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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.

ZusammenfassungDer Barrett-Ösophagus (BE) stellt den wichtigsten Risikofaktor für das ösophageale Adenokarzinom dar. Derzeit ist kein hinreichend effizientes Screening-Programm verfügbar, um in der Gesamtpopulation Patienten mit einem hohen Risiko für ein ösophageales Adenokarzinom auf dem Boden eines Barrett-Ösophagus zu identifizieren. Das aktuelle endoskopische Screening zielt auf symptomatische Refluxpatienten, aus denen sich aber nur ein Teil der Risikopatienten rekrutiert. Derzeit werden verschiedene neue Verfahren untersucht, die die Effektivität des Screenings deutlich erhöhen könnten.Selektive Literaturrecherche in MEDLINE/PubMed unter Berücksichtigung deutscher und internationaler Leitlinien.Alternative Screening-Verfahren könnten zweistufig angelegt sein: Zunächst die Identifikation von Personen „at risk“ über eine Erfassung geeigneter biologischer Marker, dann deren gezielte endoskopisch-bioptische Abklärung, Risikostratifikation, Überwachung (Surveillance) und ggf. Therapie. Neue diagnostische Methoden wie der Cytosponge® in Kombination mit einer Auswertung von Markern für Barrett-Schleimhaut könnten einen wesentlichen Fortschritt darstellen.Barrett-Karzinome zeigen nach wie vor eine zunehmende Inzidenz und eine (trotz therapeutischer Fortschritte) ungünstige Prognose, wobei aber Patienten mit Barrett-Frühkarzinomen eine gute Prognose hinsichtlich Langzeitüberleben aufweisen. Eine verbesserte Früherkennung ist dringend wünschenswert, da bisher die meisten Patienten erst im fortgeschrittenen Stadium endoskopisch diagnostiziert werden, was eine kurative Therapie erschwert. Nur eine effiziente frühzeitige Identifizierung von Risikopatienten mit Barrett-Ösophagus durch ein praktikables Screening-Programm auf Populationsebene wird zur Verbesserung der Prognose beitragen können.

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access) 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.

Though showing an increasing incidence over the past 20 years, esophageal adenocarcinoma (EAC) remains a rather uncommon cancer (i. e., compared to colorectal and gastric cancer). Once detected, the prognosis of this cancer entity is still very poor. Hence, in spite of some unfavorable prerequisites to systematic screening, the development of a screening concept for Barrett's esophagus (BE) and EAC seems worthwhile. Nowadays, screening for BE and EAC is based on conventional endoscopy, mostly conducted individually in patients with reflux complaints (gastroesophageal reflux disease-GERD). Biopsies are taken obligatorily and are the centerpiece of diagnosis and scheduling of surveillance. So far, endoscopy is the diagnostic gold standard, but it is expensive and obviously lacks effectiveness-8 of 10 cases of EAC are not detected in endoscopic screening (and surveillance) but by an opportunistic first-time endoscopy. Therefore, new methods for BE/EAC screening are strongly desirable. Research must be concentrated to favor procedures applicable for a screening of the population in a primary care setting. For that, the first step needs to consist of identifying a subgroup of people "at risk", which in a second step can be risk assessed and followed up by endoscopy and biopsy. From all screening variants, which have been actually tested in clinical application and experimental research, biomarker-based techniques seem to be most promising. Among those-under the aspect of costs and practicability-the Cytosponge, in addition with a panel of biomarkers, seemed to be promising in clinical trials.Der Barrett-Ösophagus (BE) stellt den wichtigsten Risikofaktor für das ösophageale Adenokarzinom dar. Derzeit ist kein hinreichend effizientes Screening-Programm verfügbar, um in der Gesamtpopulation Patienten mit einem hohen Risiko für ein ösophageales Adenokarzinom auf dem Boden eines Barrett-Ösophagus zu identifizieren. Das aktuelle endoskopische Screening zielt auf symptomatische Refluxpatienten, aus denen sich aber nur ein Teil der Risikopatienten rekrutiert. Derzeit werden verschiedene neue Verfahren untersucht, die die Effektivität des Screenings deutlich erhöhen könnten.Selektive Literaturrecherche in MEDLINE/PubMed unter Berücksichtigung deutscher und internationaler Leitlinien.Alternative Screening-Verfahren könnten zweistufig angelegt sein: Zunächst die Identifikation von Personen „at risk“ über eine Erfassung geeigneter biologischer Marker, dann deren gezielte endoskopisch-bioptische Abklärung, Risikostratifikation, Überwachung (Surveillance) und ggf. Therapie. Neue diagnostische Methoden wie der Cytosponge

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?0⁻⁸) and novel candidate loci (5?0⁻⁸ ≤ P ≤ 5?0⁻⁵). 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?0⁻⁷ and rs1540, Pcₒmbinₑd = 4.16?0⁻⁶) 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. CA extern

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.

Contains fulltext : 215282.pdf (Publisher’s version ) (Closed access) 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.

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.

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.

Wir arbeiten in Erlangen mit dem Prototyp eines gepulsten Neodym: YAG-Lasers der Wellenlange 1064 nm des Schweizer Herstellers LASAG/Thun. Dieses Gerat kann in der Betriebsart “free running mode” fur Gallensteine eingesetzt werden. Fur Harnsteine ist Betriebsart Q-switch erforderlich. Die Lithotripsie erfolgt bei einer Pulslange von 20 ns, Pulsfrequenz 20 – 25 Hz und 15 – 30 mJ Pulsenergie an der Faserspitze. Als Lichtleitfaser dient eine hochflexible Quarz-Glasfaser mit Kerndurchmesser 300 μm, deren nackte Spitze annahernd tropfenformig zugeschmolzen ist. Mit dieser Spitzenausformung waren die hochsten Drucke und die besten Fragmentationsraten in vitro zu erzielen.

In Erlangen wird in Zusammenarbeit von Urologen und Gastroenterologen der Prototyp eines Laserlithotripsiegerates der Schweizer Firma Lasag AG/ Thun erprobt. Es handelt sich dabei um einen gepulsten Neodym Yag-Laser der Wellenlange 1064 nm, der zwei Betriebsarten in sich vereinigt. Mit der Einstellung Freerun wurden bereits einige Erfahrungen in der Behandlung von Choledochussteinen gesammelt. Hierbei werden thermische Pulse von einer Dauer bis 4 msec, und Energien bis zu 5 J bei bis zu 20 Hertz genutzt. Fur Harnsteine ist die Betriebsart Q-switch erforderlich mit Pulsdauern bis zu 20 nsec, Pulsenergien bis 40 mJoule bei Frequenzen bis 20 Hertz. Als Lichtleitsystem dient eine Quarzglasfaser von nur 300 μ Durchmesser, deren Spitze so geformt ist, das es durch Fokussierung zum optischen Durchbruch und dadurch zu Stoswellen fur die Steinzerstorung kommt. Fur die Applikation verwenden wir ein Ureteroskop (ll,5 Charr.) und die Absaug-Einrichtung der Fa. Wolf/Knittlingen mit einem eigens entwickelten Zusatzinstrument, welches einen in Bezug auf die Faser konzentrischen Spulstrom sowie periphere Absaugung gewahrleistet.