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Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the β-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation. (Mol Cancer Res 2007;5(12):1263–75)

Supplementary Data from Transcriptome Profile of Human Colorectal Adenomas

There is a lack of validated predictors on which to decide the timing of discharge in patients already hospitalized for upper nonvariceal bleeding.Identify factors that appear to protect nonvariceal bleeders from the development of negative outcome (rebleeding, surgery, death).Secondary analysis of two prospective multicenter studies. Multivariate analyses for each investigated outcome were performed; a single model was developed including all factors that were statistically significant in each sub-model. A final score was developed to predict favourable outcomes. Prognostic accuracy was tested with ROC curve analysis.Out of 2398 patients, 211 (8.8%) developed one or more adverse outcomes: 87 (3.63%) had rebleeding, 46 (1.92%) needed surgery and 107 (4.46%) died. Predictors of favourable prognosis were: ASA score 1 or 2, absence of neoplasia, outpatient bleeding, use of low-dose aspirin, no need for transfusions, clean-based ulcer, age70 years, no haemodynamic instability successful endoscopic diagnosis/therapy, no Dieulafoy's lesion at endoscopy, no hematemesis on presentation and no need for endoscopic treatment. Overall prognostic accuracy of the model was 83%. The final score accurately identified 20-30% of patients that eventually do not develop any negative outcome.The "good luck score" may be a useful tool in deciding when to discharge a patient already hospitalized for acute non-variceal bleeding.

From an Italian Registry of patients with upper gastrointestinal hemorrhage (UGIH), we assessed the clinical outcomes and explored the roles of clinical, endoscopic, and therapeutic factors on 30-day mortality in a real life setting.Prospective analysis of consecutive patients endoscoped for UGIH at 23 community and tertiary care institutions from 2003 to 2004. Covariates and outcomes were defined a priori and 30-day follow-up obtained. Logistic regression analysis identified predictors of mortality.One thousand and twenty patients were included. A total of 46 patients died for an overall 4.5% mortality rate. In all, 85% of deaths were associated with one or more major comorbidity. Sixteen of 46 patients (35%) died within the first 24 h of the onset of bleeding. Of these, eight had been categorized as ASA class 1 or 2 and none of them was operated upon, despite a failure of endoscopic intention to treatment in four. Regression analysis showed advanced age, presence of severe comorbidity, low hemoglobin levels at presentation, and worsening health status as the only independent predictors of 30-day mortality (P0.001). The acute use of a PPI exerted a protective effect (OR 0.23, 95% CI 0.09-0.73). Recurrent bleeding was low (3.2%). Rebleeders accounted for only 11% of the total patients deceased (OR 3.27, 95% CI 1.5-11.2).These results indicate that 30-day mortality for nonvariceal bleeding is low. Deaths occurred predominantly in elderly patients with severe comorbidities or those with failure of endoscopic intention to treatment.

GERD is the most frequent disorder of the esophagus. Endoscopic minimally invasive treatment is desirable. However, the results of injection techniques have been disappointing.A pilot study was conducted in patients with GERD, who required continuous therapy with a proton pump inhibitor, in which ethylene-vinyl-alcohol was injected into the muscle of the gastric cardia. Primary endpoints were the safety of the procedure, the effect on lower esophageal sphincter pressure and the stability of the injected material. A secondary endpoint was the effect on heartburn score after discontinuation of treatment with a proton pump inhibitor.Ethylene-vinyl-alcohol injection into the cardia resulted in circular diffusion of the product in 10 of 15 cases, suggesting that implantation into the muscle is feasible. Lower esophageal sphincter pressure was increased in 13 of 15 cases at 1 month and was sustained at a median follow-up of 6 months (range 4-12 months). Mean plus minus SEM of lower esophageal sphincter pressures (15 patients) were 12.2 plus minus 0.9, 18.7 plus minus 1.5 (p = 0.001 at baseline), and 16.7 plus minus 1.3 mm Hg (p = 0.038 from baseline) at, respectively, baseline, 1 month follow-up, and final follow-up. There was also a sustained reduction in heartburn score (off proton pump inhibitor) (3.40 plus minus 0.13 vs. 1.53 plus minus 0.24 and 1.87 plus minus 0.26 at baseline vs. 1 month and final follow-up, respectively; p0.01). Nine of the 15 patients had more than 50% of the injected material in place at second follow-up (at 6 months for 8 patients; at 12 months for 1 patient). In only 2 patients was there loss of more than 75% of injected ethylene-vinyl-alcohol. Persistence of greater than 50% of the material was associated with achievement of a circular injection. Only 4 patients had to resume therapy with a proton pump inhibitor. Mild retrosternal discomfort was observed in 8 patients; this disappeared in all cases after a maximum of 3 days.Ethylene-vinyl-alcohol implantation in the muscle of the cardia is feasible and safe. It leads to a sustained increase in resting lower esophageal sphincter pressure. This is associated with a sustained improvement in heartburn score for patients who previously required continuous therapy with a proton pump inhibitor.

BACKGROUND/AIMS The involvement of a direct viral cytopathic effect or an immune-mediated mechanism in the progression of hepatic damage in chronic hepatitis C is controversial. The type of immune response is itself a matter of controversy, and histological data are lacking. The aim of this study was to identify the factors associated with the progression of liver injury in 30 HCV/RNA-positive untreated patients with chronic hepatitis. METHODS Necroinflammatory and architectural damage were evaluated using Ishak's score. Activated hepatic stellate cells (HSC) were visualized by immunohistochemistry for alpha-smooth muscle actin (alphaSMA) and quantitated by morphometry. Plasma HCV/RNA was evaluated using a competitive RT-PCR method. To study the type of immune response involved in the progression of liver injury, interferon gamma (IFNgamma)-positive cells (as expression of a Th1-like response) were evaluated by immunohistochemistry and quantitated by morphometry. RESULTS HSC were mostly detected close to areas of lobular necroinflammation or lining fibrotic septa. The alphaSMA- and Sirius Red-positive parenchyma correlated significantly with necroinflammatory and architectural scores. IFNgamma-positive cells were detected in periportal areas associated with the inflammatory infiltrates and significantly correlated with architectural damage. No relationship was found between the histological features of liver injury and viral load. CONCLUSIONS HSC activation and progression of liver injury are unrelated to viral load but associated with a Th1-like response, a plausible target for the treatment of chronic hepatitis C.

We compared the efficacy of two therapies toeradicate H. pylori infection including ranitidinebismuth citrate (400 mg twice daily), clarithromycin(500 mg twice daily), and tinidazole (500 mg twicedaily), administered for six or seven days. Eighty H.pylori-positive patients were consecutively recruitedand randomly subdivided into groups A and B, receivingone of the two treatment regimens. The H. pylori status was evaluated by means of histology andrapid urease test at entry, and by [13C]ureabreath test alone eight weeks after treatment. All 40patients in group A and 39/40 in group B completed the study. Thirty-six of 40 patients in thegroup A (90%) and 36 of 39 in the group B (92%) becameH. pylori-negative. Slight or mild side-effects occurredin 4/40 patients (10%) of group A and in 5/39 (13%) of group B. In conclusion, both regimenswe tested yielded high eradication rates with modestside effects. This is the first trial investigating atriple-drug RBC-based regimen administered for only six days.

Background: Helicobacter pylori plays a key role in production of reactive oxygen metabolites (ROMs). However, the importance of virulent CagA-positive H. pylori strains remains to be determined. The aim of this study was to assess ROMs production in gastric biopsies of patients infected by H. pylori. Results were correlated to CagA status and acute inflammatory infiltration. Methods: Patients undergoing gastroscopy were enrolled. H. pylori infection was assessed by histology and C-13 urea breath test. CagA status was assessed through serology. ROMs were assayed in gastric biopsies by luminol-enhanced chemiluminescence (CLS). Gastric mucosal inflammation was histologically graded and neutrophils were individually counted. Macroscopical damage was scored according to a modified Lanza score. Results: 40 out of 60 patients evaluated were H. pylori (HP) positive. Of the 40 infected patients, 24 were CagA-positive. CLS emission was significantly higher in HP-CagA-positive patients than in HP-CagA-negatives and uninfected. ROMs production showed a significant correlation to neutrophil infiltrate in all groups. Conclusions: Gastric mucosa of patients infected by HP-CagA-positive strains is characterized by a higher generation of ROMs and by greater neutrophil counts than that observed in HP-CagA-negative subjects. Since ROMs production is associated with DNA oxidative damage, a long-term stimulation by these strains might be relevant in the pathogenesis of gastric malignancies. Assessment of CagA status might be useful to discriminate patients in which H. pylori eradication is advisable.

Factors That Affect Complete Small Bowel Transit of Capsule Endoscope Hoon Jai Chun, Yong Sik Kim, Kyung Jo Kim, Young-Ho Kim, Tae Il Kim, Jae Hyuk Do, Ji Kon Ryu, Jeong Seop Moon, Soo-Heon Park, Cheol Hee Park, Ki-Nam Shim, Kee Myung Lee, In Seok Lee, In Seop Jung, Myung Gyu Choi Background/Aims: Capsule endoscopy (CE) is a new method of investigating entire small bowel (SB). Some reported that current battery time was sufficient for observing entire SB, but others reported negatively. The aims of this study were to know the complete SB transit rate of CE and determine the factors affect the entire SB transit of CE in Koreans by multi-center study. Methods: 482 cases of CE performed in 7 institutions in Korea (Korea Gut Image Study Group) from Sep. 2002 to Jul. 2004 were retrospectively reviewed. 54 cases were excluded due to anatomical abnormality or endoscopic assistance. 428 cases were devided into complete and incomplete SB transit groups according to getting ileocecal valve image. Multiple logistic regression analysis was used to identify influencing factors. Results: The complete SB transit rate was 67% and mean battery time was 7 1/2 hrs. Age (p ! 0.05, OR Z 1.028), patient position after capsule ingestion (p ! 0.05, OR Z 4.900), crohn’s disease (p ! 0.05, OR Z 6.122), gastric transit time (p ! 0.05, OR Z 1.102), battery time (p ! 0.05, OR Z 0.989), are related to complete SB transition. Other factors including sex, underlying disease, patient’s activity, bowel preparation method and ingestion of prokinetics have no correlation with complete SB transition. Mean small bowel transit time in complete SB transit group was 4 1/2 hrs and ranged from 44 to 514 min. In incomplete SB transit group (141 cases), 5 cases were reached to stomach, 4 cases to proximal jejunum, 10 cases to distal jejunum, 24 cases to proximal ileum, and the other 98 cases to distal ileum. Conclusions: Complete SB transit rate of CE in Koreans was 67% under current battery time. Age, patient position after capsule ingestion, crohn’s disease, gastric emptying time and battery time were the significant factor influencing complete SB transit of CE. M1355 Risk Score and Predictive Models of Mortality From Non Variceal Acute Upper Gastrointestinal Haemorrhage in Italy: A National Survey Riccardo Marmo, Maurizio Koch, Livio Cipolletta, Lucio Capurso, Mariano Amuso, Alfredo Pastorelli, Elena Sanz Torre, Omero Triossi, Andrea Buzzi, Renzo Cestari, Domenico Della Casa, Massimo Proietti, Anna Tanzilli, Giovanni Aragona, Francescoo Giangregorio, Leonardo Allegretta, Salavatore Tronci, Paolo Michetti, Paola Romagnoli, Andrea Nucci, Francesca Rogai, Morena Tebaldi, Fabrizio Bonfante, Giorgio Chiozzini, Lisa Gerardi, Alessandro Casadei, Claudio Cortini, Claudio Leoci, Gianpiero Bagnalasta, Mario Salvagnini, Mario Gatto Mortality associated with acute upper gastrointestinal bleeding is described high despite advances in diagnosis and therapy but, at our knowledge, study on the recent epidemiology, of acute upper gastrointestinal haemorrhage, on PPI epoch, are few Endoscopic and more recent pharmacologic treatment has recently been shown to reduce rebleeding rates and perhaps mortality. These advances in therapy are becoming more widely adopted and may influence the outcomes of patients with upper gastro intestinal bleeding (UGIB). Aim of the study was 1) verify the mortality rate of patients with UGIB in a nationwide survey, 2) evaluate the treatment role on the outcomes considered, 3) provide a predictive model of mortality taking in account also the therapeutic role. The data presented were collected over 12 months as part of a national audit of the management and outcome of acute upper gastrointestinal haemorrhage. From march 2003 to march 2004 a population based, unselected, multicentre, prospective survey, with 175 items, was conducted from 23 hospitals receiving emergency admissions in various regions equally distributed. 1175 cases of acute upper gastrointestinal haemorrhage ,in which patients aged from 10 to 99 years old, were identified. Results: the mean age was 67,03G 15,76 SD range 10-99, males account for 62% of the serie. Non variceal bleeding (NVB) is the main cause of bleeding in 86,8% (1020 patients). The main co-morbities was hypertension 29.3% and neoplasia was present in 7.8%; Endoscopic treatment was not done in 523 (51.3%); when employed, the more frequent was injection with adrenaline solution 319 (64.2%). After endoscopy the main used pharmacological treatment was proton pump inhibitors 76.7%, while H2 antagonists used in. 3.9% Overall mortality rate was 4,5%. Of the 175 items analyzed, 14 give independent gain in the mortality predictive model: ASA class, time to recovery, age, blood pressure, cardiac frequency, haemoglobin value, neoplasia, renal failure, cirrhosis, hematemesis, blood in gastric lumen, active bleeding, endoscopic treatment failure, and rebleeding. The area under the Roc curve give a .847 value that is one of the most relevant predictive model proposed. Conlusion mortality rate from UGIB in Italy is not so high but rise with age and comorbities. The challenge is to identify those patients who have most high risk for death so that their treatment and survelliance can be optimized. Various risk.