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1.  Prognostic prediction across a gradient of total tumor volume in patients with hepatocellular carcinoma undergoing locoregional therapy 
BMC Gastroenterology  2010;10:146.
Background
The size and number of tumors are important prognostic indicators for hepatocellular carcinoma (HCC). However, it is difficult to assess the prognosis for patients with a variable number and size of tumors. By combining these two factors, we investigated the role and prognostic accuracy of total tumor volume (TTV) for HCC.
Methods
A total of 786 patients undergoing locoregional therapy (transarterial chemoembolization, percutaneous radiofrequency ablation and acetic acid or ethanol injection) for HCC were prospectively evaluated.
Results
The mean and median TTV was 177 cm3 (range, 0.1-3,591 cm3) and 21 cm3, respectively. Of all, 38%, 29%, 15%, 7% and 11% of patients had TTV of <10 cm3, 10-50 cm3, 50-200 cm3, 200-500 cm3 and >500 cm3, respectively. TTV was significantly larger in patients with higher serum α-fetoprotein (AFP) levels or with vascular invasion. The Child-Turcotte-Pugh score, performance status, vascular invasion, AFP level and TTV were significant independent prognostic predictors in the Cox proportional hazards model. After adjustment, patients with TTV 50-200 cm3 (relative risk [RR]: 1.74, p = 0.009), 200-500 cm3 (RR: 2.15, p = 0.006) and >500 cm3 (RR: 3.92, p < 0.001) had a significantly increased mortality risk in comparison to patients with TTV <10 cm3.
Conclusions
TTV is a feasible prognostic predictor across a wide gradient and can be used to predict the mortality risk of HCC. Selecting appropriate cutoffs of TTV may help refine the design of cancer staging system and treatment planning. Future clinical trials of HCC may include this parameter for mortality risk stratification.
doi:10.1186/1471-230X-10-146
PMCID: PMC3022616  PMID: 21194431
2.  Association between HLA-DRB1 alleles polymorphism and hepatocellular carcinoma: a meta-analysis 
BMC Gastroenterology  2010;10:145.
Background
HLA-DRB1 allele polymorphisms have been reported to be associated with hepatocellular carcinoma susceptibility, but the results of these previous studies have been inconsistent. The purpose of the present study was to explore whether specific HLA-DRB1 alleles (DRB1*07, DRB1*12, DRB1*15) confer susceptibility to hepatocellular carcinoma.
Methods
Case-control studies on HLA-DRB1 alleles association with HCC were searched up to January 2010 through a systematic review of the literature. The odds ratios (ORs) of HLA-DRB1 allele distributions in patients with hepatocellular carcinoma were analyzed against healthy controls. The meta-analysis software REVMAN 5.0 was applied for investigating heterogeneity among individual studies and for summarizing all the studies. Meta-analysis was performed using fixed-effect or random-effect methods, depending on absence or presence of significant heterogeneity.
Results
Eight case-control studies were included in the final analysis. Among the 3 HLA-DRB1 alleles studied, DRB1*07 and DRB1*12 were significantly associated with the risk of HCC in the whole populations (OR = 1.65, 95% CI: 1.08-2.51, P = 0.02 and OR = 1.59, 95% CI: 1.09-2.32, P = 0.02, respectively). No significant association was established for DRB1*15 allele with HCC in the whole populations. Subgroup analysis by ethnicity showed that DRB1*07, DRB1*12 and DRB1*15 alleles significantly increased the risk of hepatocellular carcinoma in Asians (OR = 2.10, 95% CI: 1.06-4.14, P = 0.03; OR = 1.73, 95% CI: 1.17-2.57, P = 0.006 and OR = 2.88, 95%CI: 1.77-4.69, P <0.001, respectively).
Conclusion
These results support the hypothesis that specific HLA-DRB1 alleles might influence the susceptibility of hepatocellular carcinoma. Large, multi-ethnic confirmatory and well designed studies are needed to determine the host genetic determinants of hepatocellular carcinoma.
doi:10.1186/1471-230X-10-145
PMCID: PMC3016400  PMID: 21172035
3.  Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988-2008 
BMC Gastroenterology  2010;10:144.
Background
A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX requirements in PBC over the past 20 years in the Netherlands.
Methods
Analysis of PBC transplant data of the Dutch Organ Transplant Registry during the period 1988-2008, including both absolute and proportional numbers. The indication for LTX was categorized as liver failure, hepatocellular carcinoma or poor quality of life (severe fatigue or pruritus). Data were analysed for two decades: 1.1.1988-31.12.1997 (1st) and 1.1.1998-31.12.2007 (2nd). The severity of disease was quantified using MELD scores. To fit lines which show trends over time we applied a linear regression model.
Results
A total of 110 patients (87% women) was placed on the waiting list. 105 patients were transplanted (1st: 61, 2nd: 44), 5 (5%) died while listed. The absolute annual number of LTX for PBC slightly decreased during the 20 year period, the proportional number decreased significantly. At the time of LTX the mean age was 53.6 yrs. (1st: 53.4, 2nd: 53.8), the mean MELD score 13.9 (1st:14.5, 2nd:13.0). The median interval from diagnosis to LTX was 90.5 months (1st:86.5, 2nd: 93.5). 69% of patients was treated with UDCA (1st 38%, 2nd 82%).
Conclusions
Over the past 20 years the absolute number of LTX for PBC in the Netherlands showed a tendency to decrease whereas the proportional decrease was significant. There was a trend over time toward earlier transplantation.
doi:10.1186/1471-230X-10-144
PMCID: PMC3020176  PMID: 21172005
4.  Relationship of 24-hour ambulatory blood pressure and heart rate with markers of hepatic function in cirrhotic patients 
BMC Gastroenterology  2010;10:143.
Background
There is evidence that in cirrhotic patients, certain hemodynamic parameters, such as blood pressure and heart rate, are related to the severity of liver disease. This study investigated whether non-invasive 24-hour ambulatory blood pressure and heart rate are more closely associated with markers of liver disease severity than conventional office measurements.
Methods
Ambulatory patients with cirrhosis underwent office blood pressure and heart rate measurements, 24-hour ambulatory blood pressure monitoring and blood laboratory tests.
Results
Fifty-one patients (32 men, mean age 57.4 ± 11.3 years) completed the study. Twenty six patients had compensated liver cirrhosis (group A) and 25 patients had more advanced liver disease (group B). Group A and B patients differed significantly both in ambulatory asleep diastolic blood pressure (p < 0.05) and office diastolic blood pressure (p < 0.01), which were lower in more advanced liver disease. Office blood pressure and heart rate correlations were similar to or even stronger than ambulatory ones. Ambulatory blood pressure and heart rate awake-asleep variation (dipping) showed a relatively flat pattern as markers of liver dysfunction were deteriorating. The strongest correlations were found with both ambulatory and office heart rate, which increased as indicators of severity of liver disease were worsening.
Conclusions
Heart rate seems to be a more reliable marker of ongoing liver dysfunction than blood pressure. Evaluation of blood pressure and heart rate with 24-hour ambulatory measurement does not seem to offer more information than conventional office measurements.
doi:10.1186/1471-230X-10-143
PMCID: PMC3013079  PMID: 21143998
5.  Ectopic opening of the common bile duct and duodenal stenosis: an overlooked association 
BMC Gastroenterology  2010;10:142.
Background
Ectopic opening of the common bile duct into the duodenal bulb (EO-CBD-DB) is a rare disease that may be complicated by duodenal ulcer, deformity, stenosis and biliary stones. The aim of this study is to report clinical presentations, endoscopic diagnosis and treatment of this entity as well as to investigate its association with duodenal stenosis.
Methods
Gastroduodenoscopic findings and radiological imaging were evaluated for ectopic papilla and duodenal stenosis. Diagnostic methods, endoscopic procedures and long-term outcomes of the endoscopic treatment were presented.
Results
EO-CBD-DB was found in 74 (77.1%) of the 96 patients with duodenal deformity/stenosis (79 male, 17 female, mean age: 58.5, range: 30-87 years). The papilla with normal appearance was retracted to the bulb in 11 while it was at its usual location in the remaining 11. The history of biliodigestive surgery was more common in patients with EO-CBD-DB who were frequently presented with the common bile duct stone-related symptoms than the other patients. Thirteen (17.6%) of the patients with EO-CBD-DB were referred to surgery. Endoscopic treatment was completed in 60 (81.1%) patients after an average of 1.7 (range: 1-6) procedures. These patients were on follow-up for 24.8 (range: 2-46) months. Endoscopic intervention was required in 12 (20%) of them because of recurrent biliary problems. Treatment of the patient who had stricture due to biliary injury during laparoscopic cholecystectomy is still continued.
Conclusions
The presence of EO-CBD-DB should be considered particularly in middle-aged male patients who have duodenal deformity/stenosis. Endoscopic treatment is feasible in these patients. The long-term outcomes of endoscopic therapy need to be compared with surgical treatment.
doi:10.1186/1471-230X-10-142
PMCID: PMC3003235  PMID: 21129223
6.  Primary repair of colon injuries: clinical study of nonselective approach 
BMC Gastroenterology  2010;10:141.
Background
This study was designed to determine the role of primary repair and to investigate the possibility of expanding indications for primary repair of colon injuries using nonselective approach.
Methods
Two groups of patients were analyzed. Retrospective (RS) group included 30 patients managed by primary repair or two stage surgical procedure according to criteria published by Stone (S/F) and Flint (Fl). In this group 18 patients were managed by primary repair. Prospective (PR) group included 33 patients with primary repair as a first choice procedure. In this group, primary repair was performed in 30 cases.
Results
Groups were comparable regarding age, sex, and indexes of trauma severity. Time between injury and surgery was shorter in PR group, (1.3 vs. 3.1 hours). Stab wounds were more frequent in PR group (9:2), and iatrogenic lesions in RS group (6:2). Associated injuries were similar, as well as segmental distribution of colon injuries. S/F criteria and Flint grading were similar.
In RS group 15 primary repairs were successful, while in two cases relaparotomy and colostomy was performed due to anastomotic leakage. One patient died. In PR group, 25 primary repairs were successful, with 2 immediate and 3 postoperative (7-10 days) deaths, with no evidence of anastomotic leakage.
Conclusions
Results of this study justify more liberal use of primary repair in early management of colon injuries.
Trial registration
Current Controlled Trials ISRCTN94682396
doi:10.1186/1471-230X-10-141
PMCID: PMC3014882  PMID: 21126337
7.  Reduction of novel circulating long-chain fatty acids in colorectal cancer patients is independent of tumor burden and correlates with age 
BMC Gastroenterology  2010;10:140.
Background
Serum levels of novel hydroxy polyunsaturated ultra long-chain fatty acids (hPULCFAs) have been previously shown to be reduced in pre-treatment CRC patients compared to disease-free subjects, independent of disease stage. However, whether reduced levels of hPULCFAs result from the presence of cancer is currently unknown, as is the distribution of hPULCFAs in the general population. The following studies were carried out to assess whether conventional therapy would result in restoration of systemic hPULCFAs in CRC patients, and to investigate the relationship between hPULCFA levels and age.
Methods
Tandem mass spectrometry was used to determine serum levels of the 28 carbon-containing hPULCFA C28H46O4 (CRC-446) in the following cohorts: two independent Japanese CRC populations following surgical tumor removal (n = 86), a North American Caucasian CRC cohort (n = 150) following post-surgery combination chemo/radiation therapy, 990 randomly selected anonymized serum samples from subjects ranging between 11 and 99 years of age, as well as longitudinally collected serum samples from healthy normals (n = 8, up to 90 weeks) and stage IV CRC subjects on combination therapy (n = 12, up to 63 weeks).
Results
Serum CRC-446 levels in CRC subjects were significantly lower than controls (mean of 0.297 ± 0.07 ug/ml in controls versus 0.092 ± 0.03 in CRCs, p < 0.001), and were unaffected by surgical tumor removal or by chemo/radiation treatment (p > 0.05 between pre vs post surgery). CRC-446 levels showed a strong inverse association with age (p < E-11) across the randomly-selected cohort of 990 subjects, with no correlation observed in the CRC-positive subjects. Longitudinal intra-subject results, however, showed relatively stable CRC-446 levels over the short term of up to 90 weeks in both disease-free subjects and late-stage CRC patients.
Conclusions
Our findings show that CRC-446 levels are not affected by conventional CRC treatment and inversely correlate with age, which suggest that reduced serum CRC-446 levels likely exist prior to the development of CRC. Extrapolation of the results to a simple screening scenario showed that, compared to fecal blood testing, pre-colonoscopy screening using serum CRC-446 levels would require 80% fewer colonoscopies, would identify risk in subjects under the age of 50, and would result in increased numbers of early cases detected. The precise role these serum metabolites play in the aetiology of cancer development remains to be determined.
doi:10.1186/1471-230X-10-140
PMCID: PMC3009636  PMID: 21114854
8.  A shift from distal to proximal neoplasia in the colon: a decade of polyps and CRC in Italy 
BMC Gastroenterology  2010;10:139.
Background
In the last years a trend towards proximalization of colorectal carcinomas (CRC) has been reported. This study aims to evaluate the distribution of CRC and adenomatous polyps (ADP) to establish the presence of proximalization and to assess the potential predictors.
Methods
We retrieved histology reports of colonic specimens excised during colonoscopy, considering the exams performed between 1997 and 2006 at Cuneo Hospital, Italy. We compared the proportion of proximal lesions in the period 1997-2001 and in the period 2002-2006.
Results
Neoplastic lesions were detected in 3087 people. Proximal CRC moved from 25.9% (1997-2001) to 30.0% (2002-2006). Adjusting for sex and age, the difference was not significant (OR 1.23; 95% CI: 0,95-1,58). The proximal ADP proportion increased from 19.2% (1997-2001) to 26.0% (2002-2006) (OR: 1.43; 95% CI: 1.17-1.89). The corresponding figures for advanced proximal ADP were 6.6% and 9.5% (OR: 1.48; 95% CI: 1.02-2.17). Adjusting for gender, age, diagnostic period, symptoms and number of polyps the prevalence of proximal advanced ADP was increased among people ≥ 70 years compared to those aged 55-69 years (OR 1.49; 95% CI: 1.032.16). The main predictor of proximal advanced neoplasia was the number of polyps detected per exam (> 1 polyp versus 1 polyp: considering all ADP: OR 2.16; 95% CI: 1.59-2.93; considering advanced ADP OR 1.63; 95% CI: 1.08-2.46). Adjusting for these factors, the difference between the two periods was no longer significant.
Conclusions
CRC do not proximalize while a trend towards a proximal shift in adenomas was observed among people ≥ 70 years.
doi:10.1186/1471-230X-10-139
PMCID: PMC3001711  PMID: 21108823
9.  The gene-reduction effect of chromosomal losses detected in gastric cancers 
BMC Gastroenterology  2010;10:138.
Background
The level of loss of heterozygosity (LOH) that reduces a gene dose and exerts a cell-adverse effect is known to be a parameter for the genetic staging of gastric cancers. This study investigated if the cell-adverse effect induced with the gene reduction was a rate-limiting factor for the LOH events in two distinct histologic types of gastric cancers, the diffuse- and intestinal-types.
Methods
The pathologic specimens obtained from 145 gastric cancer patients were examined for the level of LOH using 40 microsatellite markers on eight cancer-associated chromosomes (3p, 4p, 5q, 8p, 9p, 13q, 17p and 18q).
Results
Most of the cancer-associated chromosomes were found to belong to the gene-poor chromosomes and to contain a few stomach-specific genes that were highly expressed. A baseline-level LOH involving one or no chromosome was frequent in diffuse-type gastric cancers. The chromosome 17 containing a relatively high density of genes was commonly lost in intestinal-type cancers but not in diffuse-type cancers. A high-level LOH involving four or more chromosomes tended to be frequent in the gastric cancers with intestinal and mixed differentiation. Disease relapse was common for gastric cancers with high-level LOH through both the hematogenous (38%) and non-hematogenous (36%) routes, and for the baseline-level LOH cases through the non-hematogenous route (67%).
Conclusions
The cell-adverse effect of gene reduction is more tolerated in intestinal-type gastric cancers than in diffuse-type cancers, and the loss of high-dose genes is associated with hematogenous metastasis.
doi:10.1186/1471-230X-10-138
PMCID: PMC2994793  PMID: 21092121
10.  The overmethylated genes in Helicobacter pylori-infected gastric mucosa are demethylated in gastric cancers 
BMC Gastroenterology  2010;10:137.
Background
The transitional-CpG sites between weakly methylated genes and densely methylated retroelements are overmethylated in the gastric mucosa infected with Helicobacter pylori (H. pylori) and they are undermethylated in the gastric cancers depending on the level of loss of heterozygosity (LOH) events. This study delineated the transitional-CpG methylation patterns of CpG-island-containing and -lacking genes in view of the retroelements.
Methods
The transitional-CpG sites of eight CpG-island-containing genes and six CpG-island-lacking genes were semi-quantitatively examined by performing radioisotope-labelling methylation-specific PCR under stringent conditions. The level of LOH in the gastric cancers was estimated using the 40 microsatellite markers on eight cancer-associated chromosomes. Each gene was scored as overmethylated or undermethylated based on an intermediate level of transitional-CpG methylation common in the H. pylori-negative gastric mucosa.
Results
The eight CpG-island genes examined were overmethylated depending on the proximity to the nearest retroelement in the H. pylori-positive gastric mucosa. The six CpG-island-lacking genes were similarly methylated in the H. pylori-positive and -negative gastric mucosa. In the gastric cancers, long transitional-CpG segments of the CpG-island genes distant from the retroelements remained overmethylated, whereas the overmethylation of short transitional-CpG segments close to the retroelements was not significant. Both the CpG-island-containing and -lacking genes tended to be decreasingly methylated in a LOH-level-dependent manner.
Conclusions
The overmethylated genes under the influence of retroelement methylation in the H. pylori-infected stomach are demethylated in the gastric cancers influenced by LOH.
doi:10.1186/1471-230X-10-137
PMCID: PMC2995475  PMID: 21092120
11.  Management of irritable bowel syndrome in primary care: feasibility randomised controlled trial of mebeverine, methylcellulose, placebo and a patient self-management cognitive behavioural therapy website. (MIBS trial) 
BMC Gastroenterology  2010;10:136.
Background
IBS affects 10-22% of the UK population. Abdominal pain, bloating and altered bowel habit affect quality of life, social functioning and time off work. Current GP treatment relies on a positive diagnosis, reassurance, lifestyle advice and drug therapies, but many suffer ongoing symptoms.
A recent Cochrane review highlighted the lack of research evidence for IBS drugs. Neither GPs, nor patients have good evidence to inform prescribing decisions. However, IBS drugs are widely used: In 2005 the NHS costs were nearly £10 million for mebeverine and over £8 million for fibre-based bulking agents. CBT and self-management can be helpful, but poor availability in the NHS restricts their use. We have developed a web-based CBT self-management programme, Regul8, based on an existing evidence based self-management manual and in partnership with patients. This could increase access with minimal increased costs.
Methods/Design
The aim is to undertake a feasibility factorial RCT to assess the effectiveness of the commonly prescribed medications in UK general practice for IBS: mebeverine (anti-spasmodic) and methylcellulose (bulking-agent) and Regul8, the CBT based self-management website.
135 patients aged 16 to 60 years with IBS symptoms fulfilling Rome III criteria, recruited via GP practices, will be randomised to 1 of 3 levels of the drug condition: mebeverine, methylcellulose or placebo for 6 weeks and to 1 of 3 levels of the website condition, Regul8 with a nurse telephone session and email support, Regul8 with minimal email support, or no website, thus creating 9 groups.
Outcomes: Irritable bowel symptom severity scale and IBS-QOL will be measured at baseline, 6 and 12 weeks as the primary outcomes. An intention to treat analysis will be undertaken by ANCOVA for a factorial trial.
Discussion
This pilot will provide valuable information for a larger trial. Determining the effectiveness of commonly used drug treatments will help patients and doctors make informed treatment decisions regarding drug management of IBS symptoms, enabling better targeting of treatment. A web-based self-management CBT programme for IBS developed in partnership with patients has the potential to benefit large numbers of patients with low cost to the NHS. Assessment of the amount of email or therapist support required for the website will enable economic analysis to be undertaken.
Trial Registration
ClinicalTrials.gov Identifier (NCT number): NCT00934973.
doi:10.1186/1471-230X-10-136
PMCID: PMC2998449  PMID: 21087463
12.  Rectal laterally spreading tumors successfully treated in two steps by endoscopic submucosal dissection and endoscopic mucosal resection 
BMC Gastroenterology  2010;10:135.
Background
Endoscopic submucosal dissection (ESD) is an advanced technique of therapeutic endoscopy alternative to endoscopic mucosal resection (EMR) for superficial gastrointestinal neoplasms >2 cm. ESD allows for the direct dissection of the submucosa and large lesions can be resected en bloc. ESD is not limited by resection size, increases histologically complete resection rates and may reduce the local recurrence.
Nevertheless, the technique is time-consuming, technically demanding and associated with a high complication rate. To reduce the risk of complications, different devices and technical advances have been proposed with conflicting results and, still, ESD en bloc resections of huge lesions are associated with increased complications.
Case Presentation
We successfully used a combined ESD/EMR technique for huge rectal laterally spreading tumors (LSTs). ESD was used for circumferential resection of 2/3 of the lesion followed by piecemeal resection (2-3 pieces) of the central part of the tumour.
In all three patients we obtained the complete dissection of the polyp and the complete histological evaluation in absence of complications and recurrence at 6 months' follow up.
Conclusions
In the treatment of rectal LSTs, the combined treatment - ESD/EMR resection may be considered a suitable therapeutic option, indicated in selected cases as an alternative to surgery, in which the two techniques are neither reliable nor safe separately. However, to confirm our results, larger trials with longer follow up are required together with improvement of the technique and of the technical devices.
doi:10.1186/1471-230X-10-135
PMCID: PMC2994792  PMID: 21083919
13.  Ulcerative colitis and irritable bowel patients exhibit distinct abnormalities of the gut microbiota 
BMC Gastroenterology  2010;10:134.
Background
Previous studies suggest a link between gut microbiota and the development of ulcerative colitis (UC) and irritable bowel syndrome (IBS). Our aim was to investigate any quantitative differences in faecal bacterial compositions in UC and IBS patients compared to healthy controls, and to identify individual bacterial species that contribute to these differences.
Methods
Faecal microbiota of 13 UC patients, 11 IBS patients and 22 healthy volunteers were analysed by PCR-Denaturing Gradient Gel Electrophoresis (DGGE) using universal and Bacteroides specific primers. The data obtained were normalized using in-house developed statistical method and interrogated by multivariate approaches. The differentiated bands were excised and identified by sequencing the V3 region of the 16S rRNA genes.
Results
Band profiles revealed that number of predominant faecal bacteria were significantly different between UC, IBS and control group (p < 10-4). By assessing the mean band numbers in UC (37 ± 5) and IBS (39 ± 6), compared to the controls (45 ± 3), a significant decrease in bacterial species is suggested (p = 0.01). There were no significant differences between IBS and UC. Biodiversity of the bacterial species was significantly lower in UC (μ = 2.94, σ = 0.29) and IBS patients (μ = 2.90, σ = 0.38) than controls (μ = 3.25, σ = 0.16; p = 0.01). Moreover, similarity indices revealed greater biological variability of predominant bacteria in UC and IBS compared to the controls (median Dice coefficients 76.1% (IQR 70.9 - 83.1), 73.8% (IQR 67.0 - 77.5) and 82.9% (IQR 79.1 - 86.7) respectively). DNA sequencing of discriminating bands suggest that the presence of Bacteroides vulgatus, B. ovatus, B. uniformis, and Parabacteroides sp. in healthy volunteers distinguishes them from IBS and UC patients. DGGE profiles of Bacteroides species revealed a decrease of Bacteroides community in UC relative to IBS and controls.
Conclusion
Molecular profiling of faecal bacteria revealed abnormalities of intestinal microbiota in UC and IBS patients, while different patterns of Bacteroides species loss in particular, were associated with UC and IBS.
doi:10.1186/1471-230X-10-134
PMCID: PMC3002299  PMID: 21073731
14.  Intestinal Epithelial Serum Amyloid A Modulates Bacterial Growth In Vitro and Pro-Inflammatory Responses in Mouse Experimental Colitis 
BMC Gastroenterology  2010;10:133.
Background
Serum Amyloid A (SAA) is a major acute phase protein of unknown function. SAA is mostly expressed in the liver, but also in other tissues including the intestinal epithelium. SAA reportedly has anti-bacterial effects, and because inflammatory bowel diseases (IBD) result from a breakdown in homeostatic interactions between intestinal epithelia and bacteria, we hypothesized that SAA is protective during experimental colitis.
Methods
Intestinal SAA expression was measured in mouse and human samples. Dextran sodium sulfate (DSS) colitis was induced in SAA 1/2 double knockout (DKO) mice and in wildtype controls. Anti-bacterial effects of SAA1/2 were tested in intestinal epithelial cell lines transduced with adenoviral vectors encoding the CE/J SAA isoform or control vectors prior to exposure to live Escherichia coli.
Results
Significant levels of SAA1/SAA2 RNA and SAA protein were detected by in situ hybridization and immunohistochemistry in mouse colonic epithelium. SAA3 expression was weaker, but similarly distributed. SAA1/2 RNA was present in the ileum and colon of conventional mice and in the colon of germfree mice. Expression of SAA3 was strongly regulated by bacterial lipopolysaccharides in cultured epithelial cell lines, whereas SAA1/2 expression was constitutive and not LPS inducible. Overexpression of SAA1/2 in cultured epithelial cell lines reduced the viability of co-cultured E. coli. This might partially explain the observed increase in susceptibility of DKO mice to DSS colitis. SAA1/2 expression was increased in colon samples obtained from Crohn's Disease patients compared to controls.
Conclusions
Intestinal epithelial SAA displays bactericidal properties in vitro and could play a protective role in experimental mouse colitis. Altered expression of SAA in intestinal biopsies from Crohn's Disease patients suggests that SAA is involved in the disease process..
doi:10.1186/1471-230X-10-133
PMCID: PMC2992040  PMID: 21067563
15.  Mycoplasma hyorhinis infection in gastric carcinoma and its effects on the malignant phenotypes of gastric cancer cells 
BMC Gastroenterology  2010;10:132.
Background
Mycoplasma hyorhinis infection has been postulated to play a role in the development of several types of cancer, but the direct evidence and mechanism remained to be determined.
Methods
Immunohistochemistry assay and nested polymerase-chain reaction (PCR) were performed to examine the mycoplasma hyorhinis infection in gastric cancer tissues. Statistical analysis was used to check the association between mycoplasma infection and clinicopathologic parameters. Transwell chamber assay and metastasis assay were used to evaluate mycoplasma hyorhinis' effects on metastasis in vitro and in vivo. Mycoplasma hyorhinis-induced extracellular signal-regulated kinase (ERK) and epidermal growth factor receptor (EGFR) activation were investigated by Western blot.
Results
Mycoplasma hyorhinis infection in gastric cancer tissues was revealed and statistical analysis indicated a significant association between mycoplasma infections and lymph node metastasis, Lauren's Classification, TNM stage, and age of the patients. Mycoplasma hyorhinis promoted tumor cell migration, invasion and metastasis in vitro and in vivo, which was possibly associated with the enhanced phosphorylation of EGFR and ERK1/2. The antibody against p37 protein of Mycoplasma hyorhinis could inhibit the migration of the infected cells.
Conclusions
The infection of mycoplasma hyorhinis may contribute to the development of gastric cancer and Mycoplasma hyorhinis-induced malignant phenotypes were possibly mediated by p37.
doi:10.1186/1471-230X-10-132
PMCID: PMC2993648  PMID: 21062494
16.  The role of colonoscopy in the management of intestinal obstruction: a 20-year retrospective study 
BMC Gastroenterology  2010;10:130.
Purpose
The aim of the study was to assess the use colonoscopy over time in the assessment of large bowel obstruction in a tertiary university hospital.
Methods
Retrospective analysis of surgical and colonoscopy records for the years 1990-2009 in a university hospital. All patients diagnosed with non-conservatively managed bowel obstruction were included.
Results
We recorded 644 patients diagnosed with non-conservatively managed bowel obstruction. Four hundred forty-one (67.3%) were managed only by surgery, 157 (23.6%) were managed by colonoscopy, and 46 (6.9%) by combined colonoscopy and surgery. Patients over 77 years were more likely to receive colonoscopy as monotherapy or combined with surgery as compared to younger patients. Management by colonoscopy only and by combined colonoscopy and surgery increased over time.
Conclusions
Colonoscopy in the management of non-conservatively treated bowel obstruction increased over time. However, therapeutic colonoscopy still has a limited role in bowel obstruction either as monotherapy or combined with surgery.
doi:10.1186/1471-230X-10-130
PMCID: PMC2988711  PMID: 21059218
17.  Lymphatic marker podoplanin/D2-40 in human advanced cirrhotic liver- Re-evaluations of microlymphatic abnormalities 
BMC Gastroenterology  2010;10:131.
Background
From the morphological appearance, it was impossible to distinguish terminal portal venules from small lymphatic vessels in the portal tract even using histochemical microscopic techniques. Recently, D2-40 was found to be expressed at a high level in lymphatic endothelial cells (LECs). This study was undertaken to elucidate hepatic lymphatic vessels during progression of cirrhosis by examining the expression of D2-40 in LECs.
Methods
Surgical wedge biopsy specimens were obtained from non-cirrhotic portions of human livers (normal control) and from cirrhotic livers (LC) (Child A-LC and Child C-LC). Immunohistochemical (IHC), Western blot, and immunoelectron microscopic studies were conducted using D2-40 as markers for lymphatic vessels, as well as CD34 for capillary blood vessels.
Results
Imunostaining of D2-40 produced a strong reaction in lymphatic vessels only, especially in Child C-LC. It was possible to distinguish the portal venules from the small lymphatic vessels using D-40. Immunoelectron microscopy revealed strong D2-40 expression along the luminal and abluminal portions of the cell membrane of LECs in Child C-LC tissue.
Conclusion
It is possible to distinguish portal venules from small lymphatic vessels using D2-40 as marker. D2-40- labeling in lymphatic capillary endothelial cells is related to the degree of fibrosis in cirrhotic liver.
doi:10.1186/1471-230X-10-131
PMCID: PMC2995474  PMID: 21059220
18.  Laparoscopic versus conventional appendectomy - a meta-analysis of randomized controlled trials 
BMC Gastroenterology  2010;10:129.
Background
Although laparoscopic surgery has been available for a long time and laparoscopic cholecystectomy has been performed universally, it is still not clear whether open appendectomy (OA) or laparoscopic appendectomy (LA) is the most appropriate surgical approach to acute appendicitis. The purpose of this work is to compare the therapeutic effects and safety of laparoscopic and conventional "open" appendectomy by means of a meta-analysis.
Methods
A meta-analysis was performed of all randomized controlled trials published in English that compared LA and OA in adults and children between 1990 and 2009. Calculations were made of the effect sizes of: operating time, postoperative length of hospital stay, postoperative pain, return to normal activity, resumption of diet, complications rates, and conversion to open surgery. The effect sizes were then pooled by a fixed or random-effects model.
Results
Forty-four randomized controlled trials with 5292 patients were included in the meta-analysis. Operating time was 12.35 min longer for LA (95% CI: 7.99 to 16.72, p < 0.00001). Hospital stay after LA was 0.60 days shorter (95% CI: -0.85 to -0.36, p < 0.00001). Patients returned to their normal activity 4.52 days earlier after LA (95% CI: -5.95 to -3.10, p < 0.00001), and resumed their diet 0.34 days earlier(95% CI: -0.46 to -0.21, p < 0.00001). Pain after LA on the first postoperative day was significantly less (p = 0.008). The overall conversion rate from LA to OA was 9.51%. With regard to the rate of complications, wound infection after LA was definitely reduced (OR = 0.45, 95% CI: 0.34 to 0.59, p < 0.00001), while postoperative ileus was not significantly reduced(OR = 0.91, 95% CI: 0.57 to 1.47, p = 0.71). However, intra-abdominal abscess (IAA), intraoperative bleeding and urinary tract infection (UIT) after LA, occurred slightly more frequently(OR = 1.56, 95% CI: 1.01 to 2.43, p = 0.05; OR = 1.56, 95% CI: 0.54 to 4.48, p = 0.41; OR = 1.76, 95% CI: 0.58 to 5.29, p = 0.32).
Conclusion
LA provides considerable benefits over OA, including a shorter length of hospital stay, less postoperative pain, earlier postoperative recovery, and a lower complication rate. Furthermore, over the study period it was obvious that there had been a trend toward fewer differences in operating time for the two procedures. Although LA was associated with a slight increase in the incidence of IAA, intraoperative bleeding and UIT, it is a safe procedure. It may be that the widespread use of LA is due to its better therapeutic effect.
doi:10.1186/1471-230X-10-129
PMCID: PMC2988072  PMID: 21047410
19.  Vesicocutaneous fistula formation during treatment with sunitinib malate: Case report 
BMC Gastroenterology  2010;10:128.
Background
The oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described.
Case presentation
We describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient.
Conclusion
This is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.
doi:10.1186/1471-230X-10-128
PMCID: PMC2988710  PMID: 21040530
20.  Laparoscopic and open resection for colorectal cancer: an evaluation of cellular immunity 
BMC Gastroenterology  2010;10:127.
Background
Colorectal cancer is one kind of frequent malignant tumors of the digestive tract which gets high morbidity and mortality allover the world. Despite the promising clinical results recently, less information is available regarding the perioperative immunological effects of laparoscopic surgery when compared with the open surgery. This study aimed to compare the cellular immune responses of patients who underwent laparoscopic(LCR) and open resections(OCR) for colorectal cancer.
Methods
Between Mar 2009 and Sep 2009, 35 patients with colorectal carcinoma underwent LCR by laparoscopic surgeon. These patients were compared with 33 cases underwent conventional OCR by colorectal surgeon. Clinical data about the patients were collected prospectively. Comparison of the operative details and postoperative outcomes between laparoscopic and open resection was performed. Peripheral venous blood samples from these 68 patients were taken prior to surgery as well as on postoperative days(POD) 1, 4 and 7. Cell counts of total white blood cells, neutrophils, lymphocyte subpopulations, natural killer(NK) cells as well as CRP were determined by blood counting instrument, flow cytometry and hematology analyzer.
Results
There was no difference in the age, gender and tumor status between the two groups. The operating time was a little longer in the laparoscopic group (P > 0.05), but the blood loss was less (P = 0.039). Patients with laparoscopic resection had earlier return of bowel function and earlier resumption of diet as well as shorter median hospital stay (P < 0.001). Compared with OCR group, cell numbers of total lymphocytes, CD4+T cells and CD8+T cells were significant more in LCR group (P < 0.05) on POD 4, while there was no difference in the CD45RO+T or NK cell numbers between the two groups. Cellular immune responds were similar between the two groups on POD1 and POD7.
Conclusions
Laparoscopic colorectal resection gets less surgery stress and short-term advantages compared with open resection. Cellular immune respond appears to be less affected by laparoscopic colorectal resection when compared with open resection.
doi:10.1186/1471-230X-10-127
PMCID: PMC2988071  PMID: 21029461
21.  Association of IL1B -511C/-31T haplotype and Helicobacter pylori vacA genotypes with gastric ulcer and chronic gastritis 
BMC Gastroenterology  2010;10:126.
Background
The association between proinflammatory cytokine gene polymorphisms and gastric diseases related to Helicobacter pylori varies by population and geographic area.
Our objective was to determine if the IL-1B -511 T>C and -31 C>T polymorphisms and H. pylori vacA genotypes are associated with risk of chronic gastritis and gastric ulcer in a Mexican population.
Methods
We conducted endoscopic studies in 128 patients with symptoms of dyspepsia. We took two biopsies from the body, antrum, or ulcer edge from each patient, and classified our histopathological findings according to the Sydney System. H. pylori infection and vacA genotyping were accomplished via PCR from total DNA of the gastric biopsies. We confirmed the presence of anti-H. pylori serum IgG and IgM in 102 control subjects. In both case subjects and control subjects, the IL-1B -511 T>C polymorphism was genotyped by PCR-RFLPs and the IL-1B -31 C>T polymorphism was genotyped by pyrosequencing.
Results
Sixty-two point seven (62.7%) of the 102 control subjects were H. pylori-seropositive. Among the case subjects, 100 were diagnosed with chronic gastritis and 28 with gastric ulcer. We found that 77% of the patients with chronic gastritis and 85.7% of the patients with gastric ulcer were H. pylori-positive. The predominant H. pylori genotype was vacA s1m1 (58.4%) and the most frequent subtype was vacA s1. The -511 TC, (rs16944 -511 T>C) genotype and the -511C allele were associated with chronic gastritis (OR = 3.1, 95% CI = 1.4-6.8 and OR = 3.0, 95% CI = 1.4-6.0, respectively). The subjects carrying -31T (rs1143627 -31 C>T) were found to be at a higher risk of having chronic gastritis (OR = 2.8, 95% CI = 1.3-5.8). The IL-1B -511C/-31T haplotype was associated with chronic gastritis (OR = 2.1, 95% CI = 1.2-3.8) but not with gastric ulcer.
Conclusions
The H. pylori vacA genotypes identified herein were similar to those reported for other regions of Mexico. The vacA s1m1 genotype was not associated with gastric ulcer. In the southern Mexican population, the IL-1B -511C and -31T alleles and the -511C/-31T and -511T/-31T haplotypes are associated with increased risk of chronic gastritis and gastric ulcer.
doi:10.1186/1471-230X-10-126
PMCID: PMC2988070  PMID: 20979650
22.  IQGAP1 and IQGAP2 are Reciprocally Altered in Hepatocellular Carcinoma 
BMC Gastroenterology  2010;10:125.
Background
IQGAP1 and IQGAP2 are homologous members of the IQGAP family of scaffold proteins. Accumulating evidence implicates IQGAPs in tumorigenesis. We recently reported that IQGAP2 deficiency leads to the development of hepatocellular carcinoma (HCC) in mice. In the current study we extend these findings, and investigate IQGAP1 and IQGAP2 expression in human HCC.
Methods
IQGAP1 and IQGAP2 protein expression was assessed by Western blotting and immunohistochemistry. IQGAP mRNA was measured by quantitative RT-PCR. The methylation status of the Iqgap2 promoter was determined by pyrosequencing of bisulfite-treated genomic DNA.
Results
IQGAP1 and IQGAP2 expression was reciprocally altered in 6/6 liver cancer cell lines. Similarly, immunohistochemical staining of 82 HCC samples showed that IQGAP2 protein expression was reduced in 64/82 (78.0%), while IQGAP1 was present in 69/82 (84.1%). No IQGAP1 staining was detected in 23/28 (82.1%) normal livers, 4/4 (100.0%) hepatic adenomas and 23/23 (100.0%) cirrhosis cases, while IQGAP2 was increased in 22/28 (78.6%), 4/4 (100.0%) and 23/23 (100.0%), respectively. Although the Iqgap2 promoter was not hypermethylated in HCC at any of the 25 CpG sites studied (N = 17), IQGAP2 mRNA levels were significantly lower in HCC specimens (N = 23) than normal livers (N = 6).
Conclusions
We conclude that increased IQGAP1 and/or decreased IQGAP2 contribute to the pathogenesis of human HCC. Furthermore, downregulation of IQGAP2 in HCC occurs independently of hypermethylation of the Iqgap2 promoter. Immunostaining of IQGAP1 and IQGAP2 may aid in the diagnosis of HCC, and their pharmacologic modulation may represent a novel therapeutic strategy for the treatment of liver cancer.
doi:10.1186/1471-230X-10-125
PMCID: PMC2988069  PMID: 20977743
23.  Management of patients with biliary sphincter of Oddi disorder without sphincter of Oddi manometry 
BMC Gastroenterology  2010;10:124.
Background
The paucity of controlled data for the treatment of most biliary sphincter of Oddi disorder (SOD) types and the incomplete response to therapy seen in clinical practice and several trials has generated controversy as to the best course of management of these patients. In this observational study we aimed to assess the outcome of patients with biliary SOD managed without sphincter of Oddi manometry.
Methods
Fifty-nine patients with biliary SOD (14% type I, 51% type II, 35% type III) were prospectively enrolled. All patients with a dilated common bile duct were offered endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy whereas all others were offered medical treatment alone. Patients were followed up for a median of 15 months and were assessed clinically for response to treatment.
Results
At follow-up 15.3% of patients reported complete symptom resolution, 59.3% improvement, 22% unchanged symptoms, and 3.4% deterioration. Fifty-one percent experienced symptom resolution/improvement on medical treatment only, 12% after sphincterotomy, and 10% after both medical treatment/sphincterotomy. Twenty percent experienced at least one recurrence of symptoms after initial response to medical and/or endoscopic treatment. Fifty ERCP procedures were performed in 24 patients with an 18% complication rate (16% post-ERCP pancreatitis). The majority of complications occurred in the first ERCP these patients had. Most complications were mild and treated conservatively. Age, gender, comorbidity, SOD type, dilated common bile duct, presence of intact gallbladder, or opiate use were not related to the effect of treatment at the end of follow-up (p > 0.05 for all).
Conclusions
Patients with biliary SOD may be managed with a combination of endoscopic sphincterotomy (performed in those with dilated common bile duct) and medical therapy without manometry. The results of this approach with regards to symptomatic relief and ERCP complication rate are comparable to those previously published in the literature in cohorts of patients assessed by manometry.
doi:10.1186/1471-230X-10-124
PMCID: PMC2975654  PMID: 20969779
24.  Maximizing the general success of cecal intubation during propofol sedation in a multi-endoscopist academic centre 
BMC Gastroenterology  2010;10:123.
Background
Achieving the target of 95% colonoscopy completion rate at centres conducting colorectal screening programs is an important issue. Large centres and teaching hospitals employing endoscopists with different levels of training and expertise risk achieving worse results. Deep sedation with propofol in routine colonoscopy could maximize the results of cecal intubation.
Methods
The present study on the experience of a single centre focused on estimating the overall completion rate of colonoscopies performed under routine propofol sedation at a large teaching hospital with many operators involved, and on assessing the factors that influence the success rate of the procedure and how to improve this performance, analyzing the aspects relating to using of deep sedation. Twenty-one endoscopists, classified by their level of specialization in colonoscopic practice, performed 1381 colonoscopies under deep sedation. All actions needed for the anaesthesiologist to restore adequate oxygenation or hemodynamics, even for transient changes, were recorded.
Results
The "crude" overall completion rate was 93.3%. This finding shows that with routine deep sedation, the colonoscopy completion rate nears, but still does not reach, the target performance for colonoscopic screening programs, at centers where colonoscopists of difference experience are employed in such programs.
Factors interfering with cecal intubation were: inadequate colon cleansing, endoscopists' expertise in colonoscopic practice, patients' body weight under 60 kg or age over 71 years, and the need for active intervention by the anaesthesiologist. The most favourable situation - a patient less than 71 years old with a body weight over 60 kg, an adequate bowel preparation, a "highly experienced specialist" performing the test, and no need for active anaesthesiological intervention during the procedure - coincided with a 98.8% probability of the colonoscopy being completed.
Conclusions
With routine deep sedation, the colonoscopy completion rate nears the target performance for colonoscopic screening programs, at centers where colonoscopists of difference experience are employed in such programs. Organizing the daily workload to prevent negative factors affecting the success rate from occurring in combination may enable up to 85% of incomplete procedures to be converted into successful colonoscopies.
doi:10.1186/1471-230X-10-123
PMCID: PMC2975653  PMID: 20961451
25.  Life-threatening hypersplenism due to idiopathic portal hypertension in early childhood: case report and review of the literature 
BMC Gastroenterology  2010;10:122.
Background
Idiopathic portal hypertension (IPH) is a disorder of unknown etiology and is characterized clinically by portal hypertension, splenomegaly, and hypersplenism accompanied by pancytopenia. This study evaluates the pathogenic concept of the disease by a systematic review of the literature and illustrates novel pathologic and laboratory findings.
Case Presentation
We report the first case of uncontrolled splenic hyperperfusion and enlargement with subsequent hypersplenism leading to life-threatening complications of IPH in infancy and emergent splenectomy.
Conclusions
Our results suggest that splenic NO and VCAM-1, rather than ET-1, have a significant impact on the development of IPH, even at a very early stage of disease. The success of surgical interventions targeting the splenic hyperperfusion suggests that the primary defect in the regulation of splenic blood flow seems to be crucial for the development of IPH. Thus, beside other treatment options splenectomy needs to be considered as a prime therapeutic option for IPH.
doi:10.1186/1471-230X-10-122
PMCID: PMC2988068  PMID: 20961440

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