GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level.

OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Video: Clinical evaluation of a laparoscopic hyperspectral imaging system.

BACKGROUND: Hyperspectral imaging (HSI) during surgical procedures is a new method for perfusion quantification and tissue discrimination. Its use has been limited to open surgery due to large camera sizes, missing color video, or long acquisition times. A hand-held, laparoscopic hyperspectral camera has been developed now to overcome those disadvantages and evaluated clinically for the first time. METHODS: In a clinical evaluation study, gastrointestinal resectates of ten cancer patients were investigated using the laparoscopic hyperspectral camera. Reference data from corresponding anatomical regions were acquired with a clinically approved HSI system. An image registration process was executed that allowed for pixel-wise comparisons of spectral data and parameter images (StO2: oxygen saturation of tissue, NIR PI: near-infrared perfusion index, OHI: organ hemoglobin index, TWI: tissue water index) provided by both camera systems. The mean absolute error (MAE) and root mean square error (RMSE) served for the quantitative evaluations. Spearman's rank correlation between factors related to the study design like the time of spectral white balancing and MAE, respectively RMSE, was calculated. RESULTS: The obtained mean MAEs between the TIVITA® Tissue and the laparoscopic hyperspectral system resulted in StO2: 11% ± 7%, NIR PI: 14±3, OHI: 14± 5, and TWI: 10 ± 2. The mean RMSE between both systems was 0.1±0.03 from 500 to 750 nm and 0.15 ±0.06 from 750 to 1000 nm. Spearman's rank correlation coefficients showed no significant correlation between MAE or RMSE and influencing factors related to the study design. CONCLUSION: Qualitatively, parameter images of the laparoscopic system corresponded to those of the system for open surgery. Quantitative deviations were attributed to technical differences rather than the study design. Limitations of the presented study are addressed in current large-scale in vivo trials.

New Intraoperative Imaging Tools and Image-Guided Surgery in Gastric Cancer Surgery.

Innovations and new advancements in intraoperative real-time imaging have gained significant importance in the field of gastric cancer surgery in the recent past. Currently, the most promising procedures include indocyanine green fluorescence imaging (ICG-FI) and hyperspectral imaging or multispectral imaging (HSI, MSI). ICG-FI is utilized in a broad range of clinical applications, e.g., assessment of perfusion or lymphatic drainage, and additional implementations are currently investigated. HSI is still in the experimental phase and its value and clinical relevance require further evaluation, but initial studies have shown a successful application in perfusion assessment, and prospects concerning non-invasive tissue and tumor classification are promising. The application of machine learning and artificial intelligence technologies might enable an automatic evaluation of the acquired image data in the future. Both methods facilitate the accurate visualization of tissue characteristics that are initially indistinguishable for the human eye. By aiding surgeons in optimizing the surgical procedure, image-guided surgery can contribute to the oncologic safety and reduction of complications in gastric cancer surgery and recent advances hold promise for the application of HSI in intraoperative tissue diagnostics.

Recipient obesity as a risk factor in kidney transplantation.

BACKGROUND: The aim of the study was to investigate the effect of recipient obesity on the short- and long-term outcomes of patients undergoing primary kidney transplantation (KT). PATIENTS AND METHODS: A total of 578 patients receiving primary KT in our department between 1993 and 2017 were included in the study. Patients were divided according to their body mass index (BMI) into normal weight (BMI 18.5-24.9 kg/m2; N = 304), overweight (BMI 25-29.9 kg/m2; N = 205) and obese (BMI ≥ 30 kg/m2; N = 69) groups. Their clinicopathological characteristics, outcomes, and survival rates were analyzed retrospectively. RESULTS: Obesity was associated with an increased rate of surgical complications such as wound infection (P < 0.001), fascial dehiscence (P = 0.023), and lymphoceles (P = 0.010). Furthermore, the hospital stay duration was significantly longer in the groups with obese patients compared to normal weight and overweight patients (normal weight: 22 days, overweight: 25 days, and obese: 33 days, respectively; P < 0.001). Multivariate analysis showed that recipient obesity (BMI ≥ 30) was an independent prognostic factor for delayed graft function (DGF) (OR 2.400; 95% CI, 1.365-4.219; P = 0.002) and postoperative surgical complications (OR 2.514; 95% CI, 1.230-5.136; P = 0.011). The mean death-censored graft survival was significantly lower in obese patients (normal weight: 16.3 ± 0.6 years, overweight: 16.3 ± 0.8 years, obese 10.8 ± 1.5 years, respectively; P = 0.001). However, when using the Cox proportional hazards model, the association between recipient obesity and death-censored renal graft failure disappeared, after adjustment for important covariates, whereas the principal independent predictors of graft loss were recipient diabetes mellitus and hypertension and kidneys from donors with expanded donor criteria. CONCLUSION: In conclusion, obesity increases the risk of DGF and post-operative surgical complications after primary KT. Appropriate risk-adapted information concerning this must be provided to such patients before KT. Furthermore, obesity-typical concomitant diseases seem to negatively influence graft survival and need to be considered after the transplantation of obese patients.

Venous thromboembolism after esophagectomy for cancer: a systematic review of the literature to evaluate incidence, risk factors, and prophylaxis.

PURPOSE: Although esophagectomy remains the preferred treatment for esophageal cancer, it is still associated with a number of complications, including post-operative venous thromboembolism (VTE). The aim of this study was to summarize the reported incidence of VTE after esophagectomy, its risk factors, and prevention strategies. METHODS: We conducted a systematic search of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Fourteen studies met our inclusion criteria and were selected in the present review. Overall, we identified 9768 patients who underwent esophagectomy, with a post-operative VTE rate of 4% (440 patients). The reported risk factors for VTE included advanced age, American Society of Anesthesiologists (ASA) class III or IV, a history of cardiovascular or pulmonary disease, and the implementation of preoperative chemo-radiotherapy. Postoperative acute respiratory distress syndrome was also associated with VTE. No universally applied prevention strategies for VTE after esophagectomy were identified in the literature. CONCLUSIONS: Despite advances in perioperative care, VTE after esophagectomy still represents a source of morbidity for about 4% of patients. Low molecular weight heparin is suggested as the routine standard prophylactic regimen after esophageal cancer surgery.

Characterization of Total RNA, CD44, FASN, and PTEN mRNAs from Extracellular Vesicles as Biomarkers in Gastric Cancer Patients.

In-depth characterization has introduced new molecular subtypes of gastric cancer (GC). To identify these, new approaches and techniques are required. Liquid biopsies are trendsetting and provide an easy and feasible method to identify and to monitor GC patients. In a prospective cohort of 87 GC patients, extracellular vesicles (EVs) were isolated from 250 µL of plasma. The total RNA was isolated with TRIZOL. The total RNA amount and the relative mRNA levels of CD44, PTEN, and FASN were measured by qRT-PCR. The isolation of EVs and their contained mRNA was possible in all 87 samples investigated. The relative mRNA levels of PTEN were higher in patients already treated by chemotherapy than in chemo-naïve patients. In patients who had undergone neoadjuvant chemotherapy followed by gastrectomy, a decrease in the total RNA amount was observed after neoadjuvant chemotherapy and gastrectomy, while FASN and CD44 mRNA levels decreased only after gastrectomy. The amount of RNA and the relative mRNA levels of FASN and CD44 in EVs were affected more significantly by chemotherapy and gastrectomy than by chemotherapy alone. Therefore, they are a potential biomarker for monitoring treatment response. Future analyses are needed to identify GC-specific key RNAs in EVs, which could be used for the diagnosis of gastric cancer patients in order to determine their molecular subtype and to accompany the therapeutic response.

Hyperspectral Imaging: A New Intraoperative Tool for Pouch Assessment in Patients Undergoing Restorative Proctocolectomy.

INTRODUCTION: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is a challenging operation. Especially the mobilization of the pouch into the pelvis can be complex. Adequate perfusion of the pouch is required for optimal healing and functioning. METHODS: With hyperspectral imaging (HSI) wavelengths between 500 and 1,000 nm can be analyzed in addition to visible light and by reflecting patterns. This intraoperative procedure is non-invasive, contact-free, and no contrast medium is needed. Fifteen patients undergoing IPAA were examined prospectively, and the pouch was evaluated by HSI intraoperatively. HSI was measured in standardized fashion at 4 defined locations of the J-pouch. Each measurement took about 10 s. The clinical postoperative course was assessed in all patients and correlated to the intraoperative HSI findings. RESULTS: Mean near-infrared perfusion and oxygenation of patients showed values ≥74% for all defined pouch areas, revealing good blood supply. Three minor anastomotic leaks were detected by standard pouchoscopy in the postoperative course, which could be treated conservatively with endosponge therapy. CONCLUSION: HSI values of perfusion and oxygenation of the IPAA were high. The leak rate is associated with redo procedures. This is reflected by the current literature and most likely related to the higher complexity of the revisional pouch operation. HSI has proved itself as a quick and effective new intraoperative tool to evaluate pouch perfusion objectively and quantitatively.

The WNT5A/ROR2 signaling pathway in pancreatic ductal adenocarcinoma (PDAC).

PURPOSE: WNT5A/ROR2 signaling pathway has been involved in many human cancers. Its role in pancreatic ductal adenocarcinoma (PDAC) has not been clarified yet. The purpose of this study was to determine the prognostic value of WNT5A expression in conjunction with the ROR2 expression in the same PDAC human tissues. METHODS: We retrospectively analyzed by immunohistochemistry the WNT5A and ROR2 expression in117 paraffin-embedded PDAC specimens following surgical pancreatic resection. The prognostic value of WNT5A and ROR2 was assessed using Kaplan-Meier survival curves and multivariate Cox regression models. RESULTS: High ROR2 expression was detected in 65.8% (77/117) of PDAC tumors, in 28.2% (33/117) in tumor-stroma, and in 71.1% (65/90) of normal pancreatic tissue. High WNT5A expression was found in 76.9% (90/117) of tumors, in 59.0% (69/117) of tumor-stroma, and in 83.0% (73/88) of normal pancreatic tissue. Spearman's correlation coefficiency demonstrated weak association between ROR2 and WNT5A expression in tumor (r=0.184; p=0.047), and no association in stroma (r=0.036; p=0.699). Multivariate analysis showed that regional lymph node invasion and differentiation were independent prognostic factors of survival, while ROR2- and WNT5A expression were not. CONCLUSIONS: Variable expression patterns for ROR2 and WNT5A were demonstrated in PDAC and normal pancreatic tissues suggesting a role for WNT5A/ROR2 signalling pathway, not only in PDAC but also in the normal pancreatic tissue during inflammation. The lack of prognostic significance for ROR2 and WNT5A expression in our cohort, either alone or in subgroup analysis, underlines the complexity of their role in PDAC, which is highly dependent on the different molecular receptor-ligand tissue contexts.

Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells.

Chronic acid reflux causes cellular damage and inflammation in the lower esophagus. Due to these irritating insults, the squamous epithelium is replaced by metaplastic epithelium, which is a risk factor for the development of esophageal adenocarcinoma (EAC). In this study, we investigated the acid susceptibility in a Barrett's cell culture in vitro model, using six cell lines, derived from squamous epithelium (EPC1 and EPC2), metaplasia (CP-A), dysplasia (CP-B), and EAC (OE33 and OE19) cells. Cells exposed to acidic pH showed a decreased viability dependent on time, pH, and progression status in the Barrett's sequence, with the highest acid susceptibility in the squamous epithelium (EPC1 and EPC2), and the lowest in EAC cells. Acid pulsing was accompanied with an activation of the Nrf2/Keap1- and the NFκB-pathway, resulting in an increased expression of HO1-independent of the cellular context. OE33 showed a decreased responsiveness towards 5-FU, when the cells were grown in acidic conditions (pH 6 and pH 5.5). Our findings suggest a strong damage of squamous epithelium by gastroesophageal reflux, while Barrett's dysplasia and EAC cells apparently exert acid-protective features, which lead to a cellular resistance against acid reflux.

Hyperspectral Imaging (HSI) in Acute Mesenteric Ischemia to Detect Intestinal Perfusion Deficits.

BACKGROUND: Acute mesenteric ischemia is a life-threatening acute condition, which requires an interdisciplinary approach, including vascular recanalization and surgical treatment. Visual evaluation of intestinal perfusion might be misleading, and therefore, additional tools are necessary to reliably be able to resect the ischemic intestine. Hyperspectral imaging (HSI) has been shown to be feasible and safe for real-time assessment of tissue perfusion in visceral surgery but has never been used in cases of acute mesenteric ischemia. Therefore, we applied HSI in acute mesenteric ischemia to evaluate it for potential aid in the objectively discriminating ischemic and well-perfused intestine during explorative laparotomy. METHODS: We recorded HSI measurements in 11 cases of acute mesenteric ischemia during explorative laparotomy. We evaluated the recorded images for macroscopic visual perfusion quality and divided it into three groups. Of those three groups, we calculated and compared the HSI indexes of tissue saturation, near-infrared perfusion index, organ hemoglobin index, and tissue water index, as well as the reflectance spectra. RESULTS: We found significant differences in tissue saturation (0.7% versus 0.45%; P = 0.002) and near-infrared perfusion index (0.58 versus 0.23; P < 0.001) in poorly perfused intestinal segments compared with the viable intestine. Furthermore, we could detect an increasing peak at 630 nm of the reflectance spectra in less viable tissues, indicating a maximum in necrotic tissues. We attributed this peak to an increase in met-hemoglobin content in necrotic tissues, which is supported by the increase in the HSI organ hemoglobin index. CONCLUSIONS: HSI is able to discriminate tissue perfusion in acute mesenteric ischemia reliably and therefore might be helpful for resection. In addition, HSI gives information on tissue viability via reflectance spectra.

Correction to: Preoperative Upper-GI Endoscopy Prior to Bariatric Surgery: Essential or Optional?

In the original article the name of author Matthias Blüher was incorrect. It is correct here and the original article has been corrected.

Preoperative Upper-GI Endoscopy Prior to Bariatric Surgery: Essential or Optional?

INTRODUCTION: The role of preoperative upper-gastrointestinal (GI) gastroscopy has been discussed with controversy in bariatric surgery. The aim of this study was to evaluate the incidence of upper-GI pathologies detected via endoscopy prior to bariatric surgery along with their clinical significance for patients' management. MATERIAL AND METHODS: In our single center prospectively established database of obese patients, who underwent bariatric surgery from January 2011 to December 2017, we retrospectively analyzed the perioperative endoscopic findings along with their influence on patients' management. RESULTS: In total, 636 obese patients with median BMI (body mass index) of 49 kg/m2 [range 31-92] received an upper-GI endoscopy prior to bariatric surgery. Among the surgical procedures, laparoscopic Roux-Y-gastric bypass (72.6%; n = 462) was the most frequent operation. Endoscopically detected pathological conditions were peptic ulcer 3.5% (22/636), Helicobacter pylori (Hp) gastritis 22.4% (143/636), and gastric or duodenal polyps 6.8% (43/636). Reflux esophagitis could be detected in 139/636 patients (21.9%). Barrett's esophagus (BE) was histologically diagnosed in 95 cases (15.0%), whereas BE was suspected endoscopically in 75 cases (11.3%) only. Esophageal adenocarcinomas were detected in 3 cases (0.5%). Change of the operative strategy due to endoscopically or histologically detected pathologic findings had to be performed in 10 cases (1.6%). CONCLUSION: Preoperative upper-GI endoscopy identifies a wide range of abnormal endoscopic findings in obese patients, which may have a significant impact on decision-making, particularly regarding the most suitable bariatric procedure and the appropriate follow-up. Therefore, preoperative upper-GI endoscopy should be considered in all obese patients prior to bariatric procedure.

LINX® reflux management system to bridge the "treatment gap" in gastroesophageal reflux disease: A systematic review of 35 studies.

BACKGROUND: Gastroesophageal reflux disease (GERD) occurs when the reflux of stomach contents causes troublesome symptoms and/or complications. When medical therapy is insufficient, surgical therapy is indicated and, until now, Laparoscopic fundoplication (LF) constitutes the gold-standard method. However, magnetic sphincter augmentation (MSA) using the LINX® Reflux Management System has recently emerged and disputes the standard therapeutic approach. AIM: To investigate the device's safety and efficacy in resolving GERD symptoms. METHODS: This is a systematic review conducted in accordance to the PRISMA guidelines. We searched MEDLINE, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL databases from inception until September 2019. RESULTS: Overall, 35 studies with a total number of 2511 MSA patients were included and analyzed. Post-operative proton-pump inhibitor (PPI) cessation rates reached 100%, with less bloating symptoms and a better ability to belch or vomit in comparison to LF. Special patient groups (e.g., bariatric or large hiatal-hernias) had promising results too. The most common postoperative complication was dysphagia ranging between 6% and 83%. Dilation due to dysphagia occurred in 8% of patients with typical inclusion criteria. Esophageal erosion may occur in up to 0.03% of patients. Furthermore, a recent trial indicated MSA as an efficient alternative to double-dose PPIs in moderate-to-severe GERD. CONCLUSION: The findings of our review suggest that MSA has the potential to bridge the treatment gap between maxed-out medical treatment and LF. However, further studies with longer follow-up are needed for a better elucidation of these results.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in patients with peritoneal metastasized colorectal, appendiceal and small bowel cancer.

BACKGROUND: Patients with intestinal cancer (colorectal, appendiceal, and small bowel) with peritoneal metastases (PM) have a poor prognosis. We assessed whether pressurized intraperitoneal aerosol chemotherapy (PIPAC) together with systemic chemotherapy is an effective treatment option for these entities in palliative intent. METHODS: Between November 2015 and February 2018, prospective data registry was performed (NCT03100708). Thirteen patients with intestinal cancer (median age 61 years [range 49-77]) underwent 26 PIPAC procedures with a median number of 2 interventions per patient (range 1-6). A chemoaerosol consisting of cisplatin/doxorubicin was administered during standard laparoscopy. RESULTS: The median peritoneal carcinomatosis index according to Sugarbaker before the first PIPAC was 14 (range 2-27), and the median ascites volume was 10 mL (range 0-6300 mL). Six patients who received 2 or more PIPAC procedures had decreased and stable ascites volumes, while only 1 patient displayed increased ascites. The median overall survival was 303 days (range 30-490) after the first PIPAC procedure. CONCLUSIONS: PIPAC offers a novel treatment option for patients with PM. Our data show that PIPAC is safe and well-tolerated. Ascites production can be controlled by PIPAC in patients with intestinal cancer. Further studies are required to document the significance of PIPAC within palliative therapy concepts. TRIAL REGISTRATION: NCT03100708.

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.

Tumor-associated macrophages and individual chemo-susceptibility are influenced by iron chelation in human slice cultures of gastric cancer.

Purpose: Presence of tumor-associated macrophages (TAM) and high levels of ferritin and lipocalin 2 (Lcn2) in the tumor microenvironment are associated with poor prognosis in many types of cancer. Here we investigate whether iron deprivation influences TAM phenotype and chemotherapy resistance in tumor slice cultures (TSC) of gastric cancer. Results: TAM remained morphologically and functionally stable for four DIV. DFO treatment for 72 h decreased ferritin expression in TAM and in the tumor stroma but did not alter Lcn2 expression. TAM phenotype was altered after 72 h of cisplatin or DFO treatment compared with control conditions. Single DFO treatment and combined treatment with cytotoxic drugs significantly increased tumor cell apoptosis in TSC of gastric cancer. Methods: TSC were manufactured by cutting tissue of gastric cancer resection specimens in 350 µm thick slices and cultivating them under standard conditions on a filter membrane, at an air-liquid interface. After 24 h ex vivo, TSC were treated with irinotecan (100 nM) or cisplatin (10 µM) alone and in combination with deferoxamine (DFO; 10 µM, 100 µM), respectively, for 72 h. After four days in vitro (DIV) the TSC were fixated with paraformaldehyde, paraffin embedded and analyzed by immunohistochemistry for apoptosis (cPARP), proliferation (Ki67), TAM (CD68, CD163), ferritin, and Lcn2 expression. Conclusions: TAM are well preserved and can be studied in TSC of gastric cancer. Iron deprivation significantly increased tumor cell apoptosis.

In-depth characterization of the Wnt-signaling/ß-catenin pathway in an in vitro model of Barrett's sequence.

BACKGROUND: An altered Wnt-signaling activation has been reported during Barrett's esophagus progression, but with rarely detected mutations in APC and ß-catenin (CTNNB1) genes. METHODS: In this study, a robust in-depth expression pattern analysis of frizzled receptors, co-receptors, the Wnt-ligands Wnt3a and Wnt5a, the Wnt-signaling downstream targets Axin2, and CyclinD1, as well as the activation of the intracellular signaling kinases Akt and GSK3ß was performed in an in vitro cell culture model of Barrett's esophagus. Representing the Barrett's sequence, we used normal esophageal squamous epithelium (EPC-1, EPC-2), metaplasia (CP-A) and dysplasia (CP-B) to esophageal adenocarcinoma (EAC) cell lines (OE33, OE19) and primary specimens of squamous epithelium, metaplasia and EAC. RESULTS: A loss of Wnt3a expression was observed beginning from the metaplastic cell line CP-A towards dysplasia (CP-B) and EAC (OE33 and OE19), confirmed by a lower staining index of WNT3A in Barrett's metaplasia and EAC, than in squamous epithelium specimens. Frizzled 1-10 expression analysis revealed a distinct expression pattern, showing the highest expression for Fzd2, Fzd3, Fzd4, Fzd5, Fzd7, and the co-receptor LRP5/6 in EAC cells, while Fzd3 and Fzd7 were rarely expressed in primary specimens from squamous epithelium. CONCLUSION: Despite the absence of an in-depth characterization of Wnt-signaling-associated receptors in Barrett's esophagus, by showing variations of the Fzd- and co-receptor profiles, we provide evidence to have a significant role during Barrett's progression and the underlying pathological mechanisms.