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1.  Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells 
BMC Gastroenterology  2015;15:22.
Background
Non-alcoholic steatohepatitis (NASH) is associated with hepatic fibrogenesis. Despite well-known cholesterol-lowering action of statins, their mechanisms against NASH-mediated fibrogenesis remain unclear. This study aimed at investigating the in vitro and in vivo anti-fibrotic properties of fluvastatin (Flu).
Methods
Palmitate (PA)-induced changes in intracellular hydrogen peroxide levels in primary rat hepatocytes (PRHs) and human hepatoma cell line (HepG2) were quantified by dichlorofluorescein diacetate (DCF-DA) dye assay, whereas changes in expressions of NADPH oxidase gp91phox subunit, α-smooth muscle actin (α-SMA), and NFκB p65 nuclear translocation were quantified with Western blotting. Quantitative real-time polymerase chain reaction (q-PCR) was used to investigate mRNA expressions of pro-inflammatory genes (ICAM-1, IL-6, TNF-α). Conditioned medium (CM) from PA-treated PRHs was applied to cultured rat hepatic stellate cell line, HSC-T6, with or without Flu-pretreatment for 2 h. Pro-fibrogenic gene expressions (COL1, TIMP-1, TGF-β1, α-SMA) and protein expression of α-SMA were analyzed. In vivo study using choline-deficient L-amino acid defined (CDAA) diet-induced rat NASH model was performed by randomly assigning Wistar rats (n = 28) to normal controls (n = 4), CDAA diet with vehicles, and CDAA diet with Flu (5 mg/kg or 10 mg/kg) (n = 8 each) through gavage for 4 or 8 weeks. Livers were harvested for histological, Western blot (α-SMA), and q-PCR analyses for expressions of pro-inflammatory (IL-6, iNOS, ICAM-1) and pro-fibrogenic (Col1, α-SMA, TIMP-1) genes.
Results
In vitro, Flu (1–20 μM) inhibited PA-induced free-radical production, gp91phox expression, and NFκB p65 translocation in HepG2 and PRHs, while CM-induced α-SMA protein expression and pro-fibrogenic gene expressions in HSC-T6 were suppressed in Flu-pretreated cells compared to those without pretreatment. Moreover, α-SMA protein expression was significantly decreased in HSC-T6 cultured with CM from PA-Flu-treated PRHs compared to those cultured with CM from PA-treated PRHs. Flu also reduced steatosis and fibrosis scores, α-SMA protein expression, mRNA expression of pro-inflammatory and pro-fibrogenic genes in livers of CDAA rats.
Conclusions
We demonstrated PA-induced HSC activation through paracrine effect of hepatocyte in vitro that was significantly suppressed by pre-treating HSC with Flu. In vivo, Flu alleviated steatosis-induced HSC activation and hepatic fibrogenesis through mitigating inflammation and oxidative stress, suggesting possible therapeutic role of Flu against NASH.
doi:10.1186/s12876-015-0248-8
PMCID: PMC4336504
Non-alcoholic fatty liver disease; Steatohepatitis; Statins; Fibrogenesis; Hepatocyte; Paracrine effect
2.  The NFKB1 polymorphism (rs4648068) is associated with the cell proliferation and motility in gastric cancer 
BMC Gastroenterology  2015;15:21.
Background
We have demonstrated previously that NFKB1 single nucleotide polymorphism (SNP) rs4648068 GG homozygote was associated with the increased risk of gastric cancer in Chinese Han population. In this study, we constructed the recombinant plasmid pGL3-AA, pGL3-GG, pGL3-AA-NFKB and pGL3-GG-NFKB to investigate the function of rs4648068 by cell biology experiments.
Methods
Quantitative real-time PCR was used to detect NFKB1 SNP rs4648068 genotype in the patients with gastric cancer. Anti-NF-κB1 p50 polyclonal antibodies were used for immunohistochemical analysis of the tissue specimens. The subsection of NFKB1 containing the promoter site and adjacent three consecutive exons were obtained by PCR technique and subcloned into the vector pGL3-Basic. Dual-Luciferase reporter assay was used to detect the transcriptional activity of the constructed promoter. Effects of transcription factor NFKB1 on C/EBPβ expression were determined by chromatin immunoprecipitation and Western analysis. Furthermore, proliferation and invasion ability of the transduced cell were also measured and compared.
Results
Intensive staining for p50 expression was observed in the tissues of GG genotype patients, compared with those of GA group and AA genotype patients. The transcriptional activity of rs4648068 (A > G) by dual-Luciferase reporter assay suggested that the luciferase activity of homozygote group (pGL3-GG) was greater than that of the control (pGL3-AA), especially at the stimulation of LPS. We found that the luciferase activity was also influenced by pGL3-GG levels. The effects of NFKB1 rs4648068 were enhanced by rs4648065 on the transduced cells. The interaction between NFKB1 promoter nucleotide sequence and C/EBPβ was regulated by the functional SNP rs4648068 in SGC-7901 cells. Our data indicated that the transduction of pGL3 expression plasmid pGL3-GG-NFKB improved the proliferation and motility of gastric cancer cells. Correspondingly, the homozygote GG of SNP rs4648068 strengthened the transcriptional activity of NFKB1 and influenced the cell biological activity.
Conclusion
The transcriptional activity of NFKB1 was associated with SNP rs4648068, and this functional SNP site has the important effects on cell proliferation and motility.
doi:10.1186/s12876-015-0243-0
PMCID: PMC4331381
NFKB1; Polymorphism; Gastric cancer; Susceptibility; Single nucleotide polymorphism
3.  Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial 
BMC Gastroenterology  2015;15:20.
Background
Liver surgery in perihilar cholangiocarcinoma (PHC) is associated with high postoperative morbidity because the tumor typically causes biliary obstruction. Preoperative biliary drainage is used to create a safer environment prior to liver surgery, but biliary drainage may be harmful when severe drainage-related complications deteriorate the patients’ condition or increase the risk of postoperative morbidity. Biliary drainage can cause cholangitis/cholecystitis, pancreatitis, hemorrhage, portal vein thrombosis, bowel wall perforation, or dehydration. Two methods of preoperative biliary drainage are mostly applied: endoscopic biliary drainage, which is currently used in most regional centers before referring patients for surgical treatment, and percutaneous transhepatic biliary drainage. Both methods are associated with severe drainage-related complications, but two small retrospective series found a lower incidence in the number of preoperative complications after percutaneous drainage compared to endoscopic drainage (18-25% versus 38-60%, respectively). The present study randomizes patients with potentially resectable PHC and biliary obstruction between preoperative endoscopic or percutaneous transhepatic biliary drainage.
Methods/Design
The study is a multi-center trial with an “all-comers” design, randomizing patients between endoscopic or percutaneous transhepatic biliary drainage. All patients selected to potentially undergo a major liver resection for presumed PHC are eligible for inclusion in the study provided that the biliary system in the future liver remnant is obstructed (even if they underwent previous inadequate endoscopic drainage). Primary outcome measure is the total number of severe preoperative complications between randomization and exploratory laparotomy. The study is designed to detect superiority of percutaneous drainage: a provisional sample size of 106 patients is required to detect a relative decrease of 50% in the number of severe preoperative complications (alpha = 0.95; beta = 0.8). Interim analysis after inclusion of 53 patients (50%) will provide the definitive sample size. Secondary outcome measures encompass the success of biliary drainage, quality of life, and postoperative morbidity and mortality.
Discussion
The DRAINAGE trial is designed to identify a difference in the number of severe drainage-related complications after endoscopic and percutaneous transhepatic biliary drainage in patients selected to undergo a major liver resection for perihilar cholangiocarcinoma.
Trial registration
Netherlands Trial Register [NTR4243, 11 October 2013].
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0251-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0251-0
PMCID: PMC4332425
Perihilar cholangiocarcinoma; Resection; Preoperative biliary drainage; Complications
4.  Epidemiology of appendicitis and appendectomy for the low-income population in Taiwan, 2003–2011 
BMC Gastroenterology  2015;15:18.
Background
Although numerous epidemiological studies on appendicitis have been conducted worldwide, only a few studies have paid attention to the effect of socioeconomic status on appendicitis, particularly studies focusing on the low-income population (LIP).
Methods
We analyzed the epidemiological features of appendicitis in Taiwan using data from the National Health Insurance Research Database from 2003 to 2011. All cases diagnosed as appendicitis were enrolled.
Results
Between 2003 and 2011, 2,916 patients from the LIP and 209,206 patients from the normal population (NP) were diagnosed with appendicitis. Our finding revealed that the ratios of comorbidities, complicated appendicitis, and readmissions in LIP patients were slightly higher than those of NP patients. LIP patients were more likely to live in suburban and rural areas, and hence a higher proportion of them were hospitalized in a district or regional hospital compared with NP patients. The crucially finding was that the overall incidence ratios of appendicitis, acute appendicitis, and perforated appendicitis in the LIP were substantially higher than those in the NP (36.25%, 35.33%, and 37.28%, respectively). The mean LOS in LIP patients was longer than that of NP patients. The overall case-fatality ratio of appendectomy in the LIP was higher when compared with the NP (0.41% versus 0.12%, p < 0.05). We also observed that appendicitis was occurred frequently in male patients, with a higher incidence for those aged 15–29 years in both the LIP and NP. The incidences of incidental appendectomy showed a decreasing trend in both the LIP and NP. Finally, a valuable discovery was that the total hospital cost was comparable between the laparoscopic appendectomy (LA) and open appendectomy (OA) (1,178 ± 13 USD versus 1,191 ± 19 USD, p < 0.05) in LIP patients because they saved more hospitalization costs than NP patients when the previous one chose the LA.
Conclusion
This study confirmed that a lower socioeconomic status has significantly negative impact on the occurrence and treatment of appendicitis and appendectomy. In terms of hospital costs and LOS, LIP patients benefit more from the LA approach than they do from the OA approach in the treatment of appendicitis.
doi:10.1186/s12876-015-0242-1
PMCID: PMC4329676
Appendicitis; Appendectomy; Epidemiology; Low-income population; Socioeconomic status
5.  Gastric epithelial dysplasia: characteristics and long-term follow-up results after endoscopic resection according to morphological categorization 
BMC Gastroenterology  2015;15:17.
Background
Gastric epithelial dysplasia (GED) can be morphologically categorized into adenomatous and foveolar types. To date, there have been few studies on the clinical characteristics of GEDs according to the morphologic types. Therefore, we here aimed to elucidate the clinicopathologic characteristics of patients with GED and the long-term follow-up results after endoscopic resection according to the morphologic characteristics of GEDs.
Methods
A total of 357 patients who underwent endoscopic resection for GEDs at Pusan National University Hospital between January 2008 and December 2009 were included in the study. GEDs were morphologically categorized into adenomatous, foveolar, and hybrid types on histologic examination. The clinicopathologic characteristics of patients with GEDs and outcomes of endoscopic resection were analyzed.
Results
Patients with GED were divided into 3 groups: adenomatous (n = 167, 46.8%), foveolar (n = 103, 28.9%), and hybrid (n = 87, 24.3%) types. Compared to the adenomatous type, foveolar type lesions were more frequently located in the antrum/pylorus, flat/depressed lesions, and normal/reddish in color; and showed more frequent high-grade dysplasia. During the follow–up period (median, 37.3 months), the overall incidence of synchronous and metachronous lesions was 20.8% and 20.1%, respectively; of these, the incidence of synchronous and metachronous gastric cancer was 8.7% and 5.4%, respectively. There were no significant differences in the incidence of synchronous and metachronous lesions according to morphologic types.
Conclusion
GEDs appear to have different clinicopathologic characteristics according to morphologic types. Irrespective of the morphology, synchronous and metachronous gastric cancers are commonly found after endoscopic resection of GEDs. Therefore, close follow-up surveillance after endoscopic resection of GEDs should be performed for all patients.
doi:10.1186/s12876-015-0249-7
PMCID: PMC4329662
Stomach; Gastric epithelial dysplasia; Endoscopic resection
6.  BMC Gastroenterology reviewer acknowledgement 2014 
BMC Gastroenterology  2015;15:13.
Contributing reviewers
The editors of BMC Gastroenterology would like to thank all our reviewers who have contributed to the journal in Volume 14 (2014).
doi:10.1186/s12876-015-0238-x
PMCID: PMC4318201  PMID: 25653101
7.  Co-occurrence of IBS and symptoms of anxiety or depression, among Norwegian twins, is influenced by both heredity and intrauterine growth 
BMC Gastroenterology  2015;15:9.
Background
Environmental and genetic factors contribute to variation in irritable bowel syndrome (IBS), anxiety and depression. Comorbidity between these disorders is high. A previous investigation of our population-based twin cohort revealed that low birth weight increased the risk for development of IBS, with environmental influences in utero as the most relevant contributing factor. We hypothesise that both intrauterine and genetic factors influence the co-occurrence of IBS and symptoms of anxiety and depression.
Methods
A postal questionnaire sent to 12700 Norwegian twins born between 1967 and 1979 comprised a checklist of 31 illnesses and symptoms, including IBS and symptoms of anxiety and depression. The influence of genetic factors and intrauterine growth on comorbidity between these disorders were analysed in the full sample and compared to those based on only monozygotic (MZ) twin pairs discordant for IBS (95 pairs) in birth weight group < 2500 g and ≥ 2500 g.
Results
In the co-twin analyses restricted growth (birth weight < 2500 g) was significantly associated with anxiety and depression (average birth weight difference of 181.0 g (p <0.0001) and 249.9 g (p < 0.0001), respectively).
The analysis of the full sample revealed that IBS was significantly associated with symptoms of anxiety (adjusted OR = 2.5, 95% CI: 1.9, 3.3) and depression (adjusted OR = 2.3. 95% CI: 1.8, 3.0). Analyses of MZ pairs discordant for IBS indicated significant associations between IBS and symptoms of anxiety (OR = 3.7, 95% CI: 1.3, 10.5) and between IBS and symptoms of depression (OR = 4.2, 95% CI: 1.7, 9.9) only in the birth weight group below 2500 g.
Conclusion
Our findings suggest that genetic factors partly explain the association between IBS and symptoms of anxiety and depression. In the low range of birth weight (<2500 g), restricted fetal growth seems to be a common contributing factor to the co-occurrence between these disorders.
doi:10.1186/s12876-015-0237-y
PMCID: PMC4321711  PMID: 25649866
IBS; Anxiety; Depression; Comorbidity; Birth weight; Norwegian twin registry (NTR)
8.  Increased use of hypnotics in individuals with celiac disease: a nationwide case-control study 
BMC Gastroenterology  2015;15:10.
Background
Although poor sleep is common in numerous gastrointestinal diseases, data are scarce on the risk of poor sleep in celiac disease. The objective of this study was to estimate the risk of repeated use of hypnotics among individuals with celiac disease as a proxy measure for poor sleep.
Methods
This is a nationwide case–control study including 2933 individuals with celiac disease and 14,571 matched controls from the general Swedish population. Poor sleep was defined as ≥2 prescriptions of hypnotics using prospective data from the National Prescribed Drug Register (data capture: July 2005-January 2008). We estimated odds ratios and hazard ratios for poor sleep before and after celiac disease diagnosis respectively.
Results
In this study, poor sleep was seen in 129/2933 individuals (4.4%) with celiac disease, as compared with 487/14,571 controls (3.3%) (odds ratio = 1.33; 95% CI = 1.08-1.62). Data restricted to sleep complaints starting ≥1 year before celiac disease diagnosis revealed largely unchanged risk estimates (odds ratio = 1.23; 95% CI = 0.88-1.71) as compared with the overall risk (odds ratio 1.33). The risk of poor sleep in celiac disease was essentially not influenced by adjustment for concomitant psychiatric comorbidity (n = 1744, adjusted odds ratio =1.26; 95% CI = 1.02-1.54) or restless legs syndrome (n = 108, adjusted odds ratio = 1.33; 95% CI = 1.08-1.63). Poor sleep was also more common after celiac disease diagnosis as compared with matched controls (hazard ratio = 1.36; 95% CI = 1.30-1.41).
Conclusions
In conclusion, individuals with celiac disease suffer an increased risk of poor sleep, both before and after diagnosis. Although we cannot rule out that surveillance bias has contributed to our findings, our results are consistent with previous data suggesting that sleep complaints may be a manifestation of celiac disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0236-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0236-z
PMCID: PMC4322544  PMID: 25649738
Coeliac; Immune-mediated; Insomnia; Sleep disorders; Small intestine
9.  Utility of the diffusion-weighted imaging for activity evaluation in Crohn’s disease patients underwent magnetic resonance enterography 
BMC Gastroenterology  2015;15:12.
Background
Cross-sectional imaging techniques as magnetic resonance enterography (MRE) may offer additional information on transmural inflammation, stricturing and fistulising complications in Crohn’s disease (CD). The purpose of our study was to evaluate the diagnostic accuracy of Magnetic Resonance Imaging (MRI) combined with Diffusion-weighted Imaging (DWI) and MRE for determination of inflammation in small bowel CD.
Methods
MR imaging examination was performed with a GE Signa EXCITE 3.0 T MRI scanner. The optimal b value in DWI with a learning cohort of patients was determined. The diagnostic accuracy for active lesions and disease activity were accessed by MRE combined with DWI.
Results
The b value 800 s/mm2 group showed the highest diagnostic sensitivity (74.19%) for diagnostic assessment of active Crohn’s lesions on DWI. MRE combined with DWI showed the highest sensitivity (93.55%), specificity (89.47%) and diagnostic accuracy (92%) compared with MRE or DWI alone. The segmental MR score (MR-score-S) showed a significantly positive correlation with the Capsule Endoscopy Crohn’s Disease Activity Index Score (CECDAI-S) (r = 0.717, p < 0.01). The total MR score (MR-score-T) showed significant association with C-reactive protein (CRP) (r = 0.445, p = 0.019) and erythrocyte sedimentation rate (ESR) (r = 0.688, p < 0.01).
Conclusions
MRE combined with DWI improves the diagnostic accuracy for active lesions and correlates the endoscopic disease activity. MRE with DWI could represent a non-invasive tool in assessing active inflammation in CD.
doi:10.1186/s12876-015-0235-0
PMCID: PMC4323053  PMID: 25653007
10.  Endoscopic inside stent placement is suitable as a bridging treatment for preoperative biliary tract cancer 
BMC Gastroenterology  2015;15:8.
Background
Endoscopic biliary stenting (EBS) is one of the most important palliative treatments for biliary tract cancer. However, reflux cholangitis arising from bacterial adherence to the inner wall of the stent must be avoided. We evaluated the use of EBS above the sphincter of Oddi to determine whether reflux cholangitis could be prevented in preoperative cases.
Methods
Fifty-seven patients with primary biliary tract cancer were retrospectively recruited for the evaluation of stent placement either above (n = 25; inside stent group) or across (n = 32; conventional stent group) the sphincter of Oddi. We compared the stent patency periods prior to the time of surgical resection.
Results
The preoperative periods were 96.3 days in the conventional stent group and 96.8 days in the inside stent group (P = 0.979). Obstructive jaundice and/or acute cholangitis occurred in 7 patients (28.0%) in the inside stent group and in 15 patients (46.9%) in the conventional stent group during the preoperative period (P = 0.150). The average patency periods of the stents were 85.2 days (range, 13–387 days) for the inside stent group and 49.1 days (range, 9–136 days) for the conventional stent group (log-rank test: P = 0.009). The mean numbers of re-interventions because of stent occlusion were 0.32 for the inside stent group and 1.03 for the conventional stent group (P = 0.026). Post-endoscopic retrograde cholangiopancreatography complications occurred in 2 patients in the inside stent group and 4 patients in the conventional stent group (P = 0.516). Postoperative liver abscess occurred in 1 patient in the inside stent group and 5 patients in the conventional stent group (P = 0.968). Inside stent placement was the only significant preventative factor associated with stent obstruction based on univariate (hazard ratio [HR], 0.286; 95% confidence interval [CI], 0.114-0.719; P = 0.008) and multivariate (HR, 0.292; 95% CI, 0.114-0.750; P = 0.011) analyses.
Conclusion
Temporary plastic stent placement above the sphincter of Oddi is a better bridging treatment than conventional stent placement in preoperative primary biliary tract cancer.
doi:10.1186/s12876-015-0233-2
PMCID: PMC4323119  PMID: 25649526
11.  Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes 
BMC Gastroenterology  2015;15:14.
Background
Tofacitinib, a novel, oral Janus kinase inhibitor, demonstrated a dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC). The objective of the current study was to determine the effect of tofacitinib on patient-reported outcomes (PROs).
Methods
Eligible patients (≥18 years of age) with a diagnosis of active UC (total Mayo score of 6-12 points and moderately-to-severely active disease on sigmoidoscopy) were randomized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg, 3 mg, 10 mg, or 15 mg, or placebo twice daily (BID) for 8 weeks. PROs were assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact (IBD PRTI) survey.
Results
At Week 8, mean IBDQ total scores had improved relative to baseline across all five treatment groups (baseline range 123.2-134.5; Week 8 range 149.6-175.4). Improvement from baseline was significantly greater (P = 0.001) for tofacitinib 15 mg BID versus placebo. For tofacitinib 15 mg BID, most patients reported satisfaction or extreme satisfaction, definite preference for tofacitinib, and definite willingness to use tofacitinib again on the IBD PRTI at week 8. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission.
Conclusions
Short-term treatment with tofacitinib BID was associated with dose-dependent improvement in health-related quality of life and patient preferences for tofacitinib. The results complement previously reported efficacy and safety data for the Phase II study. (NCT 00787202, November 6, 2008).
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0239-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0239-9
PMCID: PMC4323227  PMID: 25651782
Ulcerative colitis; Patient reported outcomes; Quality of life; Tofacitinib
12.  Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer 
BMC Gastroenterology  2015;15:7.
Background
Intra-tumor heterogeneity is a potential cause for failure of targeted therapy in gastric cancer, but the extent of heterogeneity of established (HER2) or potential (EGFR, CCND1) target genes and prognostic gene alterations (MYC) had not been systematically studied.
Methods
To study heterogeneity of these genes in a large patient cohort, a heterogeneity tissue microarray was constructed containing 0.6 mm tissue cores from 9 different areas of the primary gastric cancers of 113 patients and matched lymph node metastases from 61 of these patients. Dual color fluorescence in-situ hybridization was performed to assess amplification of HER2, EGFR, CCND1 and MYC using established thresholds (ratio ≥ 2.0). Her2 immunohistochemistry (IHC) was performed in addition.
Results
Amplification was found in 17.4% of 109 interpretable cases for HER2, 6.4% for EGFR, 17.4% for CCND1, and 24.8% for MYC. HER2 amplification was strongly linked to protein overexpression by IHC in a spot-by-spot analysis (p < 0.0001). Intra-tumor heterogeneity was found in the primary tumors of 9 of 19 (47.3%) cancers with HER2, 8 of 17 (47.0%) cancers with CCND1, 5 of 7 (71.4%) cancers with EGFR, and 23 of 27 (85.2%) cancers with MYC amplification. Amplification heterogeneity was particularly frequent in case of low-level amplification (<10 gene copies). While the amplification status was often different between metastases, unequivocal intra-tumor heterogeneity was not found in individual metastases.
Conclusion
The data of our study demonstrate that heterogeneity is common for biomarkers in gastric cancer. Given that both TMA tissue cores and clinical tumor biopsies analyze only a small fraction of the tumor bulk, it can be concluded that such heterogeneity may potentially limit treatment decisions based on the analysis of a single clinical cancer biopsy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0231-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0231-4
PMCID: PMC4324419  PMID: 25649416
HER2; EGFR; MYC; CCND1; Gene amplification; Gastric cancer; Heterogeneity tissue microarray
13.  Cap assisted colonoscopy for the detection of serrated polyps: a post-hoc analysis 
BMC Gastroenterology  2015;15:11.
Background
Colonoscopy offers limited protection against right-sided colon cancer, a significant proportion of which arise from the serrated pathway of carcinogenesis. The aim of this study was to compare cap-assisted colonoscopy and standard high-definition white light colonoscopy regarding serrated polyps’ detection.
Methods
Post hoc analysis was performed of a previously conducted randomized controlled trial comparing standard and cap-assisted colonoscopy for adenoma detection. Randomization was stratified based on the indication of colonoscopy and all procedures were performed by three experienced endoscopists. Following cecal intubation, the colonic mucosa was carefully inspected during withdrawal of colonoscope and all polyps detected were documented for their size, location, morphology and then removed and sent for histopathology. Detection rates of significant serrated polyps between both arms were compared using the Fisher’s exact test and Wilcoxon Rank Sum test.
Results
427 patients were enrolled (7 exclusions, 210 completed study in each arm, mean age of 61 years, 95% male, 75% Caucasian, 67% screening colonoscopies). There were no significant differences in baseline characteristics between both groups. Cap-assisted colonoscopy detected a significantly higher proportion of subjects with significant serrated polyps as well as a higher total number of significant serrated polyps compared to standard colonoscopy (12.8% vs. 6.6%, p =0.047 and 40 vs. 20,p = 0.03 respectively).
Conclusions
In this post-hoc analysis, Cap-assisted colonoscopy is a safe technique that offers a higher detection rate of significant serrated polyps when compared to standard colonoscopy. If confirmed in future trials, this simple technique has the potential to improve protection against interval colon cancers.
doi:10.1186/s12876-015-0234-1
PMCID: PMC4334853  PMID: 25652842
Colorectal cancer; Serrated polyps; Cap-assisted colonoscopy; Interval colon cancer
14.  A randomized controlled trial of endoscopic steroid injection for prophylaxis of esophageal stenoses after extensive endoscopic submucosal dissection 
BMC Gastroenterology  2015;15:1.
Background
Esophageal stenosis following endoscopic submucosal dissection (ESD) is a serious adverse event that makes subsequent management more difficult.
Methods
This parallel, randomized, controlled, open-label study was designed to examine whether local steroid injection is an effective prophylactic treatment for esophageal stenoses following extensive ESD. This single center trial was conducted at the Keiyukai Hospital, a tertiary care center for gastrointestinal disease in Japan [University Hospital Medical Network Clinical Trial Registry (UMIN-CTR) on 15 September 2011 (UMIN000006327)]. Thirty-two patients with mucosal defects involving ≥75% of the esophageal circumference were randomized to receive a single dose of triamcinolone acetonide injections (n = 16) or be treated conventionally (n = 16). The primary outcome was the frequency of stricture requiring endoscopic dilatation; the surrogate primary endpoint was the number of dilatation sessions needed. Secondary outcomes included adverse event rates, the minimum diameter of the stenotic area and the duration of the course of dilatation treatments.
Results
The frequency of stricture was not significantly different between the groups because of insufficient statistical power, but the number of dilatation sessions required was significantly less in the steroid group (6.1 sessions [95% confidence interval, CI 2.8–9.4] versus 12.5 [95% CI 7.1–17.9] sessions in the control group; P = 0.04). The perforation rate was similar in both groups. The minimum diameter of stenotic lumens was significantly greater in the treatment group than controls (11.0 mm versus 7.1 mm, respectively; P = 0.01). The perforation rate was not significantly different between the groups (1.0% versus 0.5% in the treatment and control group, respectively). Steroid injection was effective in cases of mucosal defects encompassing the entire esophageal circumference.
Conclusions
Prophylactic endoscopic steroid injection appears to be a safe means of relieving the severity of esophageal stenoses following extensive ESD.
doi:10.1186/s12876-014-0226-6
PMCID: PMC4308850  PMID: 25609176
Esophageal stenosis; Steroid; Local injection; Endoscopic submucosal dissection (ESD); Early squamous cell carcinoma of esophagus
15.  Stromal expression of miR-21 in T3-4a colorectal cancer is an independent predictor of early tumor relapse 
BMC Gastroenterology  2015;15:2.
Background
MicroRNA-21 (miR-21) is an oncogenic microRNA that regulates the expression of multiple cancer-related target genes. miR-21 has been associated with progression of some types of cancer. Metastasis-associated protein1 expression and loss of E-cadherin expression are correlated with cancer progression and metastasis in many cancer types. In advanced colorectal cancer, the clinical significance of miR-21 expression remains unclear. We aimed to investigate the impact of miR-21 expression in advanced colorectal cancer and its correlation with target proteins associated with colorectal cancer progression.
Methods
From 2004 to 2007, 277 consecutive patients with T3-4a colorectal cancer treated with R0 surgical resection were included. Patients with neoadjuvant therapy and distant metastasis at presentation were excluded. The expression of miR-21 was investigated by in situ hybridization. Immunohistochemistry was used to detect E-cadherin and metastasis-associated protein1 expression.
Results
High stromal expression of miR-21 was found in 76 of 277 (27.4%) colorectal cancer samples and was correlated with low E-cadherin expression (P = 0.019) and high metastasis-associated protein1 expression (P = 0.004). T3-4a colorectal cancer patients with high miR-21 expression had significantly shorter recurrence-free survival than those with low miR-21 expression. When analyzing colon and rectal cancer separately, high expression of miR-21 was an independent prognostic factor of unfavorable recurrence-free survival in T3-4a colon cancer patients (P = 0.038, HR = 2.45; 95% CI = 1.05-5.72) but not in T3-4a rectal cancer patients. In a sub-classification analysis, high miR-21 expression was associated with shorter recurrence-free survival in the stage II cancer (P = 0.001) but not in the stage III subgroup (P = 0.267).
Conclusions
Stromal miR-21 expression is related to the expression of E-cadherin and metastasis-associated protein1 in colorectal cancer. Stage II colorectal cancer patients with high levels of miR-21 are at higher risk for tumor recurrence and should be considered for more intensive treatment.
doi:10.1186/s12876-015-0227-0
PMCID: PMC4308857  PMID: 25609245
Colorectal neoplasms; Neoplasm recurrence; microRNA; Cadherins; MTA-1 protein
16.  Closure of iatrogenic large mucosal and full-thickness defects of the stomach with endoscopic interrupted sutures in in vivo porcine models: are they durable enough? 
BMC Gastroenterology  2015;15:5.
Background
In this study, we evaluated the technical feasibility of mucosal approximation of large ulcers via an endoscopic suturing system after endoscopic submucosal dissection (ESD), assessed the durability of these sutures, and compared this technique with serosal apposition of full-thickness gastric wall defects using the same device.
Methods
Post-ESD ulcers were closed with mucosal apposition in 7 pigs, and endoscopic full-thickness resection (EFTR) defects were closed with serosal apposition in 3 pigs. Pigs recovered for 1 week; they were then euthanized and necropsies were performed.
Results
Primary defect closure was achieved in 85.7% of the post-ESD closures and in 100% of the post-EFTR closures (p = 0.67). All pigs survived for 1 week. At necropsy, sutures had loosened in the post-ESD animals, although only minor deformity of the ulcer edges was observed in all repaired post-ESD ulcers. Meanwhile, all of the post-EFTR defect closures were sustained for 1 week.
Conclusions
Primary closure of post-therapeutic defects can be accomplished using the device. Inverted serosal apposition provides a more durable and reliable repair than everted mucosal apposition.
doi:10.1186/s12876-015-0230-5
PMCID: PMC4308917  PMID: 25608558
Endoscopic full thickness resection (EFTR); Endoscopic mucosal dissection (ESD); Endoscopic suturing device
17.  Assessment of nutritional status and health-related quality of life before and after liver transplantation 
BMC Gastroenterology  2015;15:6.
Background
Patients with chronic liver disease frequently suffer from malnutrition, together with a decline in their health-related quality of life.
This study was carried out with the aim of evaluating the nutritional status, complications of medical and surgical care, anxiety, health-related quality of life and dependence level on basic and instrumental activities of daily living in pre- and post-liver transplant patients.
Methods/Design
A prospective observational study with follow-up of patients on the waiting list for liver transplants who subsequently received a transplant at the University Hospital Complex in A Coruña during the period 2012–2014 (n = 110).
All the patients will be followed-up for a maximum of 6 months. For survivors, assessments will be re-evaluated at one, three and six months post- transplant.
Informed consent of the patient and ethical review board approval was obtained (Code: 2010/081 and 2010/082).
The following variables will be studied: socio-demographic data, reason for the transplant, comorbidity (Charlson Score), analytical parameters, time on transplant waiting list and post-transplant complications. A trained nurse will evaluate the following for each patient: nutritional indices, anthropometric variables and handgrip strength. Validated questionnaires will be used to determine the patients’ nutritional status (Subjective Global Assessment), anxiety (STAI questionnaire), Health-Related Quality of Life (LDQoL 1.0 questionnaire), dependence (Barthel Index and Lawton-Brody Scale), nursing diagnoses (NANDA) and post-transplant quality indicators.
Multiple linear/logistic regression models will be used to identify variables associated with the events of interest. Changes in nutritional status, quality of life and dependence over time will be analysed with linear mixed-effects regression models.
Actuarial survival analysis using Kaplan-Meier curves, Cox regression and competitive risk will be performed
Concordance between the different scores that assess nutritional status and interobserver agreement regarding nursing diagnoses will be studied using the statistical Kappa index and Bland Altman method.
Discussion
The risk of malnutrition can be considered as a possible prognostic factor in transplant outcomes, associated with anxiety, health-related quality of life and dependence.
For this reason we consider interesting to perform a prospective follow-up study of patients who require a transplant to survive, studying their nutritional status and health-related quality of life.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0232-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0232-3
PMCID: PMC4310167  PMID: 25608608
Liver transplantation; Nutrition status; Anxiety; Quality of life; Dependence
18.  Characteristics and factors related to quality of life in Mexican Mestizo patients with celiac disease 
BMC Gastroenterology  2015;15:4.
Background
Celiac disease (CD) is a global health problem and its prevalence is underestimated, especially in Latin American populations. Our aim was to evaluate the clinical features, psychological factors, and health-related quality of life (QoL), before and after diagnosis, in a representative sample of adult Mexican Mestizo patients presenting with CD.
Methods
A cross-sectional analysis was conducted on patients seen at two tertiary referral centers in Mexico. QoL before and after CD diagnosis was evaluated using the EuroQoL 5D, the Hospital Anxiety and Depression Scale (HADS), and the disease-specific Celiac Symptom Index (CSI) questionnaires.
Results
We included 80 patients (80% were women, with a mean age of 48.6 ± 14.1 years). The most common symptoms were diarrhea (86%), bloating (77.5%), and abdominal pain (71.3%). Mean symptom duration was 10.33 ± 6.3 years. Fifty-one patients (63.8%) had a previous diagnosis of irritable bowel syndrome (IBS) and 23 (28.8%) had one of functional dyspepsia. Questionnaire respondents rated their health status at 50% before diagnosis (0 = worst imaginable state, 100 = best imaginable state) and there was a significant improvement of 26% after diagnosis. Thirty-nine percent of the patients had a CSI score > 45 and they were the ones that had been previously diagnosed most often with IBS (p = 0.13) or dyspepsia (p = .036).
Conclusions
At the time of diagnosis, Mexican Mestizo patients with CD had poor QoL. Long-standing symptoms and a previous diagnosis of functional disorders were associated with worse QoL. As in other populations, our results support the need for a detailed examination of cost-effective strategies for increasing CD awareness in clinical practice.
doi:10.1186/s12876-015-0229-y
PMCID: PMC4310198  PMID: 25608449
Celiac disease; Quality of life; Hispanic; Mexico
19.  Intestinal and neuronal myenteric adaptations in the small intestine induced by a high-fat diet in mice 
BMC Gastroenterology  2015;15:3.
Background
The prevalence of obesity has increased at alarming rates, particularly because of the increased consumption of high-fat diets (HFDs). The influence of HFDs on intrinsic innervation and the intestinal wall has not been fully characterized. The aim of this study was to investigate the morpho-quantitative aspects of myenteric neurons and the wall of the small intestine in mice fed a HFD.
Methods
Swiss mice were fed a HFD (59% kcal from fat) or standard chow (9% Kcal from fat) for 8 weeks. Segments of the duodenum, jejunum, and ileum were subjected to histological processing for morpho-quantitative examination of the intestinal wall and mucosal cells, and immunohistochemistry was performed to evaluate myenteric neurons. The data for each segment were compared between the groups using an unpaired Student’s t-test or an equivalent nonparametric test.
Results
The HFD increased body weight and visceral fat and decreased the length of the small intestine and the circumference of the ileum. In the duodenum, the HFD increased the density of the nitrergic subpopulation and decreased the area of nitrergic neurons and vasoactive intestinal peptide (VIP) varicosities. In the jejunum, the density of the nitrergic subpopulation was increased and the neuronal areas of the general population, nitrergic subpopulation and (VIP) varicosities were reduced. In the ileum, the density of the general population and nitrergic subpopulation were increased and the neuronal areas of the general population, nitrergic subpopulation and (VIP) varicosities were reduced. The morphometric parameters of the villi, crypts, muscular layer and total wall generally increased in the duodenum and jejunum and decreased in the ileum. In the duodenum and jejunum, the HFD promoted a decreased in the proportion of intraepithelial lymphocytes. In the ileum, the proportion of intraepithelial lymphocytes and goblet cells reduced, and the enteroendocrine cells increased.
Conclusions
The high-fat diet induces changes in the myenteric innervation of the small intestine, intestinal wall and mucosal cells responsible for the secretion of hormones and maintenance of the protective intestinal barrier. The morpho-quantitative data provide a basis for further studies to clarify the influence of HFD in the motility, digestive and absorptive capacity, and intestinal barrier.
doi:10.1186/s12876-015-0228-z
PMCID: PMC4316644  PMID: 25609418
Intestinal wall; Myenteric plexus; Myosin-V; Neuronal nitric oxide synthase; Vasoactive intestinal peptide; Enteroendocrine cells; Goblet cells; Intraepithelial lymphocytes
20.  [No title available] 
PMCID: PMC4296537  PMID: 25551469
21.  Mutational profiles of different macroscopic subtypes of colorectal adenoma reveal distinct pathogenetic roles for KRAS, BRAF and PIK3CA 
BMC Gastroenterology  2014;14(1):221.
Background
Investigations of genetic alterations and correlations with histology or morphology could provide further insights into colorectal carcinogenesis. Nevertheless, such genetic changes were less investigated in adenoma stage and a comprehensive survey of oncogenic mutations in EGFR signaling pathway according to different morphologic subtypes has not been performed.
Methods
A total of 94 neoplasms, including 34 polypoid adenoma, 16 lateral spreading tumors-granular (LST-G), 20 non-granular LST (LST-NG), and 24 depressed tumors, were subjected for mutational analysis of KRAS (exon 2), BRAF (exon 11 and 15), PIK3CA (exon 9 and 20), AKT (exon 4), EGFR (exon 18–24) and HER2 (exon18-24).
Results
KRAS mutation was noted more frequently in LST (13/36, 36.1%) than polypoid neoplasms (5/34, 14.7%, p = 0.041). When comparing with LST-NG, LST-G had a significantly higher frequency of KRAS mutation. (9/16, 56.3% vs. 4/20, 20.0%, p = 0.024). BRAF mutation (V600E) was found in 2 of 36 (5.6%)LSTs and 1 of 34 (2.9%) polypoid lesions. The two LST lesions with BRAF mutation were pathologically proven to be serrated adenoma. PIK3CA mutation (exon 9 E545K) was identified only in LST (5/36, 13.9%). Mutations in KRAS, BRAF or PIK3CA occurred in a mutually exclusive manner. All mutations were absent in the specimens obtained from depressed type neoplasms.
Conclusions
Three different macroscopic subtypes of colorectal neoplasms display distinct carcinogenetic pathways in EGFR networking. Further molecular studies of CRCs should take macroscopic subtypes into consideration and highlight the importance of consensus and communication between endoscopic and pathologic diagnosis.
doi:10.1186/s12876-014-0221-y
PMCID: PMC4296683  PMID: 25551625
Gene mutation; Non-polypoid colorectal neoplasm; EGFR
22.  The influence of astragalus polysaccharide and β-elemene on LX-2 cell growth, apoptosis and activation 
BMC Gastroenterology  2014;14(1):224.
Background
Activated hepatic stellate cells are the main source of excessive collagen deposition in liver fibrosis. Here we report the inhibitory effects of the combinational treatment of two natural products, astragalus polysaccharide (APS) and β-elemene (ELE) on the activation of human liver hepatic stellate cell line LX-2 cells.
Methods
Cultured LX-2 cells were treated with different concentrations of APS or ELE for 24 or 48 hours. Cell viability/apoptosis was measured by MTT assay and Annexin V/PI staining , activation related genes including α-SMA and CD44 expressions were measured by real-time PCR and western blot respectively.
Results
The majority of LX-2 cells showed morphological change in the presence of APS or ELE for 24 hours. Treatment with APS + ELE for 24 or 48 hours significantly inhabited the cell proliferation compared with APS or ELE treatment alone on LX-2 cells. APS + ELE may block the up-regulation of α-SMA and CD44 both in mRNA and protein levels through TGF-β pathway in LX-2 cells.
Conclusion
APS or ELE treatment alone on LX-2 cells could inhibit cell proliferation and induce apoptosis. The combinational treatment using APS + ELE significantly increased the killing efficiency on LX-2 cells. α-SMA and CD44 expressions was inhibited upon APS + ELE treatment through TGF-β pathway in LX-2 cells. The results indicated a novel treatment using natural products for liver diseases with anti-fibrotic effect.
doi:10.1186/s12876-014-0224-8
PMCID: PMC4297370  PMID: 25551689
Astragalus polysaccharide; β-elemene; Hepatic stellate cells
23.  Liver ENPP1 protein increases with remission of type 2 diabetes after gastric bypass surgery 
BMC Gastroenterology  2014;14(1):222.
Background
Type 2 diabetes mellitus (T2DM) is a progressive disease resulting from increasing insulin resistance and reduced pancreatic β-cell insulin secretion. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibits insulin signalling and may contribute to the pathogenesis of T2DM. Others have found elevated ENPP1 levels in muscle, fat, and skin tissues from insulin resistant individuals, but similar data on liver ENPP1 is lacking. The purpose of this study was to compare expression and protein concentrations of ENPP1 in liver between patients with and without T2DM.
Methods
Roux-en-Y gastric bypass surgery (RYGB) results in remission of insulin resistance and T2DM thus presenting an opportunity to examine some critical aspects of these conditions. We measured liver ENPP1 gene and protein expression in individuals with or without T2DM at RYGB and on average 17 (±5.6) months later.
Results
We found liver ENPP1 protein abundance was lower in individuals with T2DM than in those with normal glucose tolerance, and increased after RYGB surgery in those individuals who had remission of T2DM. ENPP1 positively correlated with insulin sensitivity at the liver (as measured by HOMA-IR), which is contrary to what others have reported in other insulin target tissues.
Conclusions
Liver ENPP1 expression in T2DM is the reverse of that expected based on expression in other tissues and is likely due to the unique role the liver has in insulin clearance. The work presented here adds another dimension to the role of ENPP1, and supports the hypothesis that ENPP1 may act as a natural modulator of insulin signalling in the liver.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-014-0222-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-014-0222-x
PMCID: PMC4296549  PMID: 25539584
24.  Clinical value of wireless pH-monitoring of gastro-esophageal reflux in children before and after proton pump inhibitors 
BMC Gastroenterology  2014;14(1):3.
Background
Wireless pH-monitoring is an accurate method for diagnosing adults with gastroesophageal reflux disease (GERD). The aim of this study was to evaluate the use of the Bravo capsule on children investigated for GERD in terms of safety, tolerability and feasibility before and after administration of proton pump inhibitors.
Methods
A Bravo capsule was inserted during upper endoscopy under general anaesthesia or deep sedation with propofol. 48-hour pH-metry was performed in 106 children (50 males, 56 females) at the median age of 11 years (range 17 months-18 years). On the second day of investigation, proton pump inhibitor (PPI) was given at a mean dose of 1.6 mg/kg (SD ±0.6 mg). The definition of GERD was set to a reflux index (RI) of ≥5% and DeMeester score (DMS) ≥14.7.
Results
Application of the capsule was successful in 103 of the 106 children (97.2%) and interpretable in 99 of these 103 (96.1%). 49 of the children with interpretable results (49.5%) had GERD according to RI, while 51 (56.7%) had GERD according to DMS. After PPI was given on day 2, RI decreased from a median of 4.9% (range 0.3-63.4%) to 2.2% (0–58.0%), while DMS decreased from a median of 17.6 (range 2.2-207.6) to 8.2 (0.3-178.6), respectively (p < 0.0001). No severe adverse events were reported.
Conclusion
Wireless pH-metry is a safe and tolerable method when investigating children for GERD. PPI given on the second day of assessment provides additional information on response to treatment suggesting that pH-metry preferably should be extended to 48 hours.
doi:10.1186/s12876-014-0225-7
PMCID: PMC4299672  PMID: 25539736
25.  The EPIYA-ABCC motif pattern in CagA of Helicobacter pylori is associated with peptic ulcer and gastric cancer in Mexican population 
BMC Gastroenterology  2014;14(1):223.
Background
Helicobacter pylori chronic infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. Cytotoxin-associated gene A (cagA)-positive H. pylori strains increase the risk of gastric pathology. The carcinogenic potential of CagA is linked to its polymorphic EPIYA motif variants. The goals of this study were to investigate the frequency of cagA-positive Helicobacter pylori in Mexican patients with gastric pathologies and to assess the association of cagA EPIYA motif patterns with peptic ulcer and gastric cancer.
Methods
A total of 499 patients were studied; of these, 402 had chronic gastritis, 77 had peptic ulcer, and 20 had gastric cancer. H. pylori DNA, cagA, and the EPIYA motifs were detected in total DNA from gastric biopsies by PCR. The type and number of EPIYA segments were determined by the electrophoretic patterns. To confirm the PCR results, 20 amplicons of the cagA 3′ variable region were sequenced, and analyzed in silico, and the amino acid sequence was predicted with MEGA software, version 5. The odds ratio (OR) was calculated to determine the associations between the EPIYA motif type and gastric pathology and between the number of EPIYA-C segments and peptic ulcers and gastric cancer.
Results
H. pylori DNA was found in 287 (57.5%) of the 499 patients, and 214 (74%) of these patients were cagA-positive. The frequency of cagA-positive H. pylori was 74.6% (164/220) in chronic gastritis patients, 73.6% (39/53) in peptic ulcer patients, and 78.6% (11/14) in gastric cancer patients. The EPIYA-ABC pattern was more frequently observed in chronic gastritis patients (79.3%, 130/164), while the EPIYA-ABCC sequence was more frequently observed in peptic ulcer (64.1%, 25/39) and gastric cancer patients (54.5%, 6/11). However, the risks of peptic ulcer (OR = 7.0, 95% CI = 3.3–15.1; p < 0.001) and gastric cancer (OR = 5.9, 95% CI = 1.5–22.1) were significantly increased in individuals who harbored the EPIYA-ABCC cagA gene pattern.
Conclusions
cagA-positive H. pylori is highly prevalent in southern Mexico, and all CagA variants were of the western type. The cagA alleles that code for EPIYA-ABCC motif patterns are associated with peptic ulcers and gastric cancer.
doi:10.1186/s12876-014-0223-9
PMCID: PMC4302603  PMID: 25539656
cagA gene 3′ region; CRPIA; EPIYA; CagA; H. pylori

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