable to speculate that the genes for subgroup I MAGEs, which play important roles during embryogenesis, could be later deactivated by a genetic mechanism such as methylation. In the case of tumor formation, these genes are reactivated and the resultant proteins may be recognized and attacked by the immune system. Thus, the subgroup I MAGEs may play important roles in the immune surveillance of certain tumor types. Here, we review the classifications of MAGE family genes and what is known of their biological functions.

Background: Cancer-associated anorexia/cachexia syndrome (CACS) is common in advanced gastrointestinal malignancies and felt to be due primarily to cytokine-induced appetite suppression. Therapy with an appetite stimulant (megesterol acetate) is commonly employed, but results are sometimes disappointing. We hypothesize that CACS not only suppresses appetite but also interferes with gastrointestinal function., Methods: We conducted a prospective study in which 21 subjects with advanced gastrointestinal cancer and weight loss had digestive function. Patients were assessed using an indirect stable isotope method, and nutritional parameters were determined following which patients were treated with megesterol acetate for 4 weeks. Nutritional parameters were then reassessed, weight change determined, and the results were correlated with digestive function results obtained at the initiation of the study., Results: Abnormal gastrointestinal function based on the stable isotope test was common (86% of patients). The majority of the abnormal function appeared to be due to abnormal pancreatic function testing, in which 17/21 subjects recorded low results. Initial albumin, prealbumin, and carotene values were also frequently abnormal (55-65% of patients). Megesterol acetate therapy resulted in a weight gain in most (75%) patients, although serum albumin fell modestly in the group (average decrease of 0.2 mg/dl). However, prealbumin levels rose in 70% and carotene levels rose in 55%. The degree of weight gain was negatively correlated with previous self-reported weight loss ( r=-0.53, p<0.05), and positively correlated ( p<0.05) with pretherapy carotene ( r=0.58), prealbumin ( r=0.61) and the pancreatic function (digestive) phase of the digestive function test ( r=0.41)., Conclusion: These data suggest that abnormal digestive function is commonly seen in subjects with CACS and advanced gastrointestinal cancer, and that both pretherapy digestive function and nutritional status can predict or possibly influence the outcome of hormonal appetite stimulation therapy.

The purpose of this study was to assess the pre- and postoperative quality of life (QOL) of patients with gastrointestinal cancer and to investigate the relationship between QOL and various psychological and clinical factors. Eighty-five patients who underwent surgery for gastrointestinal cancer and 26 control patients undergoing surgery for digestive diseases other than cancer were interviewed. Two tests were administered to assess QOL and psychological status respectively: the Japanese-language version of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the Japanese-language version of the Hospital Anxiety and Depression Scale (HADS). Each test was administered before surgery, before discharge, and 6 months after discharge. Gastrointestinal tumors were localized to the stomach, colon, or rectum in 88% of cases and classified as advanced stage or early stage according to staging protocols. Changes in EORTC QLQ-C30 subscale scores over time were compared among advanced stage, early stage, and control patients. All groups showed significant changes in subscale scores of QOL; the scores of the advanced-stage group indicated worse QOL than the early-stage and control groups in a lot of areas. The physical function (PF2) QOL subscore was influenced by diagnosis, postoperative complications, medical equipment at discharge, and the length of admission and negatively correlated with depression and anxiety. These results suggest that QOL in gastrointestinal cancer patients is variable over time and is influenced by various clinical factors. Therefore, consideration of these clinical factors is paramount to the optimal care of gastrointestinal cancer patients.

Objective: To evaluate the cardiotoxicity of LV5FU2 regimen (bolus plus infusional 5-fluorouracil/folinic acid) treatment by non-invasive methods such as echocardiography, plasma troponin I (TnI) level, QT interval and QT dispersion on ECG., Methods: Twenty-two patients with gastrointestinal cancer who received LV5FU2 chemotherapy were evaluated prospectively during 12 cycles of chemotherapy. Plasma TnI assay and ECG recording analyses were performed before the first cycle, at 24 h, before each cycle until cycle 6 and every three cycles thereafter. The longest QT interval measurement on each recording corrected with Bazzett's formula was considered as QTmax and the difference between the QTmax and the shortest corrected QT interval was considered as QT dispersion (QTd). A complete M-mode, 2D and color Doppler echocardiogram was performed at baseline and at the first, third and sixth months of treatment., Results: Echocardiography did not show any significant change in either systolic or diastolic functions. Also, TnI measurements were found to be below detectable level in all patients and in all measurements. Meanwhile, significant prolongations of QTmax and QTd were observed as early as 24 h after first administration of chemotherapy. These events persisted and became more important over the duration of chemotherapy (P < 0.05)., Conclusions: The clinical implication of these findings as predictive factors for subsequent events such as malignant arrhythmias in patients taking 5-fluorouracil-based chemotherapy need longer follow-up and further detailed evaluations.

A combination of both environmental and genetic factors contributes to the vast majority of human cancers and in particular cancers of the gastrointestinal tract, including the stomach, colon and rectum. The mechanisms associated with cancer causation or prevention are largely unknown and the subject of much research. Many of these mechanisms implicate the metabolic activities of the bacterial flora normally resident in the gastrointestinal tract. This paper examines both the detrimental and beneficial consequences of bacterial activity of the gastrointestinal tract, focusing in particular on the stomach and large intestine.

Human neuroendocrine tumors exhibit unique biological properties, and defining the molecular genetic alterations that underlie these distinctive features remains an important challenge. In addition to the MEN1 tumor suppressor gene, the cyclin D1 oncogene has demonstrated a role in the pathogenesis of parathyroid and gastroenteropancreatic neuroendocrine tumors. Up-regulation of cyclin D1 is observed early in tumor formation, implying a possible role in tumor initiation. Overexpression of cyclin D1 in the parathyroid glands of mice resulted in the tandem regulation of cellular proliferation and hormonal secretion, a feature intrinsic to neuroendocrine tumors.

Neuroendocrine gastroenteropancreatic (GEP) tumors are rare and present with variable clinical syndromes. So far, there are no detailed studies concerning the molecular pathogenesis of sporadic GEP tumors. In our study, GEP tumors from 29 patients were assessed for microsatellite instability, aberrant promoter methylation, and LOH of various tumor suppressor genes. All tumors were microsatellite stable. One tumor showed LOH close to the APC locus, one tumor had an allelic loss near the hMLH1 gene, and one tumor showed hypermethylation of the hMLH1 promoter. Interestingly, none of the tumors was aberrantly methylated at the p16 promoter. However, 13 of 20 successfully amplified tumors (65%) were hypermethylated at the APC promoter. Of the hypermethylated tumors, none showed LOH of either the hMLH1 or the APC gene. The current study is the first report demonstrating that aberrant methylation of the APC promoter is strongly involved in the molecular tumorigenesis of neuroendocrine GEP tumors. MSI does not seem to be involved in the pathogenesis of these cancers. Further studies are required to investigate the role of hypermethylation in neuroendocrine GEP tumors and to further elucidate the role of the APC pathway in these tumors.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the digestive tract. Most gastrointestinal soft tissue neoplasms, previously classified as leiomyomas, schwannomas, leiomyoblastomas or leiomyosarcomas, are today classified as GIST on the basis of molecular and immunohistological features. They originate from gastrointestinal pacemaker cells and are characterised by over-expression of the tyrosine kinase receptor KIT. Overall 5-year survival after surgical resection of GIST is approximately 60%. However, these tumours span a wide clinical spectrum from benign to highly malignant. Prognostic factors have recently been identified for GIST and include tumour size, mitotic rate and other minor factors. At present, surgery is the standard treatment for primary resectable GIST. Benign GIST have an excellent prognosis after primary surgical treatment, with over 90% 5-year survival. While recurrent or malignant GIST, which are resistant to radiotherapy and chemotherapy, had until recently an extremely poor prognosis even after surgical resection, with median survival of 12 months. The development of a tyrosine kinase inhibitor has changed the management of unresectable malignant cases. This new tyrosine kinase inhibitor, imatinib mesylate, which inhibits the c-kit receptor, has proved highly effective against GIST and has improved survival in metastatic GIST. This paper reviews the literature and our experience of GIST, including: diagnosis, pathology, treatment and prognosis.

Nitric oxide is an intracellular and intercellular messenger with important functions in a number of physiologic and pathobiologic processes within gastroenterology and hepatology, including gastrointestinal tract motility, mucosal function, inflammatory responses, gastrointestinal malignancy, and blood flow regulation. Since the broad review of this topic in Gastroenterology more than 10 years ago, a number of advances have been made in the area of NO biology and its relevance to the gastrointestinal system. The aim of this review is to focus on our expanded understanding of the role NO plays in human gastrointestinal and hepatic physiology and disease processes by drawing on data from relevant in vitro and animal models as well as observational human studies.

Inflammatory conditions are characterized by activation of the transcription factor nuclear factor kappa B (NF-kappaB), resulting in the expression of NF-kappaB-regulated, inflammation-related genes, such as inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). Expression of these genes contributes to the survival of cells. Indeed, exposure to pro-inflammatory cytokines in the absence of NF-kappaB activation leads to apoptosis.(1,2) Chronic inflammatory conditions are accompanied by constitutive activation of NF-kappaB and hence, to the continuous expression of pro-survival genes, as has been observed in chronic gastritis.(3) Although beneficial for the survival of cells during exposure to inflammatory stress, the continuous activation of NF-kappaB may also pose a risk: cells with a pro-survival phenotype may give rise to continuously proliferating cells and may thus be tumorigenic. Progression to a malignant phenotype of these cells will most likely involve additional changes in the expression of non-NF-kappaB regulated genes e.g. a shift in the balance of pro- and anti-apoptotic genes towards a more anti-apoptotic phenotype. Literature on inflammation-related genes and the apoptotic balance in pre-malignant and malignant conditions in the gastro-intestinal tract is still scarce and conflicting. In this review, we aim to give an overview of the existing literature and we will focus on inflammation- and apoptosis-related genes in the sequence of normal epithelium-inflamed epithelium-metaplasia-dysplasia-cancer in the gastrointestinal tract, in particular esophagus (Barrett's esophagus: BE), stomach (gastritis) and colon (inflammatory bowel disease: IBD)., (Copyright 2004 Kluwer Academic Publishers)

Objective: To analyse and discuss the effects of elective abdominal operation and anaesthesia on patients' cardiac output via noninvasive thoracic bioimpedance technique., Methods: Noninvasive monitoring system HeMo-601 was applied to detect the hemodynamic variables of 32 elective abdominal surgery patients. The clinical data of cardiac output (CO), cardiac index (CI), cardiac working per minute (CW), left ventricular end-diastolic pressure (LVEDP), stroke volume (SV), cardiac stroke working (SW) and heart rate (HR) were analysed at 1 hour before operation, 4-6 hours after operation and 24 hours after operation, respectively., Results: No significant differences were found in CO, CI, CW and LVEDP between various time points and preoperation (all P>0.05). SV and SW at 4-6 hours after operation were significant lower than those before operation (all P<0.05). Whereas, SV and SW at 24 hours after operation were no significant differences compared with those before operation (all P>0.05). As compared with preoperation, HR at 4-6 hours after operation was significantly faster (P<0.05). However, there was no significant difference in HR between 24 hours after operation and preoperation (P>0.05)., Conclusion: The reductions in SV and SW at 4-6 hours after operation might be a result of anaesthesia that could weaken the contraction of heart. The presence of rapidness of HR at 4-6 hours after operation might be a compensatory mechanism for the decreases in SV and SW. Therefore, optimizing adequate infusion by the greatest extent during and after operation is very crucial for the maintenance of CO, CI and tissue perfusion.

Neuroendocrine tumours of the gastroenteropancreatic tract (GEP NETs) represent a rare and heterogeneous group of tumours. Based on their ontogenetic origin, GEP NETs are classified into foregut, midgut and hindgut tumours. Although they have many features in common, their molecular backgrounds are obviously different. Elucidation of the key factors determining tumour biology has been hampered by the low incidence and high variability of these tumours in terms of origin, morphology and growth. However, recent years have shed some light on molecular genetics of these tumours, revealing important genetic factors as the RET proto-oncogene and the tumour suppressor menin as well as knowledge about the role of growth factors like IGF-1, TGF-beta, VEGF and PDGF for the regulation of differentiation, growth and secretion. In the future, emerging molecular tools in rapid individual genome analysis and in proteomic and array technologies may help to delineate common patterns of NET disease.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract. Aspects of the morphology and immunophenotype in GISTs resemble those in the interstitial cells of Cajal (ICC), which are a specialized cell type responsible for coordinating peristaltic activity throughout the gastrointestinal tract. Therefore, it is possible that GISTs result from transformation of nonneoplastic progenitor cells that would normally differentiate towards an ICC endpoint. Activation of the KIT receptor tyrosine kinase is required for differentiation and proliferation of nonneoplastic ICC, and oncogenic KIT mutations are a crucial event in the development of most GISTs. These mutations can involve either the extracellular or intracellular domains of the KIT receptor, giving rise to conformational changes that enable constitutive, ligand-independent, activation of the KIT protein. Oncogenic KIT activation leads to phosphorylation of various substrate proteins and, in turn, to activation of signal transduction cascades regulating cell proliferation, apoptosis, chemotaxis, and adhesion. Recently, a small molecule tyrosine kinase inhibitor (STI571, imatinib mesylate, Gleevec) directed against the enzymatic (kinase) domain of the KIT protein was found to produce dramatic clinical responses as monotherapy for metastatic GISTs. This review focuses on the biological and molecular genetic principles of GISTs, and particularly the role of mutant KIT as a therapeutic target.

During the period of 2001-2002 in the surgical department of the Republican clinical hospital there were 72 patients with acute small bowel obstruction. In addition to generally accepted methods of diagnosing the acute intestinal obstruction including general rentgenography of organs of the abdominal cavity, radiopaque methods, ultrasound scanning of organs of the abdominal cavity, a measuring-diagnostic system (polygastroenterograph "PGEG-2001") was used which registered and processed fluctuation of biopotentials of different parts of the gastrointestinal tract and measured instantaneous values of the intracavital gastric pressure. So, a short period of time was needed to reliably determine the kind and level of obstruction.

Patients with rare tumors represent a diagnostic and therapeutic challenge for non-specialized physicians, surgeons and other medical doctors. Whereas several specialized centers have gathered data for an improved diagnosis and therapy of neuroendocrine tumor disease, numerous clinical issues have not been resolved on an evidence-based medicine level. Furthermore, the evaluation of new treatment options has been overshadowed by the low incidence of the disease. In this article, a major medical challenge for the diagnosis and therapy of neuroendocrine tumor disease is addressed. As well, new therapeutic treatment options translated from current findings in the fields of molecular and tumor biology are discussed.

In the last decade important progresses have been obtained in the diagnosis and therapy of endocrine gastroenteropancreatic (GEP) tumors, mainly derived from the somatostatin receptors characterization and the introduction of long acting somatostatin analogues. Receptorial scintigraphy with radio-labeled analogues (Octreoscan) is the first choice investigation for staging and follow-up of endocrine GEP tumors, thanks to the high sensitivity in revealing the primary tumor and metastases, and for its capability to reveal lesions that are not identified by other imaging methods. Moreover, somatostatin analogues uptake by tumors allow us to use radiopharmaceutical compounds for advanced disease treatment. Between the radio-labeled drugs until now studied, interesting results have been obtained by DOTA-lanreotide (MAURITIUS), DOTA0 Tyr3-octreotide (DOTATOC) and DOTA0 Tyr3-octreotate, bound to beta-emitting radio-isotope suitable for therapeutic use. In the field of the pharmacological therapy of GEP tumors, the clinical trials show that somatostatin analogues reduce the symptoms related to functionally active tumors and stabilize or slow tumor growth improving the patient quality of life. Although somatostatin analogues alone could not be able to cure GEP tumors, their early utilization in association with surgical debulking of primary tumor and metastases, embolization or chemoembolization, and interferon, chemotherapy and radio-metabolic therapy (mainly directed to the destruction of micrometastases), increases the possibility of a radical therapeutic intervention. The continuous evolution of pharmacological research provides always new analogues (octreotide LAR, lanreotide, vapreotide, BIM-23244, BN 81644, PTR-3173, BIM-23A387, SOM-230, etc.) with different pharmacokinetic and receptorial properties and acting with more effectiveness in the different individual clinical situations. In this context there have been recently introduced also the "chimeric" analogues. On the other hand, the widespread utilization of molecular biology and immunohistochemical methods can allow, in perspective, to better define the receptorial pattern of individual endocrine tumors, after their surgical removal. The necessity to integrate endocrinological, nuclear medicine, surgical, oncologic and laboratory competencies behaves a multidisciplinary approach based on the utilization of diagnostic-therapeutic protocols supplying comparable results. It does not appear unjustified to expect, in the future, a scenery of more "individual" and more effective therapies for patients affected by GEP tumours.

If patients with advanced recurrent gastrointestinal cancer want home care, endeavors are made to attain early control of the symptoms and the patients are transferred to home care under the team approach while understanding and supporting the intention of the patients and families.

The common acid related diseases of the upper GI tract could be considered as primarily due to the defect in barrier function either of the gastric mucosal or duodenal epithelium leading to the formation of gastric or duodenal ulcers. An attempt was made in this chapter to discuss the history of peptic ulcer disease in humans and methods for the production of acute gastric lesions and ulcers in experimental animals with the special attention focused to the contribution of Polish scientists and investigators into this field. Early surgical advances in the management of peptic ulcers were emphasized that were then subsequently replaced by pharmacological treatment (histamine H(2)-receptor antagonists, proton pump inhibitors) and considered as the major strategy against the acid disorders. This included the immense body of work performed by numerous group of investigators, including Polish researchers, to identify the effects of acid, bile salts, aspirin and other non-steroidal anti-inflammatory drugs (NSAID), stress, Helicobacter pylori (H. pylori) infection, prostaglandins (PG) and nitric oxide (NO) on the integrity of the gastrointestinal mucosa, which all were discussed in this chapter. The concept of major defensive mechanism in the stomach called "cytoprotection", originally proposed by Andre Robert is recalled in the relevance to the great contribution of Polish scientist working at the Jagiellonian University in Cracow. These experimental studies gave a new insight into the mechanism of action of arachidonate cascade products such as PGs, tromboxanes and leukotrienes and had opened the new therapeutic avenues for the gastroprotective treatment of the acute gastric mucosal damage. Detailed studies revealed, however, that PG-induced cytoprotection offers a short-term protection against gastric lesions induced by corrosive agents but unfortunately this phenomenon gives a little, if any, impact to the process of ulcer healing. The experimental studies on healing of gastric ulcers that become supportive for the clinical trial in humans, performed also by Polish pioneers and the effect of numerous growth factors (EGF, TGF alpha), NO inhibitors, cyclooxygenase- (COX)-1 and COX-2 inhibitors and new safer derivatives of NSAID releasing NO in protection and ulcer healing are discussed. Finally, the major discovery by Warren and Marshall of H. pylori that have been studied world-wide in experimental animals including also Polish investigators, allowed for the better insight to the pathological consequences of this germ infection in the gastric mucosa and helped to establish the anti-H. pylori eradication therapy.

Aim: To investigate the expression and mutation of c-kit gene and its correlation with the clinical pathology and prognosis of gastrointestinal stromal tumors (GISTs)., Methods: A total of 94 cases of GISTs, 10 leiomyomas and 2 schwannomas were studied for the expression of KIT by immunohistochemistry. The c-kit gene mutations in exon 11 of these specimens were detected by PCR-SSCP technique., Results: Of the 94 cases of GISTs, 91 (96.8%) expressed the KIT protein. Leiomyomas and schwannomas were negative for KIT. The c-kit gene mutations of exon 11 were found in 38 out of the 94 cases of GISTs (40.4%). The mutations involved point mutations (Val560-Asp, Ile563-Met), del 557-559 and 579ins12. No mutations were detectable in benign GISTs, leiomyomas or schwannomas. The patients with mutation-positive GISTs showed more frequent recurrences, invasion and metastasis in adjacent tissues than those with mutation-negative ones., Conclusion: KIT is a useful marker for diagnosis of GISTs. Mutation of the c-kit gene may play a significant role in the pathogenesis of GISTs and may be associated with poor prognosis in patients with GISTs.

Topics discussed here include PTEN mutations and colonic polyps; WNT signaling, APC, beta-catenin, and gastrointestinal neoplasms; mismatch-repair genes (MLH1, MSH2, PMS1, MSH6) and hereditary nonpolyposis colorectal cancer; MYH mutations and autosomal recessive colorectal tumors; STK11 mutations and Peutz-Jeghers syndrome; TGFbeta and gastrointestinal cancer; BMPR1A mutations and juvenile polyposis; FGF/FGFR alterations in gastrointestinal neoplasms; PTCH mutations and gastrointestinal neoplasms; RUNX3 expression and gastric cancer; role of mucins in gastric carcinogenesis; KIT, PDGFRalpha, and gastrointestinal stromal tumors; intestinal neurofibromatosis; and gastrointestinal tumors in other disorders., (Copyright 2003 Wiley-Liss, Inc.)

Background: Gastrointestinal cancers belong to the most important causes of cancer death in the Western world. Because cure can be achieved only by complete surgical removal of the tumor, and most patients have metastasis at the time point of diagnosis, the majority of patients receive chemotherapy., Discussion: Indications for chemotherapy are either the prevention of recurrence after tumor resection (neoadjuvant or adjuvant) or palliative treatment if the tumor is already widespread at diagnosis. Although gastrointestinal cancers often respond to primary treatment, the long-term results are disappointing. This is attributable to a variety of cellular resistance mechanisms, namely: (a) kinetic resistance due to slow growth rates that preclude the use of topoisomerase IIalpha inhibitors and related drugs; (b) genetic resistance due to mutations, for example, in the p53 gene, which impede the sensing of DNA damage and obstruct apoptotic pathways; (d) pharmacokinetic resistance, due to an excess of target proteins, inadequate drug metabolism, administration period, time or drug interactions; and (d) biological resistance due to tumor-induced environmental changes. These factors interfere specifically with the molecular mode of action of standard drugs used in the therapy of gastrointestinal cancers., Conclusion: Awareness of the various causes of drug resistance may help to devise individual tumor-adapted treatment designs. Notably, nonsteroidal antiphogistics may delay carcinogenesis, anticoagulants may increase the vulnerability of circulating tumor cells and reduce the nesting abilities of single tumor cells, inhibitors of angiogenesis may quell the growth of micrometastases, and kinase inhibitors may be administered as sensitizers to cytotoxic treatment.

Although their overall incidence is uncommon, gastrointestinal stromal tumors (GIST) are the most frequently encountered mesenchymal tumors of the GI tract. Their pathology has been recently defined by the presence of KIT (transmembrane receptor tyrosine kinase). The majority of GISTs have c-kit gain-of-function mutations mainly in exon 11 (highly conserved juxtamembrane region) that eventuates in constitutive activation of KIT, promoting proliferation and antiapoptotic signaling. Imatinib mesylate (Gleevec) is a specific inhibitor of KIT kinase activation, and in phase II clinical trials has proven to be remarkably efficacious in heavily pretreated GIST patients with advanced disease. The molecular and genomic determinants of response/resistance patterns are the subject of ongoing studies, and adjuvant studies are also under way. The initial evaluations of imatinib provide proof of concept for the hypothesis-driven design of selective molecularly targeted therapies for solid tumor malignancies.

Neuroendocrine tumor (NET) cells express several voltage-operated Ca2+ channels (VOCCs). To address the question, if clinically distinct entities of NETs could be associated by specific patterns of VOCC expression, electrophysiological properties of NET primary cultures derived from consecutive surgical resections and permanent NET cell cultures were determined and analyzed by a color-coding contour diagram method. Using whole-cell patch-clamp technique, electrophysiological data were obtained from human pancreatic (foregut) BON and mouse intestinal (midgut) STC-1 cells as well as from human primary cultivated NET cells from fore- and midgut tumors or liver metastasis. To describe definite Ca2+ channel characteristics, we suggested a color-coding method to depict the contours of time- and voltage-dependence. In this study, we could demonstrate specific Ca2+ channel properties in NET cells from midgut tumors which were not found in NET cells from foregut location. This may be important functionally in respect of different cell biological functions of NET cells such as release of bioamines and neuropeptides. In addition, definite differences between the effect of specific and unspecific Ca2+ channel modulators on NET cells were detected. Although most of this information can be obtained by superimposing current-voltage curves at different times after the onset of the voltage step, the color-coding contour diagrams clearly provides a better visual summary, and hence might be generally quite useful.

The hedgehog (Hh) signaling pathway plays many roles in invertebrate and vertebrate development. For example, specific inhibition of sonic Hh expression is critical during early stages of pancreas organogenesis, but an active Hh pathway appears to be required for maintenance of adult endocrine functions. Mutational inactivation of the Hh pathway has been demonstrated in human malignancies of the skin, cerebellum, and skeletal muscle. Now, two papers implicate aberrant Hh signaling in human upper gastrointestinal cancers including those developing from the esophagus, stomach, biliary tract, and pancreas.

Peroxisome prolixferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Although previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of several types of tumor cells, the precise mechanism still remains obscure. The present study was designed to examine the effects of PPARgamma/RXRalpha transcriptional activation on cell growth in cancer cells. We compared the effects of six types of TZDs (troglitazone, RS-1303, RS-1330, RS-1387, RS-1455, and RS-1456) and 9-cis RA, an RXRalpha ligand, on the activation of PPARgamma/RXRalpha and the growth inhibition of six types of adenocarcinoma cell lines (MKN45, HT-29, HCT116, HuCCT1, KMP-2, and BxPC3) established from abdominal malignancies. PPARgamma was expressed in all six tumor cell lines and transcriptionally functional in five of the six lines. The stronger PPARgamma activator showed the stronger growth inhibitor in these five cell lines. However, no significant growth inhibitory effect of six types of PPARgamma activators was observed in BxPC3 cells, which showed no significant PPARgamma transactivation by these activators. Simultaneous addition of troglitazone and 9-cis RA enhanced both activation of PPARgamma/RXRalpha and growth inhibition in several types of cancer cells. The degree of PPARgamma/RXRalpha activation correlated with the extent of growth inhibition (r > 0.70, P < 0.05). This growth inhibition was associated with G1 cell cycle arrest and cell differentiation. These findings suggest that activation of the PPARgamma/RXRalpha pathway plays an important role in the growth inhibition of tumor cells and that this nuclear hormone receptor may be a possible novel molecular target for treatment of tumors in humans.

The past decade has seen major advances in the pharmacological understanding of the nervous system of the gastrointestinal tract, the enteric nervous system, and its importance for gut functions in several states of disease. Indeed, the enteric nervous system has become a promising target in the treatment of many gastrointestinal symptoms and disorders. Some of these new therapeutic concepts, such as botulinum toxin for achalasia and serotonergic drugs for functional bowel diseases, are already in clinical use. This paper is part 3 of three Minireviews in Pharmacology & Toxicology, and presents the neurogastrointestinal pharmacological therapeutic options in gastrointestinal pain, functional gastrointestinal disorders, inflammatory bowel diseases, cancer and related conditions with focus on future drug targets. The diagnosis of gastrointestinal neuropathy, the role of serotonin and related neuroendocrine transmitters, serotonergic drugs, and neurotrophic factors in neurogastrointestinal pharmacology will be addressed in this context.

Objective: Bioelectrical impedance vector analysis allows non-invasive evaluation of soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements., Methods: Whole-body impedance measurements were made with a single frequency (50 kHz) analyzer (BIA-101, Akern/RJL Systems) in 148 adult, white, male subjects 45 to 85 y old: 56 healthy control subjects, 31 cancer patients after surgical procedure (without disease), and 61 patients with locally advanced (30 patients) or disseminated (31 patients) disease with the same body mass index and age. All patients were free from antineoplastic treatment and active nutritional intervention., Results: Mean vectors of cancer groups without disease and locally advance disease versus the control group were characterized by a comparable normalized resistance component with a reduced reactance component (separate 95% confidence limits, P < 0.05), indicating a comparable ionic conduction (hydration) with loss of dielectric mass (cell membranes and tissue interfaces) of soft tissues. Overlapping 95% confidence limits of their mean vectors indicated comparable electrical tissue properties in less versus more advanced disease., Conclusion: Monitoring vector displacement trajectory toward the reference target vector position may represent useful feedback in support therapy planning of individual patients.

A number of studies have shown that catastrophizing is an important predictor of pain and disability in persons having persistent pain conditions. The newly developed communal model of catastrophizing maintains that catastrophizing is a part of broader, interpersonal style of coping in which coping efforts are directed at interpersonal goals, rather than solely at pain reduction. This study examined the potential interpersonal correlates of pain catastrophizing in a sample of 70 patients having gastrointestinal cancers and their caregivers. Measures of pain catastrophizing, perceptions of social support, pain level, and pain behavior were obtained from patients. Caregivers completed measures that included their judgments about the patient's pain level, caregiver stress, and their tendency to engage in negative responses (critical or avoidant behaviors). Overall, patients who engaged in catastrophizing reported receiving higher levels of instrumental support. Caregivers of patients who catastrophized, rated the patient as having more pain and engaging in more pain behavior. Caregivers of patients who catastrophized, also reported higher levels of caregiver stress and critical behaviors. Taken together, these preliminary findings suggest that pain catastrophizing has interpersonal correlates and support the need for additional research examining the social context of pain catastrophizing.

Impedance measurement is a promising technique for detecting pre-malignant changes in epithelial tissue. This paper considers how the design of the impedance probe affects the ability to discriminate between tissue types. To do this, finite element models of the electrical properties of squamous and glandular columnar epithelia have been used. The glandular tissue model is described here for the first time. Glandular mucosa is found in many regions of the gastrointestinal tract, such as the stomach and intestine, and has a large effective surface area. Firstly, the electrical properties of a small section of gland, with epithelial cells and supportive tissue, are determined. These properties are then used to build up a three-dimensional model of a whole section of mucosa containing many thousands of glands. Measurements using different types of impedance probe were simulated by applying different boundary conditions to the models. Transepithelial impedance, and tetrapolar measurement with a probe placed on the tissue surface have been modelled. In the latter case, the impedance can be affected by conductive fluid, such as mucus, on the tissue surface. This effect has been investigated, and a new design of probe, which uses a guard electrode to counteract this potential source of variability, is proposed.

Purpose of Review: The subject of gastrointestinal disorders in the elderly is timely and important because of the demographic reality that soon over 20% of our population will be older than 65 years of age, utilizing perhaps 50% of our total healthcare costs. The purpose of this review is to draw attention to some areas of clinical information that point in the direction of better clinical care for the elderly. Medicine is finally advancing from the era when most symptoms in older patients were ascribed to the aging process itself. Indeed, within gastroenterology there are few changes that occur inevitably as part of aging., Recent Findings: Progress has been made in several areas of gastrointestinal pathophysiology. These include: the pathophysiology of swallowing and evacuation disorders and the beginning of the application of techniques derived from physiological studies to improve function; recognizing the importance of reflux esophagitis and its complications and improving treatment; understanding the importance of disorders of malabsorption and their impact upon nutrition in the elderly; major issues in the diagnosis and management of inflammatory bowel disease in this age group; and approaches to the prevention and treatment of gastrointestinal cancer, particularly colorectal cancer., Summary: As we pay more attention to these areas and encourage clinical research we expect to improve the treatment of older patients with these diseases and to reduce the burden of morbidity in this population.

The mucin family has been under study by molecular biologists, biochemists, pathologists and immunologists interested in cancer because of the role these molecules can play in the diagnosis and treatment of cancer. Immense knowledge has been accumulated, but the high speed of progress in the laboratory has not been matched by the progress towards applying this knowledge in the clinic. For example, specific knowledge of cancer-associated changes in the expression and glycosylation of various mucins, which can aid in the diagnosis as well as prognosis of GI cancers, has not yet led to the use of a panel of anti-mucin antibodies as a standard diagnostic tool. Similarly, many more opportunities exist for using mucin-based therapies than are currently being considered in the clinic. This chapter aimed to highlight some of these opportunities and to interest clinician scientists in exploring them in the near future.

Anastomotic leakage after visceral surgery is one of the most important and feared complication. According to the literature the rate of clinically apparent anastomotic leakage ranges from 3.4% to as high as 12% and at least one third of the mortality after colorectal surgery is attributed to leaks at the anastomotic site. Within this context, knowledge of factors influencing anastomotic healing appears even more important. Beside surgical-technical (suture technique, suture material) and surgical-tactical factors (primary anastomosis vs. discontinuity resection or formation of protective diverting stomas) knowledge of the various endogenous (diabetes, sepsis, infection, malnutrition) and exogenous factors (steroids, radiation, preoperative bowel preparation) influencing anastomotic healing is essential. Recently, it has been demonstrated that Mycophenolate mofetil, an immunosuppressive drug that is currently used in transplantation and in chronic inflammatory diseases significantly impairs mechanical stability of the healing anastomosis. In contrary, local application of keratinocyte growth factor (KGF) as well as insulin-like growth factor-I (IGF-I) have been shown to accelerate and improve anastomotic healing and mechanical stability in an animal model. Studies that will identify further factors and drugs influencing anastomotic healing are of great importance since the use of such drugs could have enormous clinical implications. The traditional use of temporary diverting stomas following operations such as coloanal anastomosis or ileopouch anastomosis as well as Hartmann's discontinuity resection could be eliminated even in immunocompromised or other high risk patients.

DNA methylation of the 5' region of genes is often associated with gene silencing in X-chromosome inactivation and imprinting. Recent studies have indicated that altered DNA methylation plays a role in the inactivation of multiple tumor suppressor genes and DNA repair genes such as p16INK4A and hMLH1. Colorectal adenomas have a relatively high frequency of methylation, and aberrant methylation is an early event during tumorigenesis. In aging patients, even colon epithelium which appears to be normal showed a significant amount of methylation in a subset of the genes. Colon mucosa from patients with inflammatory bowel disease also showed a high level of methylation. DNA methylation can be a specific diagnostic marker in gastrointestinal cancer and inflammatory bowel disease, for which there is no perfect marker for a noninvasive diagnosis.

Background: Chemotherapy is frequently used for palliation in patients with advanced gastrointestinal (GI) cancer and improvements in quality of life (QoL) and survival are documented. Several pre-treatment factors, particularly poor performance status, influence the outcomes. The relative importance of nutrition-associated factors is less well known., Patients and Methods: Data from 152 patients treated within four randomised studies were analysed to explore the relations between weight loss, nutrition-associated parameters, performance status, response to chemotherapy, global QoL and survival., Results: Patients with weight loss, poor performance, higher frequency of nutritional problems and low haemoglobin levels had a lower probability of responding to treatment. Global QoL was decreased in patients having weight loss as well as problems with pain or fatigue. Diagnosis had the strongest association to survival. In a multivariate analysis poor performance and weight loss were also independently related to survival., Conclusion: Weight loss and several nutrition-associated problems were associated with lower QoL, less likelihood to respond to chemotherapy and poor survival.

This article discusses how staff development educators can conduct an innovative class for nurses caring for patients with gastrointestinal cancer. The nurse's role in caring for these patients includes knowledge of the pathophysiology, risk factors, detection methods, signs and symptoms, treatments, conventional and integrative holistic nursing interventions, and community resources. However, consideration should be given to the total learning experience rather than technical skills alone.

Though new agents have recently been approved for the treatment of gastrointestinal malignancies, cure rates remain low and survival times of patients short. Because of these discouraging numbers, there is a vigorous search for new agents and new strategies. This article reviews some of these strategies and the status of agents in clinical development. Though an exhaustive search is impossible and the field is changing so rapidly, the agents selected here for discussion may be considered representative of others. Discussed here are agents targeting the vascular endothelial growth factor as an example of an angiogenesis inhibitor, and agents targeting the epidermal growth factor receptor, the ras oncogene, and the immune system.

The aims of this study were to investigate 'satisfaction with care' and its possible relationships to hope, health-related quality of life, anxiety and depression. Eighty-five patients with endocrine gastrointestinal (GI) tumours responded to questionnaires a few days after a hospital visit. 'Satisfaction with care' was assessed by the Comprehensive Assessment of Satisfaction with Care (CASC), health-related quality of life by the EORTC QLQ C-30 and anxiety and depression by the Hospital Anxiety and Depression Scale (HADS). Patients' highest satisfaction scores were obtained for 'general satisfaction' and 'nurses' and doctors' technical skills'. The lowest satisfaction was expressed for 'doctors' interpersonal skills', 'nurses' communication skills' and 'care organization'. Patients reporting a clinically relevant level of anxiety were less satisfied with several care aspects than those reporting less anxiety. Satisfaction with 'nurses' communication skills' and 'doctors' interpersonal skills' was associated with several aspects of health-related quality of life, whereas satisfaction with 'doctors' information', 'nurses' technical skills' and 'general satisfaction' was not. Satisfaction with psychosocial aspects of care is related to the psychosocial function of patients with endocrine GI tumours.

Background: A regional initiative, called the 'three-day rule', has recently been introduced in Italy to facilitate the earlier diagnosis of malignancy. It requires patients with suspected severe diseases to have a diagnostic procedure performed within three working days of referral by a general practitioner., Aim: To assess prospectively the effectiveness and compliance with the three-day rule for upper digestive malignancies., Methods: We compared patients referred for gastroscopy under the three-day rule initiative with contemporaneous open access referrals over a 12-month period at a single large teaching hospital in west Milan. We compared the prevalence of malignancies and other serious non-neoplastic diseases as well as the waiting times in the two groups. The appropriateness of the indications for each referral was also reviewed by a gastroenterologist blind to the outcome of the test., Results: One hundred and forty-two patients referred for gastroscopy under the three-day rule scheme and 767 routine referrals were studied. Significantly more oesophageal/gastric cancers (6% vs. 1%) and serious benign gastrointestinal lesions (grade II-III oesophagitis or peptic ulcer) were diagnosed in three-day rule patients in comparison with routine referrals (P < 0.05). The rate of inappropriate referral was significantly lower in the three-day rule group than in the open access group (39% vs. 22%) (P < 0.01). The estimated cost of the three-day rule scheme (in extra list examinations alone) was 10 780 euros, with about 1198 euros per diagnosis of cancer, but only 229.5 euros per 'useful' diagnosis (including peptic ulcer disease and oesophagitis)., Conclusions: Significantly more upper gastrointestinal cancers and serious benign diseases can be found within a short period to comply with the three-day rule scheme. However, some general practitioners appear to over-interpret alarm symptoms, leading to some inappropriate referrals. Better awareness of appropriate urgent referral criteria is needed in order to ensure that the best use is made of the resources available.

Epidemiological studies suggest that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of and mortality from colorectal, gastric, and esophageal cancers. The precise mechanisms by which NSAIDs exert their chemopreventive effects are not fully explained, but likely involve inhibition of cyclo-oxygenase, the enzyme that converts arachidonic acid to prostaglandins. Two isoforms of this enzyme, cyclo-oxygenase 1 (COX-1) and COX-2, have been identified. COX-2 is absent in normal mucosa but is overexpressed in colonic, gastric, and esophageal cancers, as well as their precursor lesions. The inhibition of COX-2 through either pharmacological agents or gene deletion results in suppression of colonic polyp formation. NSAIDs reduce colonic, gastric, and esophageal cancer cell growth, in part, by inducing apoptosis. However, the antineoplastic effects of NSAIDs may be partly independent of their ability to inhibit COX-2. The mechanisms involved in the antineoplastic actions of NSAIDs include inhibition of angiogenesis (essential for delivery of oxygen and nutrients to a growing tumor), induction of apoptosis (which is usually reduced in cancer cells) by stimulation of proapoptotic genes, and direct inhibition of cancer cell growth by blocking signal transduction pathways responsible for cell proliferation.

The mitochondrial uncoupling proteins-2 and -3 are putative mediators of thermogenesis and energy expenditure. We measured the mRNA levels of uncoupling proteins-2 and -3 in skeletal muscle from 12 gastrointestinal adenocarcinoma patients, of whom six had stable weight and six had lost 2-18 kg, and from six healthy controls undergoing elective surgery. Uncoupling proteins-3 mRNA levels were significantly higher in the muscle of the cancer patients with weight loss (2.2 +/- 0.47 arbitrary units) compared both with controls (0.39 +/- 0.20) and with cancer patients who had not lost weight (0.47 +/- 0.23; P<0.02). Uncoupling proteins-2 mRNA levels did not differ significantly between groups. Elevations in muscle uncoupling proteins-3 activity may enhance energy expenditure and this in turn could contribute to tissue catabolism., (Copyright 2002 The Cancer Research Campaign)

Background: Recent studies have shown that cyclooxygenase-2 (COX-2) inhibitors may participate in the proliferation of cancer cells. Because the cadherin-catenin complex is not only a key component of the adherens junction but also has been suggested to regulate cell proliferation, modulation of these molecules may be a mechanism by which COX-2 activity affects cell proliferation. In this study, we evaluated the effect of a COX-2 inhibitor on the proliferation and expression of E-cadherin-complexes in gastrointestinal cancer cell lines., Methods: The gastrointestinal cancer cell lines Caco2, HT29, and MKN45 were grown for 24 h in the presence and absence of a selective COX-2 inhibitor, etodolac (10(-5), 10(-4), and 10(-3) M). Cell proliferation was assessed by (3)H-thymidine incorporation, and the expression of E-cadherin and catenins was assessed by Western blotting, Northern blotting, and immunofluorescence., Results: Etodolac induced a significant reduction in cell proliferation in Caco2 and MKN45 cells. E-cadherin expression was upregulated after stimulation with etodolac in Caco2 cells, whereas the expression of alpha-, beta-, gamma- and p120-catenins was not modified. The expression of E-cadherin mRNA was also upregulated in Caco2 cells, and was upregulated also in MKN45 cells, which did not express normal E-cadherin protein by the use of a mouse monoclonal antibody against human E-cadherin, HECD-1 antibody. Immunofluorescence revealed that the increased E-cadherin was localized at the cytoplasmic membrane., Conclusions: The inhibition of cell growth by etodolac in Caco-2 cells was associated with a dose-dependent upregulation and intense cytoplasmic localization of E-cadherin. No quantitative change in catenin expression was found in this phenomenon. These findings suggest that the COX-2 inhibitor affects the transcription of E-cadherin, or that there may be some homeostatic link between the cell cycle and E-cadherin transcription.