Search

Introduction: In patients with gastrointestinal (GI) cancer, severe malnutrition is associated with increased morbidity and mortality, reduction of treatment efficacy, and increased length of hospital stay. Therefore, systematic screening and care of malnutrition is mandatory., Materials and Methods: Data for this review were identified by searches of Medline with and without MeSH database and Cancerlit. Studies were selected only if they were randomised clinical trials or historical reports. References were also identified from reference lists in relevant previously published articles. Recent guidelines and meta-analyses were included. Only articles published in English were taken into consideration., Results: For surgical patients, practical information such as weight loss or subjective global assessment would provide a better basis for deciding whether or not to delay surgery. At least 10 days of nutritional support is recommended in severely malnourished patients before major digestive surgery. In non-severely malnourished patients, preoperative oral immunonutrition is associated with a 50% decrease in postoperative complications. The benefit of immune-enhancing diets in severely malnourished patients remains to be proven. For patients undergoing radiochemotherapy, dietary counselling should be proposed to all patients. In cases of severely malnourished patients or if dietary counselling suffers a setback, enteral nutrition should be recommended. Parenteral nutrition should be reserved for patients with severe digestive intolerance when enteral nutrition is not possible., Conclusion: Propose an adaptive nutritional support at each step of a multimodal GI oncological treatment is essential. These recommendations should be used in daily practice but should also be included in all clinical research protocols.

Clinical manifestations of gastrointestinal (GI) involvement in multiple myeloma (MM) are uncommon. We report a case of plasmacytoma presenting as upper GI bleeding in a patient with a known diagnosis of MM. Gastrointestinal bleeding persists despite aggressive medical and endoscopic treatment. The aim of our report is to heighten the awareness of plasmacytoma as an etiology of GI bleeding in patients with MM. Abnormal hemostasis, specifically the imbalance in function of all major components of the coagulation cascade, increasing bleeding risk in patients with MM, is also discussed.

Epithelial-mesenchymal transition (EMT) is a highly conserved process that has been well characterised in embryogenesis. Studies have shown that the aberrant activation of EMT in adult epithelia can promote tumour metastasis by repressing cell adhesion molecules, including epithelial (E)-cadherin. Reduced intracellular adhesion may allow tumour cells to disseminate and spread throughout the body. A number of transcription proteins of the Snail superfamily have been implicated in EMT. These proteins have been shown to be over-expressed in advanced gastrointestinal (GI) tumours including oesophageal adenocarcinomas, colorectal carcinomas, gastric and pancreatic cancers, with a concomitant reduction in the expression of E-cadherin. Regulators of EMT may provide novel clinical targets to detect GI cancers early, so that cancers previously associated with a poor prognosis such as pancreatic cancer can be diagnosed before they become inoperable. Furthermore, pharmacological therapies designed to inhibit these proteins will aim to prevent local and distant tumour invasion.

Gastrointestinal carcinoid tumors arise from cells of the diffuse neuroendocrine system localized in the digestive trace and represent more than 70% of all carcinoid tumors in humans. The present article reviews the following topics: 1) The biological profile of these tumors (histopathology, cytokine markers, metabolic alterations, storage of neuroamines and hormonal proteins, cytodynamic behavior, and biological behavior according to embryological origin). 2) The etiological circumstances (exceptional hereditary factors, association of gastric carcinoid tumors with autoimmune gastritis, little-known exogenous factors). 3) Pathogenic aspects (persistent mitogenesis of endocrine cells associated with hypergastrinemia, inactivation of some putative tumor suppressor genes, the doubtful participation of oncogenes, autocrine action of some cellular growth-stimulating proteins). 4) The repercussions of certain physiopathological events (peritumoral desmoplastic reaction causing the "mass effect" on the digestive tube, the "kidnapping" of dietary tryptophan by tumoral cells toward an abnormal metabolic pathway; the easy metastatic dissemination coexisting with low tumoral aggressivity, and the release into the bloodstream of stored secretory products leading to "carcinoid syndrome" and some endocrine hyperfunction syndromes. Finally, it should be remembered that gastrointestinal carcinoid tumors represent only a proportion of the neoplasms classified as neuroendocrine tumors.

Opinion Statement: The management of malignant ascites is a significant challenge in gastrointestinal medical oncology. Current treatment strategies include diuretic therapy, paracentesis, peritoneal drains, and venous shunts. However, there are no established evidence-based guidelines, and there is a lack of randomized controlled trials identifying optimal therapy. Newer therapies are emerging and will need further study. By summarizing published studies, this review is intended to add some clarity to currently available strategies for the management of malignant ascites associated with hepatobiliary cancers. Notably, however, much of the available data for the management of malignant ascites comes from the gynecologic oncology experience, specifically from studies in ovarian cancer. Therefore, successful approaches used in this malignancy may be lead candidates for development in hepatobiliary cancer-associated ascites and are reviewed in this paper.

Incorporating spatial variation could potentially enhance information coming from survival data. In addition, simultaneous (joint) modeling of time-to-event data from different diseases, such as cancers, from the same patient could provide useful insights as to how these diseases behave together. This paper proposes Bayesian hierarchical survival models for capturing spatial correlations within the proportional hazards (PH) and proportional odds (PO) frameworks. Parametric (Weibull for the PH and log-logistic for the PO) models were used for the baseline distribution while spatial correlation is introduced in the form of county-cancer-level frailties. We illustrate with data from the Surveillance Epidemiology and End Results database of the National Cancer Institute on patients in Iowa diagnosed with multiple gastrointestinal cancers. Model checking and comparison among competing models were performed and some implementation issues were presented. We recommend the use of the spatial PH model for this data set., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Metastasis is the principal cause of cancer mortality, with the lymphatic system being the first route of tumor dissemination. The glycoproteins VEGF-C and VEGF-D are members of the vascular endothelial growth factor (VEGF) family, whose role has been recently recognized as lymphatic system regulators during embryogenesis and in pathological processes such as inflammation, lymphatic system disorders and malignant tumor metastasis. They are ligands for the VEGFR-3 receptor on the membrane of the lymphatic endothelial cell, resulting in dilatation of existing lymphatic vessels as well as in vegetation of new ones (lymphangiogenesis). Their determination is feasible in the circulating blood by immunoabsorption and in the tissue specimen by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Experimental and clinicopathological studies have linked the VEGF-C, VEGF-D/VEGFR3 axis to lymphatic spread as well as to the clinical outcome in several human solid tumors. The majority of these data are derived from surgical specimens and malignant cell series, rendering their clinical application questionable, due to subjectivity factors and post-treatment quantification. In an effort to overcome these drawbacks, an alternative method of immunodetection of the circulating levels of these molecules has been used in studies on gastric, esophageal and colorectal cancer. Their results denote that quantification of VEGF-C and VEGF-D in blood samples could serve as lymph node metastasis predictive biomarkers and contribute to preoperative staging of gastrointestinal malignancies.

Even after receiving analgesia, patients with gastric and liver cancer still report moderate levels of postoperative pain. The purpose of the study was to investigate the efficacy of foot reflexotherapy as adjuvant therapy in relieving pain and anxiety in postoperative patients with gastric cancer and hepatocellular cancer. The study design was a randomized controlled trial. Data were collected from 4 surgical wards of a medical center in 2005 in Taipei, Taiwan. Sixty-one patients who had received surgery for gastric cancer or hepatocellular carcinoma were randomly allocated to an intervention (n = 30) or control (n = 31) group. Patients in the intervention group received the usual pain management plus 20 minutes of foot reflexotherapy during postoperative days 2, 3, and 4. Patients in the control group received usual pain management. Outcome measures included the short-form McGill Pain Questionnaire, visual analog scale for pain, summary of the pain medications consumed, and the Hospital Anxiety and Depression Scale. Results demonstrated that studied patients reported moderately high levels of pain and anxiety postoperatively while patients were managed with patient-controlled analgesia. Using generalized estimation equations and controlling for confounding variables, less pain (P < .05) and anxiety (P < .05) over time were reported by the intervention group compared with the control group. In addition, patients in the intervention group received significantly less opioid analgesics than the control group (P < .05). Findings from this study provide nurses with an additional treatment to offer postoperative digestive cancer patients.

CD24 was first described in the early 1980s and only attributed to scattered publications, referred to as a cell surface molecule in hematopoiesis. Recently, studies are accumulating to show that CD24 conveys a function in cell-to-cell interaction and regulation of proliferation and adhesion. CD24 appears to be highly expressed in a large variety of human cancers and to contribute to the acceleration of tumor growth and metastases shedding by binding to platelet (P)-selectin, L1 and by evoking--to date unknown--intracellular signal pathways. Anti-CD24 monoclonal antibodies thus act as a promising cancer treatment as was shown in the setting of gastrointestinal cancers. Recent articles also correlate CD24 expression with the identification of 'tumor stem cells'.

Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

Yin-Deficiency (YD), representing a status of the human body under lack of nutrition and fluid in traditional Chinese medicine, is commonly seen in late stage of cancer patients. It is not known whether the severity of YD related symptoms/signs can predict the survival rate of cancer patients. This study evaluated the distribution of Yin-deficiency symptoms/signs (YDS) in cancer patients with YD, and investigated whether the severity of YDS can predict the survival rate of cancer patients with YD. From 5 January 2007 to 5 May 2007, we selected 43 cancer patients with diagnosis of YD from hospitalized patients and outpatients. The severity of YD was evaluated by a questionnaire. We further estimated the cumulative probabilities of the survival rates over 4 months since the start of study by the Kaplan-Meier product-limit method, and compared the differences among groups with various severities in each symptom/sign with the use of the log-rank test. The results revealed that, the 3 most common YDS were sleeplessness with annoyance, less or non-coated tongue with or without redness and dry mouth. In the survival rate analysis, only 2 parameters, rapidly small pulse (p = 0.002) and less-or non-coated tongue with paleness (p = 0.017), were found to be related to the decrease of cancer patients with YD. This suggests that, both rapidly small pulse and less-or non-coated tongue without redness may be used as predictors for the estimation of survival rate in cancer patients with YD.

Objective: Proinflammatory cytokines are involved in cancer-related weight loss, but the involvement of VEGF-A, VEGF-C, IL-8 and midkine in gastroesophageal cancer patients remains unknown., Design and Methods: Serum IL-1, IL-6, IL-8, TNF-alpha, VEGF-A, VEGF-C, and midkine were evaluated in 96 cancer patients and 42 controls using ELISAs and were related to the occurrence of weight loss, patient's age, gender and BMI, cancer TNM status and blood cell counts., Results: All cytokines were elevated in cancer patients with further up-regulation of IL-6, IL-8, midkine and VEGF-A in cachexia. Underweight, midkine and VEGF-A were found independent indicators of weight loss. Primary tumor seems to be a major source of pro-cachectic cytokines, yet neutrophils and platelets also contribute to cytokine elevation., Conclusions: IL-6 and IL-8, and probably midkine and VEGF-A, appear to participate in the development of cancer-related cachexia in gastroesophageal malignancies, although a detailed mechanism underlying cytokine involvement needs to be elucidated.

Novel molecular targets are being discovered as we learn more about the aberrant processes underlying various cancers. Efforts to translate this knowledge are starting to impact on the care of patients with gastrointestinal cancers. The epidermal growth factor receptor (EGFR) pathway and angiogenesis have been targeted successfully in colorectal cancer with cetuximab, panitunumab and bevacizumab. Similarly, EGFR-targeting with erlotinib yielded significant survival benefit in pancreatic cancer when combined with gemcitabine. The multi-targeting approach with sorafenib has made it the first agent to achieve significant survival benefit in hepatocellular carcinoma. Efforts to exploit the dysregulated Akt/mTOR pathway in GI cancer therapy are ongoing. These molecular targets can be disrupted by various approaches, including the use of monoclonal antibody to intercept extracellular ligands and disrupt receptor-ligand binding, and small molecule inhibitors that interrupt the activation of intracellular kinases.

The Hedgehog family of secreted morphogenetic proteins acts through a complex evolutionary conserved signaling pathway to regulate patterning events during development and in the adult organism. In this review I discuss the role of Hedgehog signaling in the development, postnatal maintenance, and carcinogenesis of the gastrointestinal tract. Three mammalian hedgehog genes, sonic hedgehog (Shh), indian hedgehog (Ihh), and desert hedgehog (Dhh) have been identified. Shh and Ihh are important endodermal signals in the endodermal-mesodermal cross-talk that patterns the developing gut tube along different axes. Mutations in Shh, Ihh, and downstream signaling molecules lead to a variety of gross malformations of the murine gastrointestinal tract including esophageal atresia, tracheoesophageal fistula, annular pancreas, midgut malrotation, and duodenal and anal atresia. These congenital malformations are also found in varying constellations in humans, suggesting a possible role for defective Hedgehog signaling in these patients. In the adult, Hedgehog signaling regulates homeostasis in several endoderm-derived epithelia, for example, the stomach, intestine, and pancreas. Finally, growth of carcinomas of the proximal gastrointestinal tract such as esophageal, gastric, biliary duct, and pancreatic cancers may depend on Hedgehog signaling offering a potential avenue for novel therapy for these aggressive cancers.

The hamartomatous polyposis syndromes are a heterogeneous group of disorders that share an autosomal-dominant pattern of inheritance and are characterized by hamartomatous polyps of the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome and the PTEN hamartoma tumor syndrome. The frequency and location of the polyps vary considerably among syndromes, as does the affected patient's predisposition to the development of gastrointestinal and other malignancies. Although the syndromes are uncommon, it is important for the clinician to recognize these disorders because they are associated with considerable morbidity and mortality, not only from malignancy but also from nonmalignant manifestations such as bleeding, intussusception, and bowel obstruction. Each hamartomatous polyposis syndrome has its own distinctive organ-specific manifestations and each requires a different surveillance strategy, which makes accurate diagnosis crucial for appropriate patient management. The availability of clinical genetic testing for these disorders means that appropriate recognition allows for timely referral for cancer genetic counseling, and often allows for predicative testing in at-risk family members. Promisingly, an understanding of the molecular pathogenesis of these disorders offers insights into the mechanisms underlying the development of sporadic malignancy, and enables rational selection of targeted therapies that warrant further investigation.

Aim: To assess the effects of poor nutritional and psychological status on tolerance of cancer treatment and the recovery of physical performance status in patients with gastrointestinal cancer., Methods: An epidemiological survey with respect to nutritional and psychological status in patients with gastrointestinal cancer was conducted among 182 operated patients in four provincial-level hospitals from December 2005 to June 2006. The food frequency survey method, state-trait anxiety inventory (STAI) and depression status inventory (DSI) were used to obtain information about the diet and psychological status in the patients. Nutritional status in the participants was reflected by serum albumin (Alb), hemoglobin (HB) and body mass index (BMI)., Results: Alb, protein intake and anxiety were associated with the severity of side effects of treatment. The adjusted relative risk (RR) for Alb, protein intake and anxiety was 3.30 (95% CI: 1.08, 10.10, P = 0.03), 3.25 (95% CI: 1.06, 9.90, P = 0.04) and 1.48 (95% CI: 1.29, 1.70, P < 0.0001), respectively. Moreover, calorie intake, HB and depression were associated with the recovery of physical performance status in the patients. Adjusted relative risk was 2.12 (95% CI: 1.09, 4.03, P = 0.028), 2.05 (95% CI: 1.08, 3.88, P = 0.026) and 1.07 (95% CI: 1.02, 1.12, P = 0.007), respectively., Conclusion: Both poor nutrition status and psychological status are independent risk factors for severe side effects of cancer treatment, and have impact on the recovery of physical performance status in patients after treatment.

Background: Symptomatic malignant ascites is a problem for patients with advanced intra-abdominal malignancy. Although the goal of paracentesis, the most common therapeutic intervention, is symptom palliation, the best method of assessing symptom improvement is unknown. The aim of this study was to assess the ability of existing symptom and quality-of-life questionnaires to detect change in symptoms after paracentesis., Methods: Patients with symptomatic ascites completed four questionnaires before and 24 hours after paracentesis. These tests were Edmonton Symptom Assessment System-Ascites Modification (ESAS:AM), Memorial Symptom Assessment Scale-Short Form, European Organization for the Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), and the EORTC Core Quality of Life Questionnaire, 26-item pancreatic cancer module (QLQ-PAN26). Sensitivity, validity, reliability, and responsiveness of the questionnaires were evaluated., Results: Sixty-one patients completed the baseline and 44 the follow-up questionnaire. Most patients had ovarian (41%) or gastrointestinal cancer (25%); Eastern Cooperative Oncology Group performance status was 2 (26%) and 3 (49%). Patients reported major symptoms at baseline; symptom scores were highest for the clinically recognized symptoms of ascites. Most patients (78%) reported that their symptoms improved after paracentesis. All questionnaires showed strong sensitivity, validity, and reliability. Subscales that included the most distressing symptoms were most responsive; great improvement was seen in abdominal bloating (42% to 54%), anorexia (20% to 37%), dyspnea (33% to 43%), insomnia (29% to 31%), fatigue (14% to 17%), and mobility (25%). The amount of fluid removed (median, 3.5 L; range, .3% to 9.7 L) did not correlate with symptom improvement (r = .29, P = -.10)., Conclusions: Paracentesis provides symptom relief that can be measured by existing questionnaires. For future clinical trials of symptomatic ascites, the QLQ-C30 and the ESAS:AM together, or the QLQ-C30 with the addition of the QLQ-PAN26 ascites and abdominal pain subscales could be used.

There is little objective data on how cancer and its therapy affect physical activity. The main aims of this pilot study were 1) to compare physical activity in patients receiving palliative chemotherapy and healthy controls, and 2) to explore the relationship between patients' activity, quality of life (QoL), and clinical performance status. A miniaturized electronic meter objectively recorded activity for one week in 20 patients with upper gastrointestinal cancer receiving palliative chemotherapy and in 13 age-matched healthy controls. Patients also completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; fatigue), and Functional Assessment of Anorexia and Cachexia Therapy (FAACT; anorexia/cachexia) quality-of-life questionnaires. The patients' median estimated total energy expenditure was 8% lower (P=0.0003), median time spent upright was approximately two hours/day less (P=0.0002), and median steps taken/day was 43% lower (P=0.002) than that of the control group. Neither estimated energy expenditure nor average steps taken/day correlated significantly with EORTC QLQ-C30 physical functioning, fatigue, or global health status/QoL. There was no correlation with the FAACT "Trial Outcome Index" (TOI), but the FACIT-F TOI and both estimated energy expenditure and the average steps taken/day correlated significantly (r=0.59, P=0.009 and r=0.59, P=0.008). It is concluded that patients receiving palliative chemotherapy were less active than healthy controls; however, the relationship between physical activity and QoL requires further characterization.

The World Health Organisation (WHO) classification (2000) is widely used to classify neuroendocrine carcinomas (NECs), yet its prognostic value needs to be confirmed. In this study, patients with metastatic NECs (n=119) were classified according to WHO guidelines into well differentiated and poorly differentiated (WDNECs and PDNECs). Histological differentiation based on WHO criteria had the highest impact on overall survival (OS) (PDNECs : WDNECs hazard ratio (HR)=4.02, P=0.02); however, PDNECs represented only a small percentage of patients (8%). In a WDNEC-restricted analysis, abnormal liver function tests (LFTs) and elevated urinary 5-hydroxyindoleacetic acid (u5HIAA) were independent prognostic factors for survival (HR=2.65, P=0.006 and HR=2.51, P=0.003, respectively) and were used to create a WDNEC-specific prognostic model (low risk=both normal, intermediate risk=one of them abnormal, high risk=both abnormal). Low-risk WDNECs had the most favourable prognosis (median OS, mOS 8.1 years), which was significantly better compared to both intermediate-risk and high-risk WDNECs (mOS 3.2 and 1.4 years, with P=0.01 and P<0.001, respectively). High-risk WDNECs displayed the shortest OS (1.3 years), which was similar to that of PDNECs (P=0.572). This analysis supports the prognostic value of WHO classification for metastatic NECs arising from the gastroenteropancreatic tract; however, risk stratification using readily available u5HIAA and LFTs may be necessary for the heterogeneous group of WDNECs.

Notch signaling is one of key pathways constituting the stem cell signaling network. DLL1, DLL3, DLL4, JAG1 and JAG2 with DSL domain are typical Notch ligands, while DNER, F3/Contactin and NB-3 without DSL domain are atypical Notch ligands. Notch-ligand binding to NOTCH1, NOTCH2, NOTCH3 or NOTCH4 receptor induces the receptor proteolysis by metalloprotease and gamma-secretase to release Notch intracellular domain (NICD). Typical Notch ligands transduce signals to the CSL-NICD-Mastermind complex for the maintenance of stem or progenitor (transit-amplifying) cells through transcriptional activation of HES1, HES5, HES7, HEY1, HEY2 and HEYL genes, and also to the NF-kappaB-NICD complex for the augmentation of NF-kappaB signaling. Atypical Notch ligands transduce signals to the CSL-NICD-Deltex complex for the differentiation of progenitor cells through MAG transcriptional activation. Notch signals are transduced to the canonical pathway (CSL-NICD-Mastermind signaling cascade) or the non-canonical pathway (NF-kappaB-NICD and CSL-NICD-Deltex signaling cascades) based on the expression profile of Notch ligands, Notch receptors, and Notch signaling modifiers. Canonical Notch signaling is activated in the stem or progenitor domain of gastrointestinal epithelium, such as basal layer in esophagus and lower part of the crypt in colon. Notch signaling to inhibit secretory cell differentiation is oncogenic in gastric cancer and colorectal cancer, while Notch signaling to promote keratinocyte differentiation is anti-oncogenic in esophageal squamous cell carcinoma (SCC). Single nucleotide polymorphism (SNP), epigenetic change, and genetic alteration of genes encoding Notch signaling-associated molecules will be utilized as biomarkers for gastrointestinal cancer. gamma-Secretase inhibitors, functioning as Notch signaling inhibitors, will be applied as anti-cancer drugs for gastric cancer and colorectal cancer.

Members of the receptor tyrosine kinase family, that include EGFR, ErbB-2/HER-2, ErbB-3/HER-3 and ErbB-4/HER-4, are frequently implicated in experimental models of epithelial cell neoplasia as well as in human cancers. Therefore, interference with the activation of these growth factor receptors represents a promising strategy for development of novel and selective anticancer therapies. Indeed, a number of inhibitors that target either EGFR or HER-2, with the exception of a few that target both; have been developed for treatment of epithelial cancers. Since most solid tumors express different ErbB receptors and/or their ligands, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. Here we describe the significance of an ErbB family of receptors in epithelial cancers, and summarize different available therapeutics targeting these receptors. It also emphasizes the need to develop pan-ErbB inhibitors and discusses EGF-Receptor Related Protein, a recently isolated negative regulator of EGFR as a potential pan-ErbB therapeutic for a wide variety of epithelial cancers.

Aim: To investigate the role of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and 2 in the growth and differentiation of gastrointestinal stromal tumors (GISTs)., Methods: Thirty-three GISTs, 15 leiomyomas and 6 schwannomas were examined by immunohistochemistry in this study., Results: VEGF protein was expressed in the cytoplasm of tumor cells, and VEGFR-1 and 2 were expressed both in the cytoplasm and on the membrane of all tumors. Immunohistochemical staining revealed that 26 GISTs (78.8%), 9 leiomyomas (60.0%) and 3 schwannomas (50.0%) were positive for VEGF; 24 GISTs (72.7%), 12 leiomyomas (80.0%) and 4 schwannomas (66.7%) were positive for VEGFR-1; 30 GISTs (90.9%), 5 leiomyomas (33.3%) and 4 schwannomas (66.7%) were positive for VEGFR-2. VEGFR-2 expression was statistically different between GISTs and leiomyomas (P < 0.0001). However, there was no correlation between the expression of VEGF pathway componenets and the clinical risk categories., Conclusion: Our results suggest that the VEGF pathway may play an important role in the differentiation of GISTs, leiomyomas and schwannomas.

Aim: To evaluate the levels of serum carnitine in patients with cancer in digestive organs and to compare them with other cancers in order to provide new insights into the mechanisms of cachexia., Methods: Fifty-five cachectic patients with or without gastrointestinal cancer were enrolled in the present study. They underwent routine laboratory investigations, including examination of the levels of various forms of carnitine present in serum (i.e., long-chain acylcarnitine, short-chain acylcarnitine, free carnitine, and total carnitine). These values were compared with those found in 60 cancer patients in good nutritional status as well as with those of 30 healthy control subjects., Results: When the cachectic patients with gastro-intestinal cancer were compared with the cachectic patients without gastrointestinal cancer, the difference was -6.8 micromol/L in free carnitine (P < 0.005), 0.04 micromol/L in long chain acylcarnitine (P < 0.05), 8.7 micromol/L in total carnitine (P < 0.001). In the cachectic patients with or without gastrointestinal cancer, the difference was 12.2 micromol/L in free carnitine (P < 0.001), 4.60 micromol/L in short chain acylcarnitine (P < 0.001), and 0.60 micromol /L in long-chain acylcarnitine (P < 0.005) and 17.4 micromol/L in total carnitine (P < 0.001). In the cachectic patients with gastrointestinal cancer and the healthy control subjects, the difference was 15.5 micromol/L in free carnitine (P < 0.001), 5.2 micromol /L in short-chain acylcarnitine (P < 0.001), 1.0 micromol/L in long chain acylcarnitine (P < 0.001), and 21.8 micromol/L in total carnitine (P < 0.001)., Conclusion: Low serum levels of carnitine in terminal neoplastic patients are decreased greatly due to the decreased dietary intake and impaired endogenous synthesis of this substance. These low serum carnitine levels also contribute to the progression of cachexia in cancer patients.

Evidence now suggests that epigenetic abnormalities, particularly altered DNA methylation, play a crucial role in the development and progression of human gastrointestinal malignancies. Two distinct DNA methylation abnormalities are observed together in cancer. One is an overall genome-wide reduction in DNA methylation (global hypomethylation) and the other is regional hypermethylation within the CpG islands of specific gene promoters. Global hypomethylation is believed to induce proto-oncogene activation and chromosomal instability, whereas regional hypermethylation is strongly associated with transcriptional silencing of tumor suppressor genes. To date, genes involved in regulation of the cell cycle, DNA repair, growth signaling, angiogenesis, and apoptosis, are all known to be inactivated by hypermethylation. Recently developed techniques for detecting changes in DNA methylation have dramatically enhanced our understanding of the patterns of methylation that occur as cancers progress. One of the key contributors to aberrant methylation is aging, but other patterns of methylation are cancer-specific and detected only in a subset of tumors exhibiting the CpG island methylator phenotype (CIMP). Although the cause of altered patterns of DNA methylation in cancer remains unknown, it is believed that epidemiological factors, notably dietary folate intake, might strongly influence DNA methylation patterns. Recent studies further suggest that polymorphisms of genes involved in folate metabolism are causally related to the development of cancer. Identifying epidemiological factors responsible for epigenetic changes should provide clues for cancer prevention in the future.

Inactivation of the transforming growth factor-beta (TGF-beta) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf+/- and elf+/- / Smad4+/- mutant mice. We found that embryonic liver fodrin (ELF), a beta-Spectrin originally identified in endodermal stem/progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell-cell contacts and E-cadherin-beta-catenin-dependent epithelial cell-cell adhesion is disrupted in elf+/- / Smad4+/- mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-beta stimulation. In contrast, elf+/- / Smad4+/- mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-beta signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.

Two kinds of variables may be differentiated within instruments measuring health-related quality of life (HRQOL). Physical symptoms may be called causal variables because their occurrence can cause a change in HRQOL, but poor HRQOL need not necessarily imply that a patient suffers from these symptoms. Other items can be regarded as indicator variables. They reflect the level of HRQOL and a patient with a poor HRQOL is likely to have low scores on all indicator variables. The aim of this study was to test the relationship of the latent HRQOL construct to items and domains on the EORTC QLQ-C30. Confirmatory factor analysis was performed on EORTC QLQ-C30 data from 205 gastrointestinal cancer patients assessed one month after surgery. Functioning scales were established as variables indicating the level of HRQOL whereas all other subscales and items were established as variables causing a change in HRQOL. The model-data fit was satisfactory. Results support the hypothesis that two kinds of variables may be differentiated within HRQOL instruments. Further research should investigate whether both kinds of variables could be combined into a higher order, aggregate score for HRQOL.

Three cases of drug-induced akathisia during palliative care in terminal cancer patients were reported. Antiemetics (metoclopramide and prochlorperazine) possessing a central antidopaminergic effect were suspected to have caused the akathisia. Akathisia, as well as extrapyramidal symptoms, is a common and unpleasant complex neurobehavioral adverse effect of conventional antipsychotic drugs. But it is not widely recognized by general clinicians. This syndrome consists of subjective (feeling of inner restlessness, mental unease, or dysphoria and the urge to move) and objective components (restless movement, including rocking on one's feet, walking in position shuffling and tramping the legs,and crossing and uncrossing one's legs while sitting). In severe cases, patients constantly pace up and down in an attempt to relieve the sense of unrest. While the pathophysiology of drug-induced akathisia remains unknown, antagonism of the mesocortical and mesolimbic dopaminergic pathways is a plausible if not completely satisfactory hypothesis. The notion that dopaminergic blockade underlies the emergence of akathisia is supported by the PET studies. Since akathisia is a drug-induced adverse effect, optimal management involves its prevention rather than treatment. Drugs which have been found to have some efficacy in the treatment of akathisia are anticholinergics, beta-blockers, benzodiazepines and clonidine. Though a number of other treatments have been proposed, no trial-based evidences for treatment of akathisia have been available. It is important that akathisia is recognized and treated appropriately as an adverse reaction to drugs and a further increase in antipsychotic medication dosage may further exacerbate the condition.

Background: Although nutritional supplementation is established in surgical practice, studies on feeding patients undergoing pancreaticoduodenectomy utilise widely disparate protocols, include small numbers of patients and have disparate endpoints. The aim of this study is to carry out a systematic review of peri-operative nutritional supplementation in patients undergoing pancreaticoduodenectomy in order to identify consistent themes., Methods: Searches of the MEDLINE and EMBASE databases yielded 10 studies examining nutritional support in 571 patients undergoing pancreaticoduodenectomy. Data were retrieved on: proportion of pre-operative weight loss, biochemical parameters (pre-operative albumin and the presence of jaundice), type and duration of nutritional support and clinical outcome (morbidity, mortality and hospital stay)., Results: Pre-operative percentage weight loss was similar in all studies evaluated. Routine post-operative total parenteral nutrition (TPN) was associated with a higher incidence of complications. Enteral nutrition reduced infective complications. Cyclical nutrition was associated with a lower incidence of post-operative gastric stasis., Conclusion: Clear themes emerge from this systematic review. Patients undergoing pancreaticoduodenectomy are nutritionally depleted at the time of surgery and the pre-operative period may present a window for intervention. Routine TPN is not beneficial. Routine post-operative enteral nutritional support, delivered on a cyclical basis appears to be the optimal mode of delivery.

The purpose of this study was to develop and pilot test an instrument, the Short Functional Dependence Scale (SFDS), to measure functional dependence in the older adult receiving cancer treatment. Patients from 2 oncology clinics affiliated with a teaching hospital participated in this descriptive, quantitative study. Participants consisted of older adults (N = 26; mean age 71, SD = 5; 54% female; 85% Caucasian) receiving chemotherapy intravenously for solid tumor cancer. Patients, nurses, oncologists, and social workers helped select instrument items and establish content validity. Measurements using the SFDS included baseline and follow-up visits. Data analysis included Cronbach alpha to determine internal consistency and repeated measures to evaluate SFDS scores and associated variables. Cronbach alpha ranged from 0.737 to 0.919 for the 12 items of the SFDS. Functional dependence increased with age, surgery, radiation therapy, and lower hemoglobin levels. Compared to participants with other types of cancer, participants with lung cancer were more dependent in basic activities of daily living, but participants with breast cancer had the highest degree of overall functional dependence. The SFDS has content validity and internal consistency. Pilot testing showed that the instrument performed well in differentiating the functional dependencies of patients receiving chemotherapy according to variables of interest.

The intestine is constantly challenged by food antigens and pathogens and is therefore in need of a good working innate and adaptive immune response. Chemokines are important modulators as they assure the directed movement of immune cells within the body. In addition, chemokines play an important role in hematopoiesis, angiogenesis and tumor metastasis. This review focuses on chemokines and gastrointestinal disorders, more particularly on inflammatory bowel diseases and gastrointestinal tumors. In a first part, the current knowledge on chemokine expression in inflammatory bowel diseases is summarized. Idiopathic inflammatory bowel diseases are characterized by an uncontrolled immune response. The resulting chronic inflammation of the intestine involves massive infiltration of immune cells, causing intestinal damage by the release of cytokines and proteolytic enzymes. Chemokines are believed to be key mediators in this process of aberrant leukocyte recruitment. Chemokine expression in inflammatory bowel disease strongly correlates with the grade of disease activity. The potential therapeutic use of chemokines in gastrointestinal tumors by the use of gene therapy is also reviewed. Chemokines have therapeutic potential in anti-tumor therapy by their angiostatic effect. On the other hand, chemokines can augment the cell-mediated adaptive immune response and thereby exert anti-tumor activity. However, chemokines can passively favor escape of tumor cells by stimulating the release of tissue degrading matrix metalloproteinases and can actively promote metastasis of chemokine receptor-expressing tumor cells.

The present manuscript focus on new data regarding gastro-intestinal (GI) tumors (pancreas excluded). Two mains issues are discussed: advances in terms of the molecular basis of GI oncogenesis, and the data on molecular targeted agents for which the cost/efficacity balance needs to be addressed.

Aberrant activation and upregulation of the Wnt pathway is a key feature of many cancers. Wnt antagonists have recently attracted wide attention. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind to Wnt proteins directly and inhibit Wnt signaling pathway. It has been reported that WIF-1 expression is down regulated in several solid tumors and that WIF-1 is silenced by promoter hypermethylation in lung and colorectal cancer. By using RT-PCR, bisulfite sequence analysis, and methylation-specific PCR, we analysed expression and methylation of WIF-1 in cancer cell lines and freshly resected cancer tissues of the esophagus, stomach, colorectum, and pancreas. Downregulation of WIF-1 mRNA expression was observed in 61 (91.0%) of 67 cancer cell lines, 16 (80.0%) of 20 esophageal, 23 (74.2%) of 31 gastric, 41 (82.0%) of 50 colorectal, and six (75.0%) of eight pancreatic cancer tissues. Downregulation of WIF-1 expression was also observed at protein level. No significant association between WIF-1 downregulation and clinicopathological characteristics was found, suggesting that downregulation of WIF-1 expression is an early event in carcinogenesis of these cancers. Indeed, downregulation of WIF-1 expression was observed in 32 (72.7%) of 44 colorectal adenoma tissues and 18 (78.2%) of 23 early mucosal or submucosal colorectal carcinoma tissues. CpG island hypermethylation in the WIF-1 promoter region correlated with downregulation of WIF-1 expression in cancer cell lines and tissues. Treatment with demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), restored WIF-1 expression in cancer cell lines. A combined treatment of 5-aza-dC and a histone deacetylase inhibitor, trichostatinA, restored WIF-1 expression synergistically, indicating the role of cytosine methylation and histone deacetylation in the silencing of the WIF-1 gene. Transfection of the WIF-1 gene construct into TE-1 esophageal cancer cell lines or SW48 colon cancer cell lines lacking WIF-1 expression resulted in a significant inhibition on colony formation, cell proliferation, anchorage-independent growth in soft agar. TOPflash assay showed WIF-1 inhibits Wnt canonical signaling in these cell lines. These results suggest tumor suppressive function of WIF-1, due to its ability to inhibit Wnt signaling. Our results suggest that WIF-1 silencing due to promoter hypermethylation is an important mechanism underlying aberrant activation of the Wnt signaling pathway in carcinogenesis of the digestive organs. Modulation of the Wnt pathway, through reversal of WIF-1 silencing by demethylating agents, is a potential target for treatment and/or prevention of gastrointestinal cancers.

The scientific search for the revelation of the multiple physiological aspects of somatostatin has already begun. Investigators have managed to clarify many pathophysiological processes that have been influenced or regulated by somatostatin. The focus of future research seems to be the therapeutic application of this accumulated knowledge. The aim of this study is to collect the available information on the action, receptors and use of somatostatin analogues in human tissues. For this reason findings were based on Internet search and complete studies with abstracts written in English. A special mention on the influence of somatostatin on the immune system and inflammatory bowel disease is also included.

Background: Patients with cancer are characterized by a profound impairment of glucose utilization, with lipids being the preferred metabolic fuel. In contrast, the energy needs of malignant tumors are almost entirely met by glucose. We therefore studied the effects of a high-fat diet, particularly on body composition., Patients and Methods: Twenty-three moderately malnourished patients with gastrointestinal carcinomas were randomized to receive either a conventional diet supplying 35 nonprotein kcal and 1.1 g of protein/kg per day (group A, n = 11) or a fat-enriched artificial liquid diet (20 nonprotein kcal/kg per day) plus normal meals (group B, n = 12) for a period of eight weeks, i.e., from the first to the third chemotherapy cycle. The fat content of the artificial diet was 66% of the nonprotein calories. The day before the nutritional interventions, and again after four and eight weeks, body compartments were determined using bioelectrical impedance analysis, lymphocyte subpopulations were quantified using flow cytometry, and some aspects of the quality of life were rated using four linear analog self-assessment (LASA) scales. The statistical calculations were done as an exploratory data analysis., Results: The consumption of non-protein calories did not differ significantly between the two patient groups. An average weight gain in group B contrasted with an average weight loss in group A after four (P < 0.01) and eight weeks (P < 0.05). Fat-free mass showed an intergroup difference in favor of group B after eight weeks (P < 0.05). Body cell mass was maintained throughout the study in group B, but declined significantly up to weeks 4 and 8 in group A (intergroup difference: P < 0.05 and 0.01, respectively). A decrease in the total lymphocyte count by 559 cells/mul occurred with the fat-enriched diet (P < 0.05). Several aspects of the quality of life were rated to be better in group B than in group A, although not all differences reached statistical significance., Conclusion: In patients with cancer, a high-fat diet may possibly support the maintenance of both body weight and body cell mass. However, monitoring the lymphocyte count is advisable.

Gastrointestinal (GI) carcinoid cells secrete multiple neuroendocrine (NE) markers and hormones including 5-hydroxytryptamine and chromogranin A. We were interested in determining whether activation of the Notch1 signal transduction pathway in carcinoid cells could modulate production of NE markers and hormones. Human pancreatic carcinoid cells (BON cells) were stably transduced with an estrogen-inducible Notch1 construct, creating BON-NIER cells. In the present study, we found that Notch1 is not detectable in human GI carcinoid tumor cells. The induction of Notch1 in human BON carcinoid cells led to high levels of functional Notch1, as measured by CBF-1 binding studies, resulting in activation of the Notch1 pathway. Similar to its developmental role in the GI tract, Notch1 pathway activation led to an increase in hairy enhancer of split 1 (HES-1) protein and a concomitant silencing of human Notch1/HES-1/achaete-scute homolog 1. Furthermore, Notch1 activation led to a significant reduction in NE markers. Most interestingly, activation of the Notch1 pathway caused a significant reduction in 5-hydroxytryptamine, an important bioactive hormone in carcinoid syndrome. In addition, persistent activation of the Notch1 pathway in BON cells led to a notable reduction in cellular proliferation. These results demonstrate that the Notch1 pathway, which plays a critical role in the differentiation of enteroendocrine cells, is highly conserved in the gut. Therefore, manipulation of the Notch1 signaling pathway may be useful for expanding the targets for therapeutic and palliative treatment of patients with carcinoid tumors.

This review was designed to show the role of expression of cyclooxygenase (COX)-1 and COX-2 in the cancerogenesis of esophagus, stomach and colon. Unlike COX-1, which is expressed in the normal esophago-gastro-colonic mucosa, COX-2 was found to be expressed mainly in the pre-cancer changes in the mucosa including Barrett's esophagus, Helicobacter pylori (H. pylori)-induced gastritis and inflammatory changes in colonic mucosa. In Barrett's esophagus, prostaglandins (PGs) derived from upregulated COX-2 contribute to the progression of low-grade to high-grade dysplasia and finally to cancer. In chronic gastritis induced by chronic H. pylori infection, overexpression of COX-2 is probably induced by inflammatory cytokines, growth factors, especially gastrin and reactive oxygen species leading to mutagenesis and subsequent metaplasia, dysplasia and cancer formation. The imbalance between cell proliferation and apoptosis caused mainly by products of COX-2 leads to cancerogenesis. Similarly, in colorectal cancer the overexpression of COX-2, possibly induced by the action of growth promoting factors including progastrin and gastrin and overexpression of survivin contribute to the colorectal cancerogenesis that could be, at least in part, amended by the treatment with specific COX-2 inhibitors. We conclude that: 1) COX-2-derived PGs play a key role in the tumorigenesis in the gastrointestinal tract; 2) The tumor-promoting effect of PGs may be attributed to their ability to stimulate cell proliferation and migration, to inhibit the apoptosis and to increase angiogenesis and invasiveness; 3) In accordance to the proposed major role of COX-2 in cancerogenesis, selective COX-2 inhibitors have been shown in numerous studies to exhibit strong chemopreventive effect on the development of gastrointestinal cancers.

Monitoring of eicosanoid synthesis in peripheral blood cells has significant potential for improving the diagnosis and therapy of many human diseases. The quantitative relation between concentrations of prostaglandins and leukotrienes is central to the physiologic function of the eicosanoid network. Here we show that this regulation, which we call the functional eicosanoid typing (FET), fluctuates dynamically in individual living blood cells from patients, thereby limiting the accuracy with which concentration circuits of eicosanoids can transfer metabolic information. Using living cells in functional cell testing, we characterised the eicosanoid pattern score (EPS). A novel technique based on binomial errors on lipid mediator partitioning enabled calibration of in vivo biochemical parameters in molecular units. We found that eicosanoid production rates fluctuate over a time scale of about twenty minutes, while intrinsic noise decays rapidly. Thus, biochemical eicosanoid parameters, noise, and slowly varying cellular states together determine the effective FET. These results can form a basis for quantitative modelling of natural eicosanoid circuits in diagnosis of eicosanoid related diseases and design of synthetic ones for the prediction other diseases.

COX-inhibitors promote nasal polyps or bronchial asthma in individuals susceptible to an alteration of the pattern of the eicosanoids, especially leukotrienes and prostaglandins. This is associated with an abnormal release of eicosanoids from white blood cells. Since COX-inhibitors also protect from colorectal cancer an analogous association may be suggested. The study was performed to detect abnormal patterns of eicosanoids in white blood cells of patients with intestinal cancer compared to healthy controls. Seventy patients with intestinal cancer (stomach = 5; colon = 25; sigma = 18; rectum = 22) were compared to 62 healthy controls. Blood leukocytes from patients in complete long-lasting remission were incubated with diluent, arachidonic acid or acetylsalicylic acid. The synthesis of prostaglandin E(2) and peptido-leukotrienes was quantified using competitive enzyme-immuno-assays and calculated for individual eicosanoid patterns. The mean basal and arachidonic- or acetylsalicylic acid-modulated PGE(2) synthesis in patients was significantly higher than in controls (4.8-fold, 9.4-fold, 3.7-fold, respectively) whereas pLT was generally less elevated. We conclude that the eicosanoid-pattern of white-blood-cells from patients with intestinal cancer differs significantly from that in healthy individuals. This abnormal cellular metabolism may contribute to the manifestation of cancer and help to detect individuals at risk.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally prescribed to ameliorate symptoms associated with acute pain and chronic inflammatory diseases such as arthritis. Recent epidemiologic studies and clinical trials indicate that use of NSAIDs and cyclooxygenase (COX)-2 selective inhibitors are associated with a reduced risk of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase enzymes are the best known targets of NSAIDs; this diverse class of compounds blocks conversion of arachidonic acid to prostanoids. Prostaglandins and other eicosanoids derived from COX-1 and COX-2 are involved in a variety of physiologic and pathologic processes in the gastrointestinal tract. Recent efforts to identify the molecular mechanisms by which COX-2-derived prostanoids exert their proneoplastic effects have provided a rationale for the possible use of NSAIDs alone or in a combination with conventional or experimental anticancer agents for the treatment or prevention of gastrointestinal cancers.

The reference cancers associated with DNA mismatch repair (MMR)deficiency are the adenocarcinomas of patients with hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome. Sporadic gastrointestinal (GI) carcinomas, most commonly colorectal and gastric carcinomas, may also be associated with deficiencies of DNA mismatch repair. Deficiency in cellular MMR leads to wide-spread mutagenesis and neoplastic development and progression. An important diagnostic feature of MMR-deficient tumors is the high rate of mutations that accumulate in repetitive nucleotide regions, and these mutations are known as microsatellite instability(MSI). A standard panel of markers to test for MSI in tumors has been recommended and efficiently separates tumors into those with high, low, or no microsatellite instability (MSI-H, MSI-L, or MSS). Tumors characterized by MSI-H characteristically show loss of one of the main DNA MMR proteins, mLH1 or MSH2, and rarely MSH6 and PMS2, detected by immunohistochemistry (IHC). The combination of MSI testing and IHC for MMR proteins in tumors tissues is used to identify underlying DNA MMR deficiency andis clinically relevant screen patients who might have hereditary non-polyposis colorectal cancer for DNA repair gene germline testing. Increasing evidence demonstrates that tumors with a positive MSI status have lower lymph node metastases burden, and these patients have an overall improved survival, suggesting that the MSI and MMR status may contribute to decision making regarding treatment approaches. Updated guidelines for MSI and IHC for DNAMMR testing, and the biological and potential clinical implications of MMR deficiency and microsatellite instability in GI polyps and cancers are reviewed.

The precise role of chemokines in neovascularization during inflammation or tumor growth is not yet fully understood. We show here that the chemokines granulocyte chemotactic protein-2 (GCP-2/CXCL6), interleukin-8 (IL-8/CXCL8), and monocyte chemotactic protein-1 (MCP-1/CCL2) are co-induced in microvascular endothelial cells after stimulation with pro-inflammatory stimuli. In contrast with its weak proliferative effect on endothelial cells, GCP-2 synergized with MCP-1 in neutrophil chemotaxis. This synergy may represent a mechanism for tumor development and metastasis by providing efficient leukocyte infiltration in the absence of exogenous immune modulators. To mimic endothelial cell-derived GCP-2 in vivo, GCP-2 was intravenously injected and shown to provoke a dose-dependent systemic response, composed of an immediate granulopenia, followed by a profound granulocytosis. By immunohistochemistry, GCP-2 was further shown to be expressed by endothelial cells from human patients with gastrointestinal (GI) malignancies. GCP-2 staining correlated with leukocyte infiltration into the tumor and with the expression of the matrix metalloproteinase-9 (MMP-9/gelatinase B). Together with previous findings, these data suggest that the production of GCP-2 by endothelial cells within the tumor can contribute to tumor development through neovascularization due to endothelial cell chemotaxis and to tumor cell invasion and metastasis by attracting and activating neutrophils loaded with proteases that promote matrix degradation.

Bacterial translocation (BT) is defined as the passage of indigenous bacteria colonizing the intestine through the epithelial mucosa to the mesenteric lymph nodes and other sites. It can even cause the development of lethal sepsis. BT is being studied extensively, most research being conducted on animal, mostly murine, models. The cause of BT is not well known. Despite advances in antimicrobial therapy, the mortality rate associated with bacteremia is still high, and sepsis can often originate from the patient's own intestinal flora. Consequently, a better understanding of the mechanisms of BT as well as mechanisms operating to prevent bacteria from translocating from the gastrointestinal tract may provide more logical treatment of particular patients. BT may be promoted by immunosuppression (probably one of the most important factors causing the increase in BT), disturbances in the normal ecology of the gastrointestinal tract, allowing some indigenous bacteria to overgrow others, and by mucosal injuries. This article discusses the potential role of various factors responsible for BT and the relationship between BT and neoplastic disease. It also emphasizes the significance of the immune system, which appears to play a role in the ontogeny of gut-associated lymphoid tissue (GALT), including the role of IL-2 (which induces an increase in BT) and the macrophage, which participates in the transport of bacteria from the intestinal lumen to mesenteric lymph nodes. A better understanding of the immunopathology of BT may contribute to the development of novel means of therapy for sepsis and other serious complications of bacterial infection.

We investigate connections between single-cell mechanical properties and subcellular structural reorganization from biochemical factors in the context of two distinctly different human diseases: gastrointestinal tumor and malaria. Although the cell lineages and the biochemical links to pathogenesis are vastly different in these two cases, we compare and contrast chemomechanical pathways whereby intracellular structural rearrangements lead to global changes in mechanical deformability of the cell. This single-cell biomechanical response, in turn, seems to mediate cell mobility and thereby facilitates disease progression in situations where the elastic modulus increases or decreases due to membrane or cytoskeleton reorganization. We first present new experiments on elastic response and energy dissipation under repeated tensile loading of epithelial pancreatic cancer cells in force- or displacement-control. Energy dissipation from repeated stretching significantly increases and the cell's elastic modulus decreases after treatment of Panc-1 pancreatic cancer cells with sphingosylphosphorylcholine (SPC), a bioactive lipid that influences cancer metastasis. When the cell is treated instead with lysophosphatidic acid, which facilitates actin stress fiber formation, neither energy dissipation nor modulus is noticeably affected. Integrating recent studies with our new observations, we ascribe these trends to possible SPC-induced reorganization primarily of keratin network to perinuclear region of cell; the intermediate filament fraction of the cytoskeleton thus appears to dominate deformability of the epithelial cell. Possible consequences of these results to cell mobility and cancer metastasis are postulated. We then turn attention to progressive changes in mechanical properties of the human red blood cell (RBC) infected with the malaria parasite Plasmodium falciparum. We present, for the first time, continuous force-displacement curves obtained from in-vitro deformation of RBC with optical tweezers for different intracellular developmental stages of parasite. The shear modulus of RBC is found to increase up to 10-fold during parasite development, which is a noticeably greater effect than that from prior estimates. By integrating our new experimental results with published literature on deformability of Plasmodium-harbouring RBC, we examine the biochemical conditions mediating increases or decreases in modulus, and their implications for disease progression. Some general perspectives on connections among structure, single-cell mechanical properties and biological responses associated with pathogenic processes are also provided in the context of the two diseases considered in this work.

The gastrointestinal tract is one of the most common sites for the development of primary neoplasms arising in patients with pre-existing infection with the human immunodeficiency virus (HIV). Over the past decade, new information on the clinical manifestation, natural history, treatment options, and related toxicity have been reported, mostly notably the integration of highly active antiretroviral therapy (HAART). The following is a concise review summarizing the current state-of-the-art for GI tract malignancies in the HIV-positive patient and is designed to assist the clinical oncology team in developing a rationale plan when caring for these patients.

The last decade has seen enormous progress in understanding the development of cancer. It is now recognized that tumor growth is a multistep process that may take years to become clinically relevant. Angiogenesis is an absolute requirement for tumors to become clinically detectable. The importance of angiogenesis for tumor growth is supported by several clinical studies that showed a positive correlation between tumor angiogenesis and tumor stage. In animal studies, inhibition of angiogenesis caused impressive reduction of tumor growth. The aim of antivascular therapy in the treatment of cancer is to attack the tumor through its vasculature. Antivascular therapy can be divided in two different areas: (1) inhibition of angiogenesis with the aim to prevent formation of new blood vessels and (2) vascular targeting agents with the goal to destroy the existing tumor vasculature. Vascular endothelial growth factor (VEGF) has been recognized as one of the most important factors involved in tumor angiogenesis and has become an important target for anticancer treatment. This review focuses mainly on the inhibition of angiogenesis in gastrointestinal tumors by blocking the VEGF receptor/ligand signaling. We will discuss the biology of the VEGF receptor/ligand signaling system and give an overview of the current approaches for therapy in gastrointestinal cancer targeting the VEGF signaling pathway., (Copyright (c) 2005 S. Karger AG, Basel.)

Background Insulin-like growth factor 1 (IGF-1) is an autocrine regulator of carcinoid tumors. Blockade of IGF-1 signaling has been proposed as a therapeutic target in the treatment of patients with carcinoid syndrome. We hypothesized that the induction of parallel raf-1/MEK1 pathways will block IGF-1-mediated chromogranin A (CgA) maintenance. Methods Human gastrointestinal carcinoid tumor cells (BON) were treated with IGF-1 (0-500 ng/mL). Raf-1/MEK1 activation was achieved with an estrogen-inducible raf-1 vector that was transduced into BON cells. Activation of IGF-1/raf-1 pathways was determined by phosphorylation of downstream targets p70s6 and ERK1/2. The secreted and intercellular levels of CgA were measured in conditioned media and whole cell extracts by Western and enzyme-linked immunosorbent assay analysis. Results IGF-1 and raf-1 pathways were activated successfully in BON cells, as shown by high levels of phosphorylated p70s6 and phosphorylated ERK1/2, respectively. Treatment of BON cells with IGF-1 stimulated the release of CgA, while high intracellular CgA levels were maintained. The activation of raf-1/MEK1 reversed the effect of IGF-1 treatment by the depletion of intracellular CgA. Conclusions The induction of the raf-1/MEK1 pathway blocks IGF-1-mediated intracellular neuroendocrine hormone regulation. Therefore, raf-1/MEK1 activation may be a viable method to block IGF-1-mediated cellular effects and serve as a therapeutic target in gastrointestinal carcinoid tumors.

Transdermal Fentanyl was released in March 2002 in Japan after the acceptance of the insurance under the office of public health. Transdermal therapy is especially effective for patients having difficulty of oral intakes, and for home care cancer patients who suffer from chronic pain only if the therapy is feasible on the long-term basis. We report our cases for long-term cancer pain management with transdermal fentanyl. A total of 52 long-term patients with chronic cancer pain (28 men and 24 women with an average age of 63.5 years, range 46-74 years) were evaluated. The most prevalent cancers were colorectum (n=14), stomach (n=10), breast (n=8), esophagus (n=6), pancreas (n=6), and others. The duration of the transdermal therapy varied from minimum of 2 days to maximum of 630 days. Two patients on this therapy were longer than 500 days. The transdermal therapy was discontinued 2-37 days for 8 patients due to uncontrolled pain relief. Case report 1: A 72-year-old woman suffering from a relapse of pancreatic cancer with chronic back pain experienced a good pain relief after switching from 60 mg/day sustained oral release morphine to 2.5 mg transdermal fentanyl. During the long-term treatment, the transdermal fentanyl dosage had to be increased. Transdermal therapy was continued until the patient's death on day 601. The last fentanyl dosage was 7.5 mg. Transdermal therapy was given 319/601 days at home and 282/601 days in the hospital. Meanwhile, a little rescue suppository morphine was used as an adjuvant during the duration of transdermal therapy. Case report 2: A 73-year-old man suffered a relapse of rectal cancer. He experienced adequate pain relief with 40 mg oral sustained release morphine, but he was switched to 2.5 mg transdermal fentanyl. Transdermal therapy was continued until today on day 630. At present, fentanyl dosage is 20 mg. The patient has been treated at home for 622/630 days. He was hospitalized only once for 8 days because of dehydrations, and has been treated at home. Only a little rescue powder morphine was needed as an adjuvant during the duration of transdermal therapy. In these 2 cases of long-term cancer pain management, transdermal therapy has resulted in good pain reduction and the side effects with transdermal therapy were not noted. Transdermal fentanyl can be recommended for treatment of palliative cancer pain at home.