Outcomes of colonoscopic polypectomy for malignant adenomas: a prospective 30­year cohort study from a single center (STROBE 1a).

INTRODUCTION: Surgery is recommended following endoscopic polypectomy for malignant adenoma (MA) in the large bowel in patients with risk factors for tumor recurrence or distant metastasis are present. OBJECTIVES: We present long­term outcomes of a prospective study in patients with endoscopically removed MAs. PATIENTS AND METHODS: A total of 128 patients who underwent endoscopic polypectomy were followed up for a median of 70.4 months. The criteria for adequate polypectomy included endoscopically and histologically (margin ≥2 mm) complete excision, lack of angioinvasion, and good tumor differentiation (G1 or G2). Sixty­seven patients did not meet 1 or more of the criteria (high­risk group) and 61 met all of the criteria (low­risk group). Unfavorable outcomes were residual disease, lymph node metastasis, recurrent disease, distant metastasis, or death due to colorectal cancer. Histological samples from 85 patients were reassessed to determine the effect of a margin width of 1 mm or more and tumor budding on the outcomes. RESULTS: Surgery was performed in 36 patients (28.1%), of whom 32 (47.7%) were high­risk and 4 (6.5%) were low­risk. Unfavorable outcome was observed in 10 patients (7.8%; all high­risk; 10 of 67 patients, 14.9%). Favorable outcome was observed in 61 of 128 patients who had a 2­mm free margin, and in 44 of 85 patients who fulfilled the modified criterion of 1­mm free margin. Tumor budding was detected in 17 of 85 patients (20.9%). Unfavorable outcome was observed in 2 of these patients (11.7%) and in 5 patients (7.3%) without tumor budding (P >0.05). DISCUSSION: Long­term outcomes of an endoscopic resection of MAs are good. Bowel resection does not prevent unfavorable outcomes, while a reduction of the tumor­free margin would not deteriorate the results (STROBE 1B).

A score to estimate the likelihood of detecting advanced colorectal neoplasia at colonoscopy.

OBJECTIVE: This study aimed to develop and validate a model to estimate the likelihood of detecting advanced colorectal neoplasia in Caucasian patients. DESIGN: We performed a cross-sectional analysis of database records for 40-year-old to 66-year-old patients who entered a national primary colonoscopy-based screening programme for colorectal cancer in 73 centres in Poland in the year 2007. We used multivariate logistic regression to investigate the associations between clinical variables and the presence of advanced neoplasia in a randomly selected test set, and confirmed the associations in a validation set. We used model coefficients to develop a risk score for detection of advanced colorectal neoplasia. RESULTS: Advanced colorectal neoplasia was detected in 2544 of the 35,918 included participants (7.1%). In the test set, a logistic-regression model showed that independent risk factors for advanced colorectal neoplasia were: age, sex, family history of colorectal cancer, cigarette smoking (p<0.001 for these four factors), and Body Mass Index (p=0.033). In the validation set, the model was well calibrated (ratio of expected to observed risk of advanced neoplasia: 1.00 (95% CI 0.95 to 1.06)) and had moderate discriminatory power (c-statistic 0.62). We developed a score that estimated the likelihood of detecting advanced neoplasia in the validation set, from 1.32% for patients scoring 0, to 19.12% for patients scoring 7-8. CONCLUSIONS: Developed and internally validated score consisting of simple clinical factors successfully estimates the likelihood of detecting advanced colorectal neoplasia in asymptomatic Caucasian patients. Once externally validated, it may be useful for counselling or designing primary prevention studies.

Randomized comparison of three palliative regimens including brachytherapy, photodynamic therapy, and APC in patients with malignant dysphagia (CONSORT 1a) (Revised II).

OBJECTIVES: Because most esophageal cancers are diagnosed at an advanced stage, a majority of patients require palliative dysphagia treatment. Dysphagia severity and the need for repeated re-canalization procedures significantly affect patients' quality of life (QoL). The aim of this study was to establish whether combining argon plasma coagulation (APC) of the neoplastic esophageal tissue with another re-canalization method results in a longer dysphagia-free period compared with APC alone. METHODS: We conducted a randomized trial in 93 patients with malignant dysphagia. Patients were followed until death. We compared three regimens of esophageal re-canalization; APC combined with high dose rate (HDR) brachytherapy, APC combined with photodynamic therapy (PDT), and APC alone. The primary outcome measure was the dysphagia-free period following randomization. Secondary measures were survival, QoL, treatment-associated complications, and treatment tolerance. A per-protocol analysis was carried out. RESULTS: The time to first dysphagia recurrence was significantly different between each combination treatment group and the control group (overall test: P=0.006; HDR vs. control, log-rank P=0.002, PDT vs. control, log-rank P=0.036), but not different between the combination groups (HDR vs. PDT, log-rank P=0.36). The median time to first dysphagia recurrence was 88, 59, and 35 days in the HDR, PDT, and control groups, respectively. There was no difference in overall survival between the study groups (P=0.27). No deaths, perforations, hemorrhages, or fistula formations were attributed to treatment. The only major complication was fever, occurring in three PDT patients. Minor complications were observed significantly more often in the combination treatment groups and included pain in both groups, transient dysphagia worsening, and skin sensitivity in the PDT group. The QoL 30 days after treatment in the HDR group was significantly better than in the other groups. CONCLUSIONS: In patients with inoperable esophageal cancer, palliative combination treatment of dysphagia with APC and HDR or PDT was significantly more efficient than APC alone, and was safe and well tolerated. APC combined with HDR resulted in fewer complications and better QoL than APC with PDT or APC alone (CONSORT 1b).

Twelve-month endoscopic and histological analysis following proton-pump inhibitor-based triple therapy in Helicobacter pylori-positive patients with gastric ulcers.

OBJECTIVE: To evaluate endoscopic and histological findings after Helicobacter pylori eradication therapy in gastric ulcer (GU) patients after 12 months' follow-up. MATERIAL AND METHODS: A total of 401 GU patients were randomized to receive either twice-daily (b.i.d.) esomeprazole 20 mg+amoxicillin 1000 mg+clarithromycin 500 mg (EAC) for 1 week followed by placebo for 3 weeks, EAC followed by once-daily (o.d.) esomeprazole 20 mg for 3 weeks or esomeprazole 20 mg b.i.d. plus placebo antibiotics for 1 week followed by esomeprazole 20 mg o.d. for 3 weeks. Endoscopy with biopsy was performed at baseline, after treatment and at 6 and 12 months' follow-up (healed patients). RESULTS: Endoscopic abnormalities, particularly in the stomach, were common at baseline and remained similar during follow-up, regardless of ulcer status and treatment. Helicobacter gastritis was present (antrum or corpus) in approximately 20% of patients following eradication therapy (versus approximately 80% with esomeprazole alone); these effects were sustained during follow-up. Similar trends were observed for other histological variables (granulocyte and lymphoplasmocytic cell infiltration, replacement of gastric surface cells by regenerative epithelium, and mucous depletion). No changes in atrophy or intestinal metaplasia were observed. Eighteen gastric cancer cases were detected: 11 at baseline endoscopy, and seven during treatment and follow-up. CONCLUSIONS: Endoscopic abnormalities are common in GU patients and persist after proton-pump inhibitor-based triple therapy for H. pylori eradication, which is associated with large, sustained improvements in histological variables. Follow-up endoscopy and histology may be necessary, even in patients with apparently non-malignant GU, to improve the detection rate of gastric malignancy in populations with a high prevalence of gastric cancer.

Quality indicators for colonoscopy and the risk of interval cancer.

BACKGROUND: Although rates of detection of adenomatous lesions (tumors or polyps) and cecal intubation are recommended for use as quality indicators for screening colonoscopy, these measurements have not been validated, and their importance remains uncertain. METHODS: We used a multivariate Cox proportional-hazards regression model to evaluate the influence of quality indicators for colonoscopy on the risk of interval cancer. Data were collected from 186 endoscopists who were involved in a colonoscopy-based colorectal-cancer screening program involving 45,026 subjects. Interval cancer was defined as colorectal adenocarcinoma that was diagnosed between the time of screening colonoscopy and the scheduled time of surveillance colonoscopy. We derived data on quality indicators for colonoscopy from the screening program's database and data on interval cancers from cancer registries. The primary aim of the study was to assess the association between quality indicators for colonoscopy and the risk of interval cancer. RESULTS: A total of 42 interval colorectal cancers were identified during a period of 188,788 person-years. The endoscopist's rate of detection of adenomas was significantly associated with the risk of interval colorectal cancer (P=0.008), whereas the rate of cecal intubation was not significantly associated with this risk (P=0.50). The hazard ratios for adenoma detection rates of less than 11.0%, 11.0 to 14.9%, and 15.0 to 19.9%, as compared with a rate of 20.0% or higher, were 10.94 (95% confidence interval [CI], 1.37 to 87.01), 10.75 (95% CI, 1.36 to 85.06), and 12.50 (95% CI, 1.51 to 103.43), respectively (P=0.02 for all comparisons). CONCLUSIONS: The adenoma detection rate is an independent predictor of the risk of interval colorectal cancer after screening colonoscopy.

Effect of esomeprazole triple therapy on eradication rates of Helicobacter pylori, gastric ulcer healing and prevention of relapse in gastric ulcer patients.

OBJECTIVES: To compare esomeprazole-based triple therapy with esomeprazole alone for the eradication of Helicobacter pylori (H. pylori), healing of ulcer and prevention of relapse in H. pylori-related gastric ulcer (GU) diseases. METHODS: In this double-blind study, 401 H. pylori-positive patients with more than or equal to two GUs were randomized to: esomeprazole (20 mg) twice daily (bid) and amoxicillin (1000 mg) bid and clarithromycin (500 mg) bid (EAC) for 1 week, followed by placebo for 3 weeks (EAC and placebo); EAC for 1 week, followed by esomeprazole (20 mg) once daily (E20) for 3 weeks (EAC and E20); or esomeprazole (20 mg) bid and placebo antimicrobials for 1 week, followed by E20 for 3 weeks (E20 bid and E20). Patients with unhealed GUs at 4 weeks received E20 for an additional 4 weeks. Healed patients were followed up for 12 months. RESULTS: Eradication rates at 4 weeks or 8 weeks were 82% for EAC and E20, 77% for EAC and placebo and 9.5% for E20 bid and E20 (intention-to-treat analysis). Significantly more patients receiving EAC than those receiving esomeprazole alone remained free of GUs during follow-up [EAC and E20, 90%; EAC and placebo, 87%; P=0.0005 for combined group vs. esomeprazole alone [E20 bid and E20 (74%)]. All treatments were well tolerated. CONCLUSION: Esomeprazole-based triple therapy is effective for the eradication of H. pylori, healing of GU and prevention of relapse. Esomeprazole monotherapy for 3 weeks after triple therapy may be beneficial in terms of healing.

Molecular defense mechanisms of Barrett's metaplasia estimated by an integrative genomics.

Barrett's esophagus is characterized by the replacement of squamous epithelium with specialized intestinal metaplastic mucosa. The exact mechanisms of initiation and development of Barrett's metaplasia remain unknown, but a hypothesis of "successful adaptation" against noxious reflux components has been proposed. To search for the repertoire of adaptation mechanisms of Barrett's metaplasia, we employed high-throughput functional genomic and proteomic methods that defined the molecular background of metaplastic mucosa resistance to reflux. Transcriptional profiling was established for 23 pairs of esophageal squamous epithelium and Barrett's metaplasia tissue samples using Affymetrix U133A 2.0 GeneChips and validated by quantitative real-time polymerase chain reaction. Differences in protein composition were assessed by electrophoretic and mass-spectrometry-based methods. Among 2,822 genes differentially expressed between Barrett's metaplasia and squamous epithelium, we observed significantly overexpressed metaplastic mucosa genes that encode cytokines and growth factors, constituents of extracellular matrix, basement membrane and tight junctions, and proteins involved in prostaglandin and phosphoinositol metabolism, nitric oxide production, and bioenergetics. Their expression likely reflects defense and repair responses of metaplastic mucosa, whereas overexpression of genes encoding heat shock proteins and several protein kinases in squamous epithelium may reflect lower resistance of normal esophageal epithelium than Barrett's metaplasia to reflux components. Despite the methodological and interpretative difficulties in data analyses discussed in this paper, our studies confirm that Barrett's metaplasia may be regarded as a specific microevolution allowing for accumulation of mucosal morphological and physiological changes that better protect against reflux injury.

Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia.

BACKGROUND: Recommendations for colorectal-cancer screening are based solely on age and family history of cancer, not sex. METHODS: We performed a cross-sectional analysis of the data from a large colonoscopy-based screening program that included 50,148 participants who were 40 to 66 years of age. People 40 to 49 years of age were eligible only if they had a family history of cancer of any type. Of the 43,042 participants 50 to 66 years of age, 13.3% reported a family history of colorectal cancer, as did 66.3% of the 7106 participants who were 40 to 49 years of age. We defined advanced neoplasia as cancer or adenoma that was at least 10 mm in diameter, had high-grade dysplasia, or had villous or tubulovillous histologic characteristics, or any combination thereof. We used multivariate logistic regression to identify associations between participants' characteristics and advanced neoplasia in a primary (or derivation) data set, and we confirmed the associations in a secondary (or validation) data set. RESULTS: Advanced neoplasia was detected in 2553 (5.9%) participants 50 to 66 years of age and in 243 (3.4%) participants 40 to 49 years of age. The rate of complications during colonoscopy was 0.1%, and no participants died. In the validation set, a logistic-regression model showed that male sex was independently associated with advanced neoplasia (adjusted odds ratio, 1.73; 95% confidence interval, 1.52 to 1.98; P<0.001). In each age group (40 to 49 years, 50 to 54 years, 55 to 59 years, and 60 to 66 years), the number of persons who would have to undergo colorectal-cancer screening in order to detect one advanced neoplasia was significantly lower in men than in women (23 vs. 36, 17 vs. 28, 12 vs. 22, and 10 vs. 18, respectively). CONCLUSIONS: We detected advanced neoplasia at a significantly higher rate in men than in women, which may warrant refinement of the screening recommendations for colorectal cancer.

Three clinical variants of gastroesophageal reflux disease form two distinct gene expression signatures.

It has been proposed recently that gastroesophageal reflux disease (GERD) patients may be categorized into three distinct groups exhibiting non-erosive reflux disease (NERD), erosive reflux disease (ERD), and Barrett's esophagus (BE). Measurement of relative gene expression levels was undertaken to identify distinct molecular subclasses in different variants of gastroesophageal disease. The measurements were made with Affymetrix U133A 2.0 GeneChips and RNA isolated from mucosal samples of normal squamous esophageal epithelium from 24, 28, and 26 patients with NERD, ERD and BE, respectively. Statistical testing of microarray data showed that gene expression profiles are discriminative for BE and NERD, but not for combinations of BE and ERD or NERD and ERD. In addition, women developing NERD exhibited transcriptional patterns that differed from those of men with BE. In clustering analyses, we did not observe correlations between sex and assignment of gene expression profile of ERD patients to either the NERD or the BE group. Although the biological significance of the identified genes remains uncertain, we hypothesize that GERD is a monophyletic disease that develops with the onset of gastroesophageal reflux and represents two main molecular classes, which may result in different progressions to inflammatory process within esophageal epithelium modulated by sexual dimorphism. While normal epithelium samples from NERD and BE patients are molecularly homogeneous, esophageal mucosa from ERD patients is molecularly similar to either NERD or BE. These findings may be useful for defining molecular markers which could predict potential progression to Barrett's metaplasia among patients with reflux disease.

Prevention of NSAID-associated gastrointestinal lesions: a comparison study pantoprazole versus omeprazole.

AIM: To investigate tolerability and efficacy of pantoprazole 20 mg, once daily (o.d.), pantoprazole 40 mg o.d., and omeprazole 20 mg o.d., in patients taking nonsteroidal anti-inflammatory drug(s) (NSAIDs). METHODS: Included in this randomized, double-blind, multicenter, parallel-group study were rheumatic patients (>55 yr) on continual NSAIDs and with at least one more recognized risk factor that contributes to the development of gastrointestinal (GI) injury. Study duration was 6 months, and the treatment consisted of pantoprazole 20 mg o.d. (N = 196), pantoprazole 40 mg o.d. (N = 199), or omeprazole 20 mg o.d. (N = 200). Patients took NSAID(s) (except COX-2 inhibitors), had no more than five erosions/petechiae in the upper GI tract, no current peptic ulcers or reflux esophagitis, and had at most moderate intensity GI symptoms. Endoscopy was performed at baseline, 3, and 6 months. The primary end points were lack of "therapeutic failure" and lack of "endoscopic failure" at 6 months. RESULTS: After 6 months, the probabilities to remain in remission were 90% pantoprazole 20 mg o.d., 93% pantoprazole 40 mg o.d., and 89% omeprazole 20 mg o.d. for lack of "therapeutic failure;" 91% pantoprazole 20 mg o.d., 95% pantoprazole 40 mg o.d., and 93% omeprazole 20 mg o.d. for lack of "endoscopic failure." CONCLUSIONS: For patients taking NSAIDs continually, pantoprazole 20 mg o.d., pantoprazole 40 mg o.d., or omeprazole 20 mg o.d. provide equivalent, effective, and well-tolerated prophylaxis against GI lesions, including peptic ulcers.

Helicobacter pylori VacA cytotoxin interacts with fibronectin and alters HeLa cell adhesion and cytoskeletal organization in vitro.

Helicobacter pylori vacuolating cytotoxin VacA causes multiple effects on epithelial cell function and morphology, but the effects of VacA on signal transduction pathways and the cytoskeleton have not been investigated in detail. In this study, we analyzed the effects of native VacA on HeLa and AGS cell adhesion to fibronectin and laminin under serum-free conditions. Confocal microscopic examination revealed increased number of cells with rounded morphology and inhibition of actin fiber formation, in the presence of VacA. VacA binds to fibronectin in vitro in a dose-dependent manner. This interaction was partly inhibited by a peptide containing an arginine-glycine-aspartic acid motif. The adhesion of HeLa cells to fibronectin, but not to laminin, was decreased in the presence of VacA. Thus, VacA may interact with fibronectin and influence integrin receptor-induced cell signaling and cytoskeleton-dependent cell functions.

Submucosal lesions.

Most of the submucosal lesions encountered on endoscopy are benign; however, the fact that some of them may be malignant considerably influences the attitude toward the whole group. This article reviews the current status of endosonography in the management of submucosal lesions and focuses on determining the risk of malignancy. The predictive value of various endoscopic ultrasonography (EUS) features and their combinations and the capabilities and limitations of EUS-guided fine needle biopsy are discussed. Other issues addressed include differentiation between extraluminal compressions and true submucosal lesions, EUS-assisted endoscopic removal of submucosal lesions, and the potential role of catheter-based endosonography in the setting of submucosal lesions. Problems related to the surveillance of patients with submucosal lesions who are not candidates for surgical treatment are outlined. An overview of the recent changes in the pathologic classification of gastrointestinal mesenchymal tumors and their impact on the role of EUS in the management of submucosal lesions is given.

Multivariate analysis of risk factors for development of duodenal ulcer in Helicobacter pylori-infected patients.

BACKGROUND: Although Helicobacter pylori is a significant etiologic factor of peptic ulcer disease, it remains unknown why ulcers develop only in the minority of infected individuals. AIM: The aim of this cross-sectional study was to evaluate the association between the presence of duodenal ulcer in H. pylori-infected patients and different risk factors. METHODS: A total of 122 H. pylori-infected patients were enrolled; 79 had duodenal ulcer and 43 gastritis. Univariate analysis was conducted using either Fisher's exact test or exact Cochrane-Armitage trend test. In multivariate analysis the logistic model was used. RESULTS: Univariate analysis indicated six factors (male sex, smoking, antral H. pylori density, CAGA presence in antrum, and VACA s1a presence in antrum and corpus). Four factors (sex, smoking-alcohol index, H. pylori density index, and CAGA index) were found to be significant in multivariate analysis. The best model predicting duodenal ulcer included male sex, smoking, presence of H. PYLORI on histopathology in antrum and CAGA presence in corpus. CONCLUSION: Although several risk factors were significantly associated with duodenal ulcer, we failed in the identification of either a single risk factor or a set of factors that can unequivocally differentiate patients with ulcer from those with gastritis.

Association of coeliac disease with primary biliary cirrhosis in Poland.

OBJECTIVES: In western and northern but not southern Europe, the prevalence of coeliac disease among patients with primary biliary cirrhosis (PBC) is higher than in the general population. We analysed the prevalence of coeliac disease among patients with PBC in Poland, a central European country. METHODS: In 115 patients with PBC, immunoglobulin A (IgA) antibodies against guinea-pig tissue transglutaminase (tTGA), monkey endomysium (EMA) and gliadin (AGA) were determined. In patients positive for tTGA and/or EMA, the DNA typing of HLA-DQB gene and small-bowel biopsy were performed. RESULTS: IgA EMA was found in one patient with PBC (0.9%, 95% CI 0-2.5%). tTGA was detected in seven patients (6%, 95% CI 1.8-10.3%). Small-bowel biopsy showed flat mucosa in one subject, who was EMA positive/tTGA negative/AGA negative, and normal histology in four tTGA-positive/EMA-negative patients. In the latter four patients, the positive tTGA result was caused by IgA reactivity to proteins other than transglutaminase. Prevalence of coeliac disease in our 115 patients with PBC was 0.9% (95% CI 0-1.9%). In one patient with silent coeliac disease presenting with the HLA-DQ2 allele, introduction of a gluten-free diet was followed by improvement in liver function tests, improvement in histology of the distal duodenum, and disappearance of EMA. CONCLUSIONS: Our results from Poland do not confirm a high prevalence of coeliac disease in PBC patients. Guinea-pig liver transglutaminase immunolinked assay cannot be used as a screening test for coeliac disease in PBC patients. A gluten-free diet may be helpful in restoration of liver function in patients with such an association.

Association of primary sclerosing cholangitis, ulcerative colitis and coeliac disease in female siblings.

Primary sclerosing cholangitis is a rare, cholestatic liver disease, most commonly affecting young men. The association of primary sclerosing cholangitis with other autoimmune disorders, although rare, indicates a genetic predisposition for this disease. We describe, for the first time, the association of primary sclerosing cholangitis, ulcerative colitis and coeliac disease in two sisters. Ulcerative colitis was mild and preceded liver disease in both patients. There were no symptoms of coeliac disease, and its silent form was diagnosed on the basis of serological tests. Both patients carried HLA molecules DR3 and DQ2. Although HLA DR4 was not found, there was a rapid progression of liver disease to cirrhosis and cholangiocarcinoma in one patient. The familial occurrence of primary sclerosing cholangitis, ulcerative colitis and coeliac disease supports the hypothesis of genetic predisposition for these diseases.