Background:In early esophageal adenocarcinoma (EAC), guidelines recommend endoscopic mucosal resection (EMR) for superficial (T1a) lesions and endoscopic submucosal dissection (ESD) for deeper (T1b) lesions based on visual assessment. We evaluated the outcomes of this targeted resection strategy. Methods:In a retrospective bicentric study (2009-2023), 311 T1 EACs (235 T1a, 76 T1b) underwent endoscopic resection: EMR for presumed T1a and ESD for suspected T1b lesions. The primary outcome was complete (R0) resection stratified by tumor stage and resection technique. Secondary outcomes were rates of curative resection, adverse events, and surgery. Results:EMR was appropriately applied in 63.0% of T1a cases, and ESD was correctly selected in 60.5% of T1b cases. R0 resection rates were higher with ESD than with EMR for both stages: T1a, 92.9% vs. 80.4%; T1b, 63.0% vs. 26.7%. Curative resection (ESD 60.9% vs. EMR 67.4%), surgery (19.5% vs. 14.0%), and adverse events (7.5% vs. 10.1%) were comparable. On multivariable analysis, ESD was the only independent predictor of complete resection. If surgery decisions had been based on R0 rather than curative outcomes, 20% of post-EMR and 50% of post-ESD esophagectomies could have been avoided. Conclusions:Endoscopic staging of early EAC is imperfect, leading to frequent mismatch between chosen and optimal resection techniques. ESD achieved higher complete resection rates for both T1a and T1b cancers without increased morbidity. ESD may therefore represent the preferred strategy for early EAC, potentially reducing unnecessary surgery.

Supplementary Figure from eQTL Set–Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

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.

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.

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.

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.

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.

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.

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.

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.

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.

In the treatment of neoplastic Barrett esophagus (BE), combined endoscopic resection and ablation of the entire BE has become standard. As an alternative to radiofrequency ablation (RFA), argon plasma coagulation (APC) had recently been combined with prior submucosal injection (Hybrid-APC, H-APC) and found to be successful in a small pilot study.

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.

SUMMARY Background: Esophageal adenocarcinoma (EA) represents one of the fastest rising oncological diseases in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available (>10,000 BE/EA patients, >17,000 controls, all of European descent). The entire GWAS-data set was also analyzed using bioinformatics approaches in order to identify pathophysiologically relevant cellular pathways. Findings: We identified nine new disease loci for BE/EA (P<5×10-8) and thereby doubled the number of known risk loci. The strongest new risk locus implicates CFTR as BE/EA risk gene. Mutations in CFTR cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. Furthermore, for the first time we identified an EA-specific association (P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45). Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council of UK, Cambridge NIHR biomedical research centre, Cambridge Experimental Cancer - 5 - Medicine Centre, Else Kroner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford.

Das Barrett-Karzinom (esophageal adenocarcinoma, EAC) betrifft die untere Speiseröhre und entsteht als Folge eines Barrett-Ösophagus (barrett's esophagus, BE). Neben dem gastroösophagealen Reflux (GERD) gelten die Adipositas (gemessen als Body-Mass-Index, BMI) und speziell die viszerale Adipositas (gemessen als Waist-Hip-Ratio, WHR) als wichtige BE/EAC-Risikofaktoren. Es wird angenommen, dass mit der Adipositas einhergehende systemische Entzündungsreaktionen für das erhöhte BE/EAC-Risiko verantwortlich sind. Zudem wird angenommen, dass der abdominale Druck durch die viszerale Adipositas ansteigt und somit einen GERD mechanisch begünstigt.

Authors Martin Götz1, Mario Anders2, Erwin Biecker3, Christian Bojarski4, Georg Braun5, Thorsten Brechmann6, Alexander Dechêne7, Matthias Dollinger8, Meinrad Gawaz9, Ralf Kiesslich10, Dieter Schilling11, Frank Tacke12, Alexander Zipprich13, Jonel Trebicka14, 15 Collaborators: Tilo Andus, Beate Appenrodt, Andrik Aschoff, Daniel Benten, Karel Caca, Ulrike Denzer, Helmut Diepolder, Wolfgang Fischbach, Bernhard Gebauer, Alexander L. Gerbes, Veit Gülberg, Horst Hohn, Ralf Jakobs, Markus Juchems, Michael Jung, Martin Keuchel, Robert Klamroth, Thomas Leyhe, Petra Lynen-Jansen, Alexander Meining, Helmut Messmann, Ralf Metzger, Jonas Mudter, Horst Neuhaus, Johannes W. Rey, Andrea Riphaus, Elke Roeb, Fred Salomon, Anja Schaible, Michael Schultheiß, Dirk Sibbing, Alfred Simon, Christian P. Strassburg Fachgesellschaften: Deutsche Gesellschaft für Gastroenterologie, Verdauungsund Stoffwechselkrankheiten (DGVS) (federführend), Deutschen Morbus Crohn und Colitis ulcerosa Vereinigung (DCCV), Deutsche Röntgengesellschaft (DRG), Deutsche Gesellschaft für interventionelle Radiologie (DeGiR), Deutsche Gesellschaft für Allgemeinund Viszeralchirurgie (DGAV) und Chirurgische Arbeitsgemeinschaft für Endoskopie und Sonographie (CAES) der DGAV, Deutsche Gesellschaft für Internistische Intensivmedizin (DGIIN), Deutsche Gesellschaft für Innere Medizin (DGIM), Deutsche Gesellschaft für Kardiologie (DGK), Akademie für Ethik in der Medizin (AEM), Gesellschaft für Thromboseund Hämostaseforschung (GTH)

Der neoplastische Barrettösophagus (BÖ) wird derzeit mit einer Kombination aus endoskopischer Resektion (ER) des sichtbaren neoplastischen Areals und Ablation des residuellen BÖ behandelt. Ziel ist die Eradikation des gesamten BÖ. Mittlerweile steht mit der Hybrid-APC (Kombination aus submukosaler Injektion und Argonplasmakoagulation) (H-APC) eine weitere Methode zur Barrettablation zur Verfügung.