Expert assessment of infiltration depth and recommendation of endoscopic resection technique in early Barrett cancer.

BACKGROUND: Early Barrett cancer can be curatively treated by endoscopic resection. The choice of the resection technique, however-endoscopic mucosal resection (EMR) or submucosal dissection (ESD)-largely depends on the assumed infiltration depth as judged by the endoscopist. However, the accuracy of endoscopic diagnosis of the degree of cancer infiltration is not known. METHODS: Three to four high-quality images (both in overview and close-up) from 202 of early Barrett esophagus cancer cases (82% men, mean age 66.9 years) were selected from our endoscopy database (73.3% stage T1a and 26.7% in stage T1b). Images were shown to 9 Barrett esophagus experts, with patients' clinical data (age, sex, Barrett esophagus length) and biopsy results. The experts were asked to predict infiltration depth (T1b vs. T1a), and to suggest the appropriate endoscopic resection technique (EMR or ESD, or surgery). Interobserver variability (kappa values) was also determined for these parameters. RESULTS: Overall positive (PPV) and negative predictive values (NPV) to diagnose T1b versus T1a infiltration were 40.7% (95% CI: 36.7, 44.8) and 79.8% (95% CI: 77.5, 81.9), respectively; kappa value was 0.41. Paris classification (kappa 0.51) and suggested treatment also varied between experts. In a post hoc analysis, only the correlation between lesions classified as invisible or flat according to the Paris classification (IIB; 25% of all cases) and the suggested resection technique was better: In this subgroup, EMR was recommended in >80% of cases, with a high complete (basal R0) resection rate (mean of 88.1%). CONCLUSIONS: Precise endoscopic distinction between mucosal and submucosal involvement of Barrett esophagus cancer by experts as a basis for choosing the resection technique has limited predictive values and high interobserver variability. It seems that mainly invisible/flat lesions may result in good resection outcomes when treated by EMR, but this stratification strategy has to be assessed in further studies.

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.

BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Hybrid APC in Combination With Resection for the Endoscopic Treatment of Neoplastic Barrett's Esophagus: A Prospective, Multicenter Study.

INTRODUCTION: The current therapy of neoplastic Barrett's esophagus (BE) consists of endoscopic resection plus ablation, with radiofrequency ablation as the best studied technique. This prospective trial assesses a potential alternative, namely hybrid argon plasma ablation. METHODS: Consecutive patients with neoplastic BE undergoing ablation after curative endoscopic resection (89.6%) or primarily were included into this prospective trial in 9 European centers. Up to 5 ablation sessions were allowed for complete eradication of BE (initial complete eradication of intestinal metaplasia [CE-IM]), by definition including BE-associated neoplasia, documented by 1 negative endoscopy with biopsies. The main outcome was the rate of initial CE-IM in intention-to-treat (ITT) and per-protocol (PP) samples at 2 years. The secondary end points were the rate of recurrence-free cases (sustained CE-IM) documented by negative follow-up endoscopies with biopsies and immediate/delayed adverse events. RESULTS: One hundred fifty-four patients (133 men and 21 women, mean age 64 years) received a mean of 1.2 resection and 2.7 ablation sessions (range 1-5). Initial CE-IM was achieved in 87.2% of 148 cases in the PP analysis (ITT 88.4%); initial BE-associated neoplasia was 98.0%. On 2-year follow-up of the 129 successfully treated cases, 70.8% (PP) or 65.9% (ITT) showed sustained CE-IM; recurrences were mostly endoscopy-negative biopsy-proven BE epithelium and neoplasia in 3 cases. Adverse events were seen in 6.1%. DISCUSSION: Eradication and recurrence rates of Barrett's intestinal metaplasia and neoplasia by means of hybrid argon plasma coagulation at 2 years seem to be within expected ranges. Final evidence in comparison to radiofrequency ablation can only be provided by a randomized comparative trial.

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies.

BACKGROUND: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits. METHODS: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association meta-analyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses. RESULTS: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (rg = 0.13, P = 2 × 10-04) and a rg of 0.12 between WHR and BE/EA (P = 1 × 10-02). Sex-specific analyses revealed a pronounced genetic correlation between BMI and EA in females (rg = 0.17, P = 1.2 × 10-03), and WHR and EA in males (rg = 0.18, P = 1.51 × 10-02). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 × 10-03) and WHR and BE/EA risk variants (P = 2 × 10-02). CONCLUSIONS: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mecha-nisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA. IMPACT: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.

No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.

BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.

Identification of loci of functional relevance to Barrett's esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data.

Esophageal adenocarcinoma (EA) and its precancerous condition Barrett's esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10-8) and novel candidate loci (5×10-8 ≤ P ≤ 5×10-5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10-7 and rs1540, Pcombined = 4.16×10-6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.

Genome-Wide Analysis of Barrett's Adenocarcinoma. A First Step Towards Identifying Patients at Risk and Developing Therapeutic Paths.

BACKGROUND: Barrett's esophagus metaplasia is the key precursor lesion of esophageal adenocarcinoma. The aim of this study was to find a subset of markers that may allow the identification of patients at risk for esophageal adenocarcinoma, and to determine genes differentially expressed in esophageal squamous cell carcinoma. METHODS: Laser capture microdissection technique was applied to procure cells from defined regions. Genome-wide RNA profiling was performed on esophageal adenocarcinoma (n = 21), Barrett's esophagus (n = 20), esophageal squamous carcinoma (n = 9) and healthy esophageal biopsies (n = 18) using the Affymetrix Human Genome U133plus 2.0 array. Microarray results were validated by quantitative real-time polymerase chain reaction in a second and independent cohort and by immunohistochemistry of two putative markers in a third independent cohort. RESULTS: Through unsupervised hierarchical clustering and principal component analysis, samples were separated into four distinct groups that match perfectly with histology. Many genes down-regulated in esophageal cancers belong to the epidermal differentiation complex or the related GO-group "cornified envelope" of terminally differentiated keratinocytes. Similarly, retinol metabolism was strongly down-regulated. Genes showing strong overexpression in esophageal carcinomas belong to the GO groups extracellular region /matrix such as MMP1, CTHRC1, and INHBA. According to an analysis of genes strongly up-regulated in both esophageal adenocarcinoma and Barrett's esophagus, REG4 might be of particular interest as an early marker for esophageal adenocarcinoma. CONCLUSIONS: Our study provides high quality data, which could serve for identification of potential biomarkers of Barrett's esophagus at risk of esophageal adenocarcinoma progression.

Prospective evaluation of the short access cholangioscopy for stone clearance and evaluation of indeterminate strictures.

BACKGROUND: Peroral cholangioscopy facilitates diagnosis and therapy of biliary disorders. This study prospectively evaluated a new short access cholangioscopy. METHODS: Consecutive patients were included as follows: difficult stones (group 1) underwent cholangioscopy with electrohydraulic lithotripsy and indeterminate biliary strictures (group 2) were evaluated with macroscopic assessment and cholangioscopy guided biopsy sampling. We evaluated the complete stone clearance rate (group 1) and diagnostic accuracy (group 2). Follow-up was performed over a median of 13 and 16 months, respectively. RESULTS: Group 1 (n=21): complete stone clearance defined as lack of stones in cholangiography and stone removal during cholangioscopy was achieved in 15 (71.4%) patients. Clinical stone clearance defined as lack of symptoms, laboratory abnormalities and hospital visits during follow-up, irrespective of stone clearance was evident in 17 (81.0%) patients. One serious adverse event occurred (bile duct perforation). Group 2 (n=28): malignancy was confirmed in 15 patients. Sensitivity, specificity and diagnostic accuracy of cholangioscopy were 85.7%, 75.0% and 80.7%, respectively. Sensitivity, specificity and diagnostic accuracy of biopsies were 54.5%, 100.0% and 72.2%, respectively. No serious adverse events occurred, and one patient was lost to follow-up. CONCLUSIONS: The novel system enabled complex stone treatment and biliary stricture diagnosis. Cholangioscopy outperformed direct biopsy regarding characterization of indeterminate strictures.

22-gauge core vs 22-gauge aspiration needle for endoscopic ultrasound-guided sampling of abdominal masses.

AIM: To compare the aspiration needle (AN) and core biopsy needle (PC) in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of abdominal masses. METHODS: Consecutive patients referred for EUS-FNA were included in this prospective single-center trial. Each patient underwent a puncture of the lesion with both standard 22-gauge (G) AN (Echo Tip Ultra; Cook Medical, Bloomington, Indiana, United States) and the novel 22G PC (EchoTip ProCore; Cook Medical, Bloomington, Indiana, United States) in a randomized fashion; histology was attempted in the PC group only. The main study endpoint was the overall diagnostic accuracy, including the contribution of histology to the final diagnosis. Secondary outcome measures included material adequacy, number of needle passes, and complications. RESULTS: Fifty six consecutive patients (29 men; mean age 68 years) with pancreatic lesions (n = 38), lymphadenopathy (n = 13), submucosal tumors (n = 4), or others lesions (n = 1) underwent EUS-FNA using both of the needles in a randomized order. AN and PC reached similar overall results for diagnostic accuracy (AN: 88.9 vs PC: 96.1, P = 0.25), specimen adequacy (AN: 96.4% vs PC: 91.1%, P = 0.38), mean number of passes (AN: 1.5 vs PC: 1.7, P = 0.14), mean cellularity score (AN: 1.7 vs PC: 1.1, P = 0.058), and complications (none). A diagnosis on the basis of histology was achieved in the PC group in 36 (64.3%) patients, and in 2 of those as the sole modality. In patients with available histology the mean cellularity score was higher for AN (AN: 1.7 vs PC: 1.0, P = 0.034); no other differences were of statistical significance. CONCLUSION: Both needles achieved high overall diagnostic yields and similar performance characteristics for cytological diagnosis; histological analysis was only possible in 2/3 of cases with the new needle.

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.

BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. FINDINGS: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10-10), MSRA (rs17749155; p=5·2 × 10-10), LINC00208 and BLK (rs10108511; p=2·1 × 10-9), KHDRBS2 (rs62423175; p=3·0 × 10-9), TPPP and CEP72 (rs9918259; p=3·2 × 10-9), TMOD1 (rs7852462; p=1·5 × 10-8), SATB2 (rs139606545; p=2·0 × 10-8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10-8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. INTERPRETATION: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. FUNDING: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.

The Barrett-associated variants at GDF7 and TBX5 also increase esophageal adenocarcinoma risk.

Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) represent two stages within the esophagitis-metaplasia-dysplasia-adenocarcinoma sequence. Previously genetic risk factors have been identified that confer risk to BE and EAC development. However, to which extent the genetic variants confer risk to different stages of the BE/EAC sequence remains mainly unknown. In this study we analyzed three most recently identified BE variants at the genes GDF7 (rs3072), TBX5 (rs2701108), and ALDH1A2 (rs3784262) separately in BE and EAC samples in order to determine their risk effects during BE/EAC sequence. Our data show that rs3072 at GDF7 and rs2701108 at TBX5 are also associated with EAC and conclude that both loci confer disease risk also at later stages of the BE/EAC sequence. In contrast, rs3784262 at ALDH1A2 was highly significantly associated with BE, but showed no association with EAC. Our data do not provide evidence that the ALDH1A2 locus confers equal risk in early and late stages of BE/EAC sequence.

Lectin Histochemistry Shows WGA, PHA-L and HPA Binding Increases During Progression of Human Colorectal Cancer.

BACKGROUND/AIM: Most colorectal carcinomas develop from an adenoma-carcinoma sequence to metastatic disease. The aim of the present study was to use lectins, carbohydrate-binding proteins, to detect changes in glycosylation during this malignant progression. MATERIALS AND METHODS: Sections from normal colorectal mucosa, high-grade intraepithelial neoplasia, submucosal colorectal carcinoma and metastases from patients who underwent colorectal surgery were stained by lectins with different sugar specificities namely agglutins from Wheatgerm (WGA), Helix pomatia (HPA), Phaseolus vulgaris (PHA-L), Ulex europaeus (UEA-I), Sambucus nigra (SNA-I), Canavalia ensiformis (Con A), Galanthus nivalis (GNA) and Dolichos biflorus (DBA). RESULTS: Binding patterns of all lectins except SNA-I, Con A and DBA changed during the adenoma-carcinoma sequence. CONCLUSION: The results indicate that lectins specific for mannose, N-acetylgalactosamine, N-acetylglucosamine, sialic acid, ß-1,6-branched oligosaccharides and α-1-fucose may be associated with malignant progression.

Supportive evidence for FOXP1, BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma.

The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett's esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P < 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P < 10(-5) ) although not genome-wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.

Long-term recurrence of neoplasia and Barrett's epithelium after complete endoscopic resection.

BACKGROUND: Current endoscopic therapy for neoplastic Barrett's oesophagus (BO) consists of complete resection/ablation of all Barrett's tissue including neoplastic lesions. Recurrence seems to be frequent after thermal therapy, such as radiofrequency ablation. OBJECTIVE: To analyse long-term recurrence of neoplasia and BO after successful widespread endoscopic mucosal resection (EMR). DESIGN: In a retrospective analysis, all patients undergoing widespread EMR of neoplastic BO between 2002 and 2007 at two referral centres were followed for at least 3 years after completion of endotherapy. Recurrence was diagnosed if neoplasia and/or BO were detected following previous successful complete removal, defined as at least two negative endoscopies and biopsies. RESULTS: Ninety patients undergoing widespread EMR were included (mean age 63 years; 82 male), 58% of whom underwent additional thermal ablation for minor residual disease. Complete eradication of neoplasia and Barrett's tissue was achieved in 90% of patients. On further follow-up (mean 64.8 months), recurrence of neoplastic and non-neoplastic BO was found in 6.2% and 39.5%, respectively. Recurring neoplasia (3 adenocarcinomas, 1 low-grade and 1 high-grade dysplasia) were found after a median of 44 months (range 38-85) and could be retreated endoscopically. In a multivariate analysis, Barrett's length was the only factor significantly associated with recurrence (OR 2.73). CONCLUSIONS: Even after seemingly complete endoscopic resection, recurrence of BO is frequent and independent of additional thermal therapy. Due to the possibility of neoplasia recurrence even after long disease-free intervals, follow-up should be extended beyond 5 years.

Subsquamous extension of intestinal metaplasia is detected in 98% of cases of neoplastic Barrett's esophagus.

BACKGROUND & AIMS: Subsquamous intestinal metaplasia (SSIM) has been observed after endotherapy in patients with neoplastic Barrett's esophagus (BE). However, it is not clear whether SSIM occurs in untreated patients. Incompletely eradicated SSIM could provide a source of recurrent disease. We assessed its prevalence in a large cohort of patients who had not received endoscopic therapy. METHODS: Two experienced pathologists analyzed 138 samples of 506 resection specimens found to contain squamous epithelium from 110 patients with neoplastic BE treated by widespread endoscopic mucosal resection (92 men; mean age, 66 years). The maximum extent of SSIM was measured. RESULTS: Of the 138 samples analyzed, 124 (89.9%) were found to contain SSIM from 108 of the 110 patients (98.2%). The mean length of SSIM was 3.3 mm (range, 0.2-9.6 mm; 25% ≥ 5 mm); SSIM length correlated with BE length (P < .05). In 83 of 138 samples (60.1%), the SSIM consisted partially or entirely of neoplasias of different grades, with a mean subsquamous extension of 3.3 mm; the extension correlated with grade of neoplasia (P = .0001). CONCLUSIONS: Most patients with BE with neoplasia (of all grades) have subsquamous extension of intestinal metaplasia, including subsquamous extension of lesions at the squamocolumnar junction. Therefore, biopsy and resection of neoplastic BE should extend at least 1 cm into the squamous epithelium.

A new endoscopically implantable device (SatiSphere) for treatment of obesity--efficacy, safety, and metabolic effects on glucose, insulin, and GLP-1 levels.

BACKGROUND: The endoluminal mechanical device SatiSphere is a new endoscopically implantable device designed to delay transit time of nutrients through the duodenum. It consists of a 1-mm nitinol wire with pigtail ends and several mesh spheres mounted along its course, released in the duodenum and gastric antrum to conform to the duodenal C loop configuration and thereby self-anchor. METHODS: The objective is to test the safety, efficacy, and effect on body weight in a 2:1 randomized study, as well as incretin secretion in a subgroup. RESULTS: Of 31 included cases (11 men, mean age 42.9 years, mean BMI 41.3 kg/m2), 21 patients treated with endoscopic device insertion with scheduled device removal after 3 months were compared with 10 controls. In 10 of 21 patients, device migration occurred, in two cases necessitating emergency surgery, which led to termination of the trial. Weight loss after 3 months was 6.7, 4.6, and 2.2 kg in the groups completing therapy, all treatment cases using intention to treat (ITT) analysis and controls. Excess weight loss was significantly increased by endoluminal mechanical device insertion (18.4, 12.2, and 4.4% in completers, ITT analysis group and controls; p = 0.02 for completers vs. controls). Measuring glucose, insulin, and glucagon-like peptide 1 (GLP-1) following a mixed-meal test with the device in place and after removal (n = 7), the device delayed glucose absorption and insulin secretion and altered kinetics in GLP-1 levels. CONCLUSIONS: The device might be short-term effective in reducing body weight, which might be mediated through alterations in incretin metabolism. However, frequent device migration necessitates device modifications.