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Vani JA Konda1, Kunal Dalal21Section of Gastroenterology, Department of Medicine, 2Department of Internal Medicine, University of Chicago Medical Center, Chicago, Illinois, USAAbstract: Esophageal adenocarcinoma and its precursor, Barrett's esophagus, are rapidly rising in incidence. This review serves to highlight the role of pharmacologic, endoscopic, and surgical intervention in the management of Barrett's esophagus, which requires acid suppression and endoscopic assessment. Treatment with a proton pump inhibitor may decrease acid exposure and delay the progression to dysplasia. Patients who require aspirin for cardioprotection or other indications may also benefit in terms of a protective effect against the development of esophageal cancer. However, without other indications, aspirin is not indicated solely to prevent cancer. A careful endoscopic examination should include assessment of any visible lesions in a Barrett's segment. An expert gastrointestinal pathologist should confirm neoplasia in the setting of Barrett's esophagus. For those patients with high-grade dysplasia or intramucosal carcinoma, careful consideration of endoscopic therapy or surgical therapy must be given. All visible lesions in the setting of dysplasia should be targeted with focal endoscopic mucosal resection for both accurate histopathologic diagnosis and treatment. The remainder of the Barrett's epithelium should be eradicated to address all synchronous and metachronous lesions. This may be done by tissue acquiring or nontissue acquiring means. Radiofrequency ablation has a positive benefit-risk profile for flat Barrett's esophagus. At this time, endoscopic therapy is not indicated for nondysplastic Barrett's esophagus. Esophagectomy is still reserved for selected cases with evidence of lymph node metastasis, unsuccessful endoscopic therapy, or with high-risk features of high-grade dysplasia or intramucosal carcinoma.Keywords: Barrett's esophagus, high-grade dysplasia, esophagectomy, ablation, endoscopic mucosal resection

Background & Aims: There is significant variability in the immediate post-operative and long-term management of patients undergoing per-oral endoscopic myotomy (POEM), largely stemming from the lack of high-quality evidence. We aimed to establish a consensus on several important questions on the after care of post-POEM patients through a modified Delphi process., Methods: A steering committee developed an initial questionnaire consisting of 5 domains (33 statements): post-POEM admission/discharge, indication for immediate post-POEM esophagram, peri-procedural medications and diet resumption, clinic follow-up recommendations, and post-POEM reflux surveillance and management. A total of 34 experts participated in the 2 rounds of the Delphi process, with quantitative and qualitative data analyzed for each round to achieve consensus., Results: A total of 23 statements achieved a high degree of consensus. Overall, the expert panel agreed on the following: (1) same-day discharge after POEM can be considered in select patients; (2) a single dose of prophylactic antibiotics may be as effective as a short course; (3) a modified diet can be advanced as tolerated; and (4) all patients should be followed in clinic and undergo objective testing for surveillance and management of reflux. Consensus could not be achieved on the indication of post-POEM esophagram to evaluate for leak., Conclusions: The results of this Delphi process established expert agreement on several important issues and provides practical guidance on key aspects in the care of patients following POEM., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3'UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, -148a or -152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3'UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.

Colorectal cancer is a leading cause of cancer deaths. The renin-angiotensin system (RAS) is upregulated in colorectal cancer, and epidemiologic studies suggest RAS inhibitors reduce cancer risk. Because vitamin D (VD) receptor negatively regulates renin, we examined anticancer efficacy of VD and losartan (L), an angiotensin receptor blocker. Control Apc +/LoxP mice and tumor-forming Apc +/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VD+L, the latter to assess additive or synergistic effects. At 6 months, mice were killed. Plasma Ca 2+ , 25(OH)D3, 1α, 25(OH)2D3, renin, and angiotensin II (Ang II) were quantified. Colonic transcripts were assessed by qPCR and proteins by immunostaining and blotting. Cancer incidence and tumor burden were significantly lower in Cre+ VD and Cre+ L, but not in the Cre+ VD+L group. In Apc +/LoxP mice, VD increased plasma 1,25(OH)2D3 and colonic VDR. In Apc +/LoxP -Cdx2P-Cre mice, plasma renin and Ang II, and colonic tumor AT1, AT2, and Cyp27B1 were increased and VDR downregulated. L increased, whereas VD decreased plasma renin and Ang II in Cre+ mice. VD or L inhibited tumor development, while exerting differential effects on plasma VD metabolites and RAS components. We speculate that AT1 is critical for tumor development, whereas RAS suppression plays a key role in VD chemoprevention. When combined with L, VD no longer increases active VD and colonic VDR in Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination., (©2019 American Association for Cancer Research.)

Nondysplastic Barrett's esophagus has a risk of progression to esophageal adenocarcinoma as low as 0.18-0.3% per person per year, and low-grade dysplasia as low as 0.5%. While adherence to guidelines and selection of management options varies, little is known about what modifies patient decision-making. This study aims to evaluate and identify factors that influence patient perceptions of risk and decisions about management. An independently developed and piloted survey was administered to patients at an academic hospital. Risk perception and desire for therapy were assessed using a standard reference gamble paradigm, and responses were stratified based on patient and disease characteristics. Data were analyzed with Student's t and chi-squared tests. A total of 42 of 50 patients with Barrett's esophagus and no prior endoscopic therapy participated (84% response; 76% nondysplastic Barrett's esophagus, 22% low-grade dysplasia, 2% indeterminate for dysplasia; mean age 61 years, 29% female). On average, patients perceived their risk of developing esophageal adenocarcinoma in the next year, 10 years and lifetime as 6, 14, and 19%, respectively. Nearly half viewed their lifetime risk of developing esophageal adenocarcinoma to be the same or higher than diabetes, heart disease, or colon cancer. Although 92% of patients felt surveillance beneficial, only 54% believed endoscopic therapy to be effective in most or all cases. As many as 83% of patients were willing to undergo endoscopic therapy with a hypothetical success rate as low as 70%, and a majority (64%) accepted complication rates up to 30%. Compared to patients with low risk perception of developing esophageal adenocarcinoma, those with high risk perception more often believed their risk for developing esophageal adenocarcinoma was greater than diabetes (p = 0.04) or colon cancer (p = 0.002). Those with lifetime low risk perception were less likely to accept modest complication rates (<10%) of therapy (P < 0.05). Age, gender, degree of dysplasia, lifetime endoscopies and duration of symptoms had no impact on perceived effectiveness of surveillance or therapy, and did not correlate with desire for treatment at varying levels of risk and effectiveness. Patients with Barrett's esophagus overestimate their risk of developing esophageal adenocarcinoma and will accept low success rates and high risk of complications to undergo endoscopic therapy. Baseline risk perception correlates with the desire for endoscopic therapy.

Background and Aims: The complex design of the elevator mechanism in duodenoscopes has been recognized as a challenge for disinfection and recently implicated as a potential source of persistent bacterial contamination. Curvilinear array (CLA) echoendoscopes also have an elevator mechanism; however, there are no recommendations or data regarding the risk of persistent bacterial contamination of echoendoscopes. Here we hoped to determine the yield of microbial growth with routine bacterial surveillance cultures of reprocessed CLA echoendoscopes., Methods: Beginning in February 2015 to February 2016, CLA echoendoscopes at a single tertiary care center underwent prospective bacterial surveillance cultures after reprocessing. Any growth of gram-negative bacilli was considered to be critical. Echoendoscopes with a positive result underwent quarantine followed by repeat disinfection and culture., Results: During the study period, 540 cultures were obtained; 521 (96.5%) were primary cultures obtained from 18 CLA echoendoscopes. Twenty-two primary cultures (4.2%) were positive for gram-negative bacilli after high-level disinfection reprocessing. Eleven different bacteria were isolated: Klebsiella pneumoniae, Citrobacter freundii, Escherichia coli, Pseudomonas aeruginosa, Klebsiella oxytoca, Sphingomonas paucimobilis, Acinetobacter baumanii, Enterobacter cloacae, Hafnia alvei, Pseudomonas putida, and Stenotrophomonas maltophilia. Antibiotic sensitivity data on 19 of 24 bacteria (79.2%) isolated from positive primary cultures revealed no documented cases of carbapenem-resistant enterobacteriaceae, cephalosporin-resistant-Klebsiella, or multidrug-resistant Acinetobacter. There have been no documented cases of patient-to-patient transmission., Conclusions: After following standard high-level disinfection and reprocessing, CLA echoendoscopes can remain culture positive for high-concern organisms. Recommendations regarding infection risk should take into consideration elevator-containing echoendoscopes in addition to duodenoscopes to ensure patient safety and endoscope reprocessing efficacy., (Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aims: EMR is increasingly used for resection of sporadic, nonampullary duodenal adenomas (SNDAs), but there are no guidelines for the management of these lesions. The aims of this study were to evaluate the safety and efficacy of EMR exclusively for SNDAs and to determine the factors predictive of outcomes., Methods: We performed a retrospective review of patients with SNDAs referred for endoscopic therapy from 2006 to 2013. The outcomes studied were successful endoscopic resection, major adverse events, early and late recurrences, and clinical remission., Results: Sixty-eight patients with SNDAs were included and 51 (75%) underwent EMR. The mean adenoma size was 22.0 ± 8.9 mm. Successful resection was achieved in 49 of 51 patients (96.1%), and major adverse events were noted in 8 of 51 patients (15.7%). Early and late recurrences were noted in 25.6% and 5.2% of patients, respectively, and were treated endoscopically. Clinical remission was achieved in 89.7% of patients after a median follow-up of 15 months. Presence of villous histology was associated with increased recurrence (P = .019), but no association of recurrence was noted with other endoscopic features or resection technique. Large adenoma size (P = .0057) and need for intraprocedural hemostasis (P = .006) were associated with increased adverse events, but no association of adverse events was noted with location or resection technique., Conclusions: Large duodenal adenomas can be effectively managed with EMR at a referral center with experienced endoscopists. However, EMR has a significant recurrence rate, especially early recurrence, and the risk of adverse events is not negligible. Endoscopic therapy is successful in managing recurrent adenomas., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Patients who have heartburn are treated with acid-reducing medications on the assumption that gastroesophageal reflux disease (GERD) is causing the symptom. In the absence of a response to therapy, patients are often assumed to have refractory GERD, and they are referred for laparoscopic antireflux surgery (LARS), often without further diagnostic evaluation., Hypothesis: We hypothesized that (1) in some patients with refractory GERD, the heartburn is not secondary to reflux, but rather to stasis and fermentation of food in the presence of achalasia and (2) esophageal manometry and pH monitoring are essential to establish proper diagnosis., Patients and Methods: Five hundred twenty-four patients, whose final diagnosis was achalasia, were referred to two quaternary care centers. Symptomatic evaluation, barium swallow, endoscopy, manometry, and pH monitoring were performed in all patients., Results: One hundred fifty-two patients (29%) had been treated with acid-reducing medications for an average of 29.3 months, and were referred for LARS because of lack of response to medical therapy. One patient had already been treated with a Nissen fundoplication. All patients were diagnosed with achalasia and underwent Heller myotomy and partial fundoplication., Conclusions: The results of this study showed that (1) one-third of achalasia patients complained of heartburn and (2) patients with heartburn not responding to medical treatment must be carefully evaluated before referral to surgery. These data confirm the importance of esophageal manometry and pH monitoring in any patient considered for LARS.

Barrett's esophagus (BE) is a pre-malignant condition affecting up to 15% of patients with gastroesophageal reflux disease. Neoplastic Barrett's mucosa is defined as harboring high grade dysplasia or intra-mucosal cancer, and carries a high risk of progression to esophageal adenocarcinoma. The rising incidence of Barrett's lesions along with the high morbidity of surgical approaches has led to the development of numerous validated endoscopic techniques capable of eradicating neoplastic mucosa in a minimally invasive manner. While there has been widespread adoption of these techniques, less is known about optimal surveillance intervals in the post-therapy period. This is due in part to limitations in current surveillance methods, questions about durability of treatment response and the risk of subendothelial progression. As we are now able to achieve organ sparing eradication of superficial neoplasia in BE, we need to also then focus our attention on how best to manage these patients after eradication is achieved. Implementing optimal surveillance practices requires additional understanding of the biology of the disease, appreciation of the limits of current tools and treatments, and exploration of the role of adjunctive technologies. The aim of this article is to provide a comprehensive review of current literature surrounding post-ablation surveillance in neoplastic BE.

Background and Aims: Diagnosis of pancreatic cystic lesions (PCLs) remains challenging. EUS with FNA is limited by sampling error and nondiagnostic cytology. Needle-based confocal laser endomicroscopy (nCLE) performed during EUS can be used to improve diagnostic yield via FNA by providing in vivo histology of PCLs. However, the interobserver agreement (IOA) of nCLE of PCLs has yet to be studied., Methods: Fifteen deidentified nCLE video clips of PCLs were sent to 6 interventional endoscopists at 5 institutions. Six variables were assessed for IOA: presence or absence of (1) vessels, (2) villi, (3) dark clumps, (4) reticular pattern, (5) acinar cells pattern, and (6) debris. PCL interpretation was categorized as mucinous, serous, pseudocyst, malignant, or indeterminate and final diagnosis as benign, malignant, or indeterminate., Results: IOA ranged from "poor" to "fair." The K statistics were -.04 (SE = .05) for vessels, .16 (SE = .07) for villi, .22 (SE = .06) for dark clumps, .13 (SE = .06) for reticular pattern, .14 (SE = .06) for acinar cells pattern, .06 (SE = .06) for debris, .15 (SE = .03) for interpretation, .13 (SE = .05) for final diagnosis, and .19 (SE = .05) for image quality. The final diagnosis was malignant (10), benign (13), and indeterminate (2). The mean accuracy of the observers was 46%, with the lowest being 20% and highest being 67%., Conclusions: The IOA and accuracy for PCL diagnosis were low. The results of this study support the need to identify and validate imaging criteria to determine whether nCLE has diagnostic value for pancreatic pathology. (, Clinical Trial Registration Number: NCT02166086.)., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Tumor cells circulate in low numbers in peripheral blood; their detection is used predominantly in metastatic disease. We evaluated the feasibility and safety of sampling portal venous blood via endoscopic ultrasound (EUS) to count portal venous circulating tumor cells (CTCs), compared with paired peripheral CTCs, in patients with pancreaticobiliary cancers (PBCs)., Methods: In a single-center cohort study, we evaluated 18 patients with suspected PBCs. Under EUS guidance, a 19-gauge EUS fine needle was advanced transhepatically into the portal vein and as many as four 7.5-mL aliquots of blood were aspirated. Paired peripheral blood samples were obtained. Epithelial-derived CTCs were sorted magnetically based on expression of epithelial cell adhesion molecules; only those with a proper morphology and found to be CD45 negative and positive for cytokeratins 8, 18, and/or 19 and 4',6-diamidino-2-phenylindole were considered to be CTCs. For 5 samples, CTCs also were isolated by flow cytometry and based on CD45 depletion. ImageStream was used to determine the relative protein levels of P16, SMAD4, and P53. DNA was extracted from CTCs for sequencing of select KRAS codons., Results: There were no complications from portal vein blood acquisition. We detected CTCs in portal vein samples from all 18 patients (100%) vs peripheral blood samples from only 4 patients (22.2%). Patients with confirmed PBCs had a mean of 118.4 ± 36.8 CTCs/7.5 mL portal vein blood, compared with a mean of 0.8 ± 0.4 CTCs/7.5 mL peripheral blood (P < .01). The 9 patients with nonmetastatic, resectable, or borderline-resectable PBCs had a mean of 83.2 CTCs/7.5 mL portal vein blood (median, 62.0 CTCs/7.5 mL portal vein blood). In a selected patient, portal vein CTCs were found to carry the same mutations as those detected in a metastatic lymph node and expressed similar levels of P16, SMAD4, and P53 proteins., Conclusions: It is feasible and safe to collect portal venous blood from patients undergoing EUS. We identified CTCs in all portal vein blood samples from patients with PBCs, but less than 25% of peripheral blood samples. Portal vein CTCs can be used for molecular characterization of PBCs and share features of metastatic tissue. This technique might be used to study the pathogenesis and progression of PBCs, as well as a diagnostic or prognostic tool to stratify risk of cancer recurrence or developing metastases., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer represents the third most common and the second deadliest type of cancer for both men and women in the United States claiming over 50000 lives in 2014. The 5-year survival rate for patients diagnosed with metastatic colon and rectal cancer is < 15%. Early detection and more effective treatments are urgently needed to reduce morbidity and mortality of patients afflicted with this disease. Here we will review the risk factors and current treatment paradigms for colorectal cancer, with an emphasis on the role of chemoprevention as they relate to epidermal growth factor receptor (EGFR) blockade. We will discuss how various EGFR ligands are upregulated in the presence of Western diets high in saturated and N-6 polyunsaturated fats. We will also outline the various mechanisms of EGFR inhibition that are induced by naturally occurring chemopreventative agents such as ginseng, green tea, and curcumin. Finally, we will discuss the current role of targeted chemotherapy in colon cancer and outline the limitations of our current treatment options, describing mechanisms of resistance and escape.

Opinion Statement: The most important tools are the eye and the brain. A detailed white-light high-resolution examination and ability to recognize subtle lesions provide the foundation of the ability to detect lesions in the gastrointestinal tract. Novel technologies are now available to provide additional information with the goals of detection, delineation, or classification often with a focus on neoplasia in the gastrointestinal tract. The observer using these new tools must still recognize, interpret, and then make a clinically relevant conclusion. Therefore, the assessment of these tools may focus on both the technical feasibility to use the respective equipment to obtain an image and then also the associated cognitive-based criteria for image interpretation.

Background: Probe-based confocal laser endomicroscopy (pCLE) provides microscopic imaging during an endoscopic procedure. Its introduction as a standard modality in gastroenterology has brought significant progress in management strategies, affecting many aspects of clinical care and requiring standardisation of practice and training., Objective: This study aimed to provide guidance on the standardisation of its practice and training in Barrett's oesophagus, biliary strictures, colorectal lesions and inflammatory bowel diseases., Methods: Initial statements were developed by five group leaders, based on the available clinical evidence. These statements were then voted and edited by the 26 participants, using a modified Delphi approach. After two rounds of votes, statements were validated if the threshold of agreement was higher than 75%., Results: Twenty-six experts participated and, among a total of 77 statements, 61 were adopted (79%) and 16 were rejected (21%). The adoption of each statement was justified by the grade of evidence., Conclusion: pCLE should be used to enhance the diagnostic arsenal in the evaluation of these indications, by providing microscopic information which improves the diagnostic performance of the physician. In order actually to implement this technology in the clinical routine, and to ensure good practice, standardised initial and continuing institutional training programmes should be established.

Background: Compared with the piecemeal resection associated with endoscopic mucosal resection, endoscopic submucosal dissection (ESD) enables en bloc resection of larger lesions, allows for more accurate histological assessments, and has reduced recurrence rates. ESD is not widely performed in Western countries given increased technical difficulty, high complication rates, and long procedure times., Aims: To evaluate the safety and efficacy of ESD in a single center in the USA., Methods: A retrospective study on a prospectively collected database identified cases in which a single operator (IW) performed ESD at a tertiary referral center. Twenty cases were identified, nine in the upper digestive tract (four esophagus and five stomach) and 11 in the lower digestive tract (nine rectal and two sigmoid colon). Data regarding lesion location, pathology, method of ESD (composition/volume of lifting injection and resection method), post-procedure complications, and margin involvement were collected., Results: En bloc resection was obtained in 14/20 patients (70 %). The average procedure time was 202 min in the esophagus, 148 min in the stomach, and 106 min for lower lesions. A major complication (perforation) occurred in 1/20 cases (5 %). Complete resection was obtained in 14/20 (70 %). R0 resection was obtained in 16/20 (80 %) cases., Conclusions: The complication, en bloc resection, and complete resection rates of this study are similar to those found in large studies on ESD performed in Eastern settings. ESD is safe and efficacious for en bloc resections of pre-malignant and early-invasive lesions, and should be offered to patients with suitable lesions in Western settings.

Background & Aims: Barrett's esophagus (BE) with high-grade dysplasia (HGD) or intramucosal carcinoma (IMC) is treated by complete eradication of areas of BE by endoscopic mucosal resection (EMR). By using this approach, histologic analysis also can be performed. We investigated the effectiveness, safety, and durability of this approach, as well as its use in diagnosis after a single referral., Methods: We collected data from 107 patients who were referred to the Center for Endoscopic Research and Therapeutics at the University of Chicago for BE (mean length, 3.6 cm) with suspected HGD or IMC, from August 2003 through December 2012. All patients underwent EMR and were followed up through January 2014 (mean follow-up time, 40.6 mo). The primary outcome was treatment efficacy (complete eradication of BE and associated neoplasia); secondary outcomes included safety, durability, and accuracy of diagnosis., Results: BE was eradicated completely by EMR in 80.4% (86 of 107) of patients based on intention-to-treat analysis, and in 98.8% (79 of 80) of patients based on per-protocol analysis. The diagnosis was changed for 25% of patients after EMR, including 4 cases that initially were diagnosed as HGD by biopsy analysis and subsequently were found to have evidence of submucosal invasion when EMR specimens were assessed. Strictures and symptomatic dysphagia developed in 41.1% and 37.3% of patients, respectively, with an average of 2.3 dilations required. Perforations occurred in 2 patients after EMR and in 1 patient after dilation. HGD and IMC recurred in 1 patient each; both were treated successfully with EMR. Based on pathology analysis of the most recently collected specimens, 71.6% of patients (53 of 74) were in complete remission from intestinal metaplasia and 100% were in complete remission from HGD (74 of 74) or cancer (74 of 74)., Conclusions: For patients with BE with HGD or neoplasia, complete EMR is an effective and durable treatment and is a relatively safe technique. Specimens collected by EMR also can be analyzed histologically to aid in diagnosis. The common complication of EMR is esophageal stricture, which can be addressed with endoscopic dilation., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: We previously showed that EGF receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. Vitamin D inhibits the renin-angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR-VDR cross-talk in colorectal carcinogenesis., Experimental Design: To examine VDR-RAS interactions, we treated Vdr(+/+) and Vdr(-/-) mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Western blotting, immunostaining, and real-time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr(+/+) mice. EGFR regulation of VDR was examined in hypomorphic Egfr(Waved2) (Wa2) and Egfr(wild-type) mice. Angiotensin II (Ang II)-induced EGFR activation was studied in cell culture., Results: Vdr deletion significantly increased tumorigenesis, activated EGFR and β-catenin signaling, and increased colonic RAS components, including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared with tumors from Egfr(Waved2) mice, tumors from Egfr(wild-type) mice showed upregulated Snail1, a suppressor of VDR, and downregulated VDR., Conclusions: VDR suppresses the colonic RAS cascade, limits EGFR signals, and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and downregulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer., (©2014 American Association for Cancer Research.)

Esophageal and gastric cancers have high mortality rates secondary to the late presentation of most patients at advanced stages. Improved survival is achievable when the disease is confined to the more superficial mucosal layers and treated. This review will focus on the detection, screening, staging, endoscopic treatment, and surveillance of early upper gastrointestinal cancer - squamous cell carcinoma of the esophagus, esophageal adenocarcinoma, and gastric adenocarcinoma.

Background and Study Aims: Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) of pancreatic cystic lesions (PCL) is flawed by inadequate diagnostic yield. Needle-based confocal laser endomicroscopy (nCLE) utilizes a sub-millimeter probe that is compatible with an EUS needle and enables real-time imaging with microscopic detail of PCL. The aims of the In vivo nCLE Study in the Pancreas with Endosonography of Cystic Tumors (INSPECT) pilot study were to assess both the diagnostic potential of nCLE in differentiating cyst types and the safety of the technique., Patients and Methods: Eight referral centers performed nCLE in patients with PCL. Stage 1 defined descriptive terms for structures visualized by an off-line, unblinded consensus review. Cases were reviewed with a gastrointestinal pathologist to identify correlations between histology and nCLE. Stage 2 assessed whether the specific criteria defined in Stage 1 could identify pancreatic cystic neoplasms (PCN) including intraductal papillary mucinous neoplasms, mucinous cystic adenoma, or adenocarcinoma in an off-line blinded consensus review., Results: A total of 66 patients underwent nCLE imaging and images were available for 65, 8 of which were subsequently excluded due to insufficient information for consensus reference diagnosis. The presence of epithelial villous structures based on nCLE was associated with PCN (P=0.004) and provided a sensitivity of 59%, specificity of 100%, positive predictive value of 100 %, and negative predictive value of 50%. The overall complication rate was 9% and included pancreatitis (1 mild case, 1 moderate case), transient abdominal pain (n=1), and intracystic bleeding not requiring any further measures (n=3)., Conclusions: These preliminary data suggested that nCLE has a high specificity in the detection of PCN, but may be limited by a low sensitivity. The safety of nCLE requires further evaluation., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Study Aims: Esophageal adenocarcinoma (EAC) has a dismal prognosis unless treated early or prevented at the precursor stage of Barrett's esophagus-associated dysplasia. However, some patients with cancer or dysplastic Barrett's esophagus (DBE) may not be captured by current screening and surveillance programs. Additional screening techniques are needed to determine who would benefit from endoscopic screening or surveillance. Partial wave spectroscopy (PWS) microscopy (also known as nanocytology) measures the disorder strength (Ld ), a statistic that characterizes the spatial distribution of the intracellular mass at the nanoscale level and thus provides insights into the cell nanoscale architecture beyond that which is revealed by conventional microscopy. The aim of the present study was to compare the disorder strength measured by PWS in normal squamous epithelium in the proximal esophagus to determine whether nanoscale architectural differences are detectable in the field area of EAC and Barrett's esophagus., Methods: During endoscopy, proximal esophageal squamous cells were obtained by brushings and were fixed in alcohol and stained with standard hematoxylin and Cyto-Stain. The disorder strength of these sampled squamous cells was determined by PWS., Results: A total of 75 patient samples were analyzed, 15 of which were pathologically confirmed as EAC, 13 were DBE, and 15 were non-dysplastic Barrett's esophagus; 32 of the patients, most of whom had reflux symptoms, acted as controls. The mean disorder strength per patient in cytologically normal squamous cells in the proximal esophagus of patients with EAC was 1.79-times higher than that of controls (P<0.01). Patients with DBE also had a disorder strength 1.63-times higher than controls (P<0.01)., Conclusion: Intracellular nanoarchitectural changes were found in the proximal squamous epithelium in patients harboring distal EAC and DBE using PWS. Advances in this technology and the biological phenomenon of the field effect of carcinogenesis revealed in this study may lead to a useful tool in non-invasive screening practices in DBE and EAC., (© Georg Thieme Verlag KG Stuttgart · New York.)

Angiogenesis has an important role in the carcinogenesis of esophageal adenocarcinoma, however, the diagnostic and prognostic utility of microvascular density counts have not been clinically established. The aim of this study is to assess the correlation between microvascular density and disease progression of non-dysplastic Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and invasive carcinoma in the superficial aspects of the tissue. Archival histological specimens from two referral centers for Barrett's esophagus and esophageal cancer were selected for review. A total of 160 regions marked according to histological grade were assessed with digitally interactive software to measure microvascular density. This was quantified in three levels: 0-50, 50-100 and 100-150 μm. In the areas of gastric cardia, Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and cancer, microvascular density was significantly different (P<0.0001) among the five groups in the most superficial 150 μm of the mucosa. Furthermore, when examining the pairwise difference between the groups, there was a significant difference between cancer and each of the lower grades of histology (P<0.05) and between high-grade dysplasia and each of the lower grades of histology (P<0.05). These statistically significant differences were preserved in examining the depth at the most superficial 50 μm. We have used digital pathology to demonstrate a significant and stepwise increase in microvascular density, which supports the hypothesis that angiogenesis has a key role in Barrett's carcinogenesis. Furthermore, the differences in the most superficial mucosal layers are consistent with findings of increased vascularity by depth-restricted imaging modalities.

Endoscopic ultrasound (EUS) is considered the most accurate tool for the TNM staging of esophageal cancer, but its role in early Barrett's neoplasia is still debatable. The aim was to evaluate the utility of EUS in Barrett's patients prior to therapy. Retrospective review of 109 patients enrolled in a treatment protocol for Barrett's neoplasia in our institution. EUS assessment was classified as suspicious for invasion in 19 patients; 84% of them had no evidence of invasion in final pathology. The assessment of depth of invasion of Barrett's neoplasia based solely on EUS findings leads to overstaging in most patients.

Endotherapy is now the mainstay of therapy for Barrett's associated neoplasia. The approach should begin with confirmation of neoplasia by a gastrointestinal pathologist, patient counseling, and appropriate endoscopic work up. Detailed examination with high-resolution white light endoscopy is the most important tool for detection of neoplasia. Further validation studies are needed for many enhanced imaging modalities before being recommended as part of the standard work up and assessment of patients with Barrett's esophagus (BE). Endoscopic mucosal resection is required for any visible lesion in the setting of dysplasia for accurate histological diagnosis. The remainder of the epithelium may be treated with resection or ablative therapy, followed by adequate surveillance. Patients with nondysplastic Barrett's require further risk stratification before incorporation of ablative therapy for this population. The future will fortify the endoscopic role in Barrett's with validation trials for endoscopic assessment, further long-term results for each of the treatment modalities, potential risk stratification for patients with BE, and improved guidelines for surveillance after therapy.

Background: Western diets increase colon cancer risk. Epidemiological evidence and experimental studies suggest that ginseng can inhibit colon cancer development. In this study we asked if ginseng could inhibit Western diet (20% fat) promoted colonic tumorigenesis and if compound K, a microbial metabolite of ginseng could suppress colon cancer xenograft growth., Methods: Mice were initiated with azoxymethane (AOM) and, two weeks later fed a Western diet (WD, 20% fat) alone, or WD supplemented with 250-ppm ginseng. After 1 wk, mice received 2.5% dextran sulfate sodium (DSS) for 5 days and were sacrificed 12 wks after AOM. Tumors were harvested and cell proliferation measured by Ki67 staining and apoptosis by TUNEL assay. Levels of EGF-related signaling molecules and apoptosis regulators were determined by Western blotting. Anti-tumor effects of intraperitoneal compound K were examined using a tumor xenograft model and compound K absorption measured following oral ginseng gavage by UPLC-mass spectrometry. Effects of dietary ginseng on microbial diversity were measured by analysis of bacterial 16S rRNA., Results: Ginseng significantly inhibited colonic inflammation and tumorigenesis and concomitantly reduced proliferation and increased apoptosis. The EGFR cascade was up-regulated in colonic tumors and ginseng significantly reduced EGFR and ErbB2 activation and Cox-2 expression. Dietary ginseng altered colonic microbial diversity, and bacterial suppression with metronidazole reduced serum compound K following ginseng gavage. Furthermore, compound K significantly inhibited tumor xenograft growth., Conclusions: Ginseng inhibited colonic inflammation and tumorigenesis promoted by Western diet. We speculate that the ginseng metabolite compound K contributes to the chemopreventive effects of this agent in colonic tumorigenesis.

Background: Challenges in EUS-guided FNA (EUS-FNA) include sampling error, nondiagnostic cytology, and limited on-site cytological evaluation. A prototype needle-based confocal laser endomicroscopy (nCLE) probe is a submillimeter probe that provides real-time imaging at the microscopic level through the FNA needle., Objective: To evaluate the feasibility of nCLE during EUS-FNA of pancreatic lesions., Design: Feasibility study., Setting: Multicenter, tertiary care., Patients: Eighteen patients presenting for EUS-FNA., Interventions: Patients were injected with 2.5 mL of 10% fluorescein. The lesion was interrogated with the nCLE probe positioned at the tip of a 19-gauge FNA needle., Main Outcome Measurements: Device integrity, technical ease, safety, and image acquisition., Results: Cases included 16 cysts and 2 masses. There were no device malfunctions. Technical challenges were encountered in 6 of 18 attempts to image and reflected challenges with a postloading technique, the longer ferule tip, and a transduodenal approach. Technical feasibility to perform imaging with nCLE during a pancreatic EUS-FNA procedure was achieved in 17 of 18 cases. Ten cases had good to very good image quality. Two serious adverse events occurred; both were pancreatitis requiring hospitalization., Limitations: Limited sample size, small number of patients with confirmed pathological diagnosis, lack of coregistered pathology and images., Conclusions: nCLE in the pancreas is technically feasible via a 19-gauge needle under endosonographic guidance. Future studies will address identification of structures, diagnostic accuracy, and complication profiles. The rate of pancreatitis needs to be further clarified and mitigated., (Copyright © 2011 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Recent developments in endoscopic therapeutic options for Barrett's esophagus (BE) early neoplasia have resulted in a dramatic paradigm shift in its clinical management. With multiple endoscopic choices available, it is important to discern subtle differences between these approaches based on the available current data and known limitations of each modality. The goals of endoscopic therapy of Barrett's neoplasia are to preserve the esophagus while ablating or removing the entire BE segment. This article reviews the currently available BE endoscopic treatments with emphasis on appropriate selection of patients, indications and timing of use, and clinical management considerations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

High-grade dysplasia (HGD) and intramucosal carcinoma (IMC) in the setting of Barrett's esophagus have traditionally been treated with esophagectomy. However, with the advent of endoscopic mucosal resection and endoscopic ablative therapies, endoscopic therapy at centers with expertise is now an established treatment of Barrett's-esophagus-related neoplasia, including HGD and IMC. Esophagectomy is today reserved for more selected cases with submucosal invasion, evidence for lymph node metastasis, or unsuccessful endoscopic therapy.

Confocal laser endomicroscopy (CLE) can serve as a useful adjunct imaging modality for targeted endoscopic biopsies during surveillance of Barrett's esophagus (BE). In addition, CLE may also have potential roles during therapeutic procedures that include localization of pathology, targeting of resections, guiding which therapy to use, and determining adequacy of treatment. This case series illustrates a range of cases in which endomicroscopy was performed during the procedure and offers possibilities of real-time decision-making to select specific therapies in patients with known high-grade dysplasia (HGD) and intramucosal carcinoma in the setting of BE presented for endoscopic treatment or follow-up. Patients with BE with HGD and intramucosal carcinoma presented for management for initial treatment or follow-up. Examinations were performed sequentially with detailed white light endoscopy, narrow band imaging (NBI), acetic acid, and CLE. This is a retrospective case series describing the characteristics of the exam findings and illustrating the role of endomicroscopy on real-time case management. Seven patients with Barrett-associated neoplasia underwent endomicroscopy as part of their endoscopic examination. CLE confirmed findings of neoplasia seen with red flag techniques such as NBI, and in one case independently suggested findings of neoplasia. In the majority of cases, these findings were incorporated into the decision of which modality of treatment was used. Future prospective studies should be done to validate the role of endomicroscopy in BE.

Purpose of Review: The key to prevention and cure of esophageal adenocarcinoma is the detection and eradication of neoplasia in patients with Barrett's esophagus. Multiple tools and technologies are emerging for this purpose., Recent Findings: A detailed white light examination with high-resolution endoscopy and recognition of lesions is paramount. A variety of imaging modalities are being studied for the detection of neoplasia in Barrett's esophagus. Chromoendoscopy, narrow band imaging, and autofluorescence provide a way to target suspicious areas. Confocal endomicroscopy and optical coherence tomography are means to pinpoint imaging to obtain information about the tissue microarchitecture., Summary: The key to detection of neoplasia is a careful white light examination with high-resolution endoscopy and recognition of lesion characteristics. Additional imaging modalities may enhance targeting of lesions or provide more information at a focused level. Many of these modalities have yet to be validated in prospective randomized, multicenter trials.

Objectives: Complete Barrett's eradication endoscopic mucosal resection (CBE-EMR) is the endoscopic removal of all Barrett's epithelium with the curative intent of eliminating high-grade dysplasia (HGD)/intramucosal carcinoma (IMC) and reducing the risk of metachronous lesion development. We report our single tertiary referral center's long-term clinical experience using this modality in HGD/IMC management., Methods: In this study, we retrospectively reviewed all patients who had CBE-EMR for Barrett's esophagus (BE) with HGD/IMC who had been entered into our center's prospectively collected database. High-definition white-light and narrow-band imaging examinations were used according to the protocol. Staging endoscopic ultrasound was done before CBE-EMR to exclude invasive disease or suspicious lymphadenopathy. High-dose proton pump inhibition was instituted after initial treatment, and Seattle-type surveillance biopsies were performed on follow-up every 6 months once the CBE-EMR procedure was completed., Results: A total of 49 patients (mean age 67 years, median 65, s.d. 11; 75% men) with histologically confirmed BE and HGD (33), IMC (16), underwent CBE-EMR from August 2003 to August 2008. The mean BE segment length was 3.2 cm (median 2, s.d. 2.2); 26 patients had short-segment BE, and 30 had visible lesions. A total of 106 EMR procedures were performed. On initial EMR, two patients had superficial submucosal carcinoma invasion (sm1) and two had IMC with lymphatic channel invasion. All four patients were referred for esophagectomy, but one opted for continued endoscopic management, without evidence of residual or recurrent carcinoma. A total of 14 patients await completion of EMR (9) or first follow-up endoscopy (5). CBE-EMR therapy was completed in 32 patients by an average of 2.1 sessions (median 2, s.d. 0.9). Surveillance biopsies showed normal squamous epithelium in 31 of 32 (96.9%) patients (mean remission time 22.9 months, median 17, s.d. 16.7, interquartile range 11-38). In all, 10 of 46 patients who continued in the endoscopic protocol had subsquamous Barrett's epithelium on EMR specimens and/or treatment endoscopy biopsies. Overall, 1 of these 10 patients had Barrett's underneath squamous mucosa on most recent surveillance biopsies. CBE-EMR upstaged pre-EMR pathology results in 7 of 49 (14%) of patients and downstaged pathology in 15 of 49 (31%) patients. In all, 18 of 49 (37%) patients developed symptomatic esophageal stenosis after a mean of 24.4 days (median 13.5, s.d. 27.8); all were successfully managed by endoscopic treatment. No perforations or uncontrollable bleeding occurred., Conclusions: To our knowledge, this is the largest American single-center experience demonstrating that CBE-EMR with close endoscopic surveillance is an effective treatment modality for BE with HGD/IMC. Although the rate of stenosis development is significant, it is easily treated by endoscopic dilation. Patients considering endoscopic ablation should be counseled appropriately. The role of CBE-EMR in patients with lymphatic invasion or superficial submucosal invasion remains to be defined.

Background: Prior studies report the presence of buried Barrett's epithelium under squamous mucosa after endoscopic ablative therapies for Barrett's esophagus (BE) with high-grade dysplasia (HGD) or intramucosal carcinoma (IMC). However, there still exists significant controversy about whether these glands represent a neoablative phenomenon or predate endoscopic therapy., Objective: To determine the prevalence of buried BE underneath squamous epithelium on initial mucosectomy specimens for complete Barrett's eradication EMR (CBE-EMR) for BE with HGD or IMC., Design: Retrospective double-blinded review., Setting: A tertiary-care academic referral center., Patients and Methods: Histopathology slides of all initial mucosectomy specimens for all patients who underwent CBE-EMR for BE with HGD or IMC at our center between August 2003 and February 2008 were reviewed retrospectively in a double-blinded fashion by 2 expert GI pathologists. None of the patients had undergone prior endoscopic ablative therapy for dysplastic BE., Main Outcome Measurements: The prevalence of buried BE underneath squamous epithelium in initial mucosectomy specimens from CBE-EMR for BE with HGD or IMC., Results: A total of 47 patients' initial mucosectomy slides were reviewed. The presence of Barrett's epithelium underneath the squamous resection margin (Z line) was identified in 13 of 47 patients (28%) at initial mucosectomy. The linear distance of the Barrett's epithelium from the resection's squamous margin ranged from 0.8 to 5.6 mm (mean 2.3 mm and median 1.9 mm). Histopathology revealed nondysplastic buried BE in 3 patients, HGD in 9 patients, and IMC in 1 patient. Thus, 10 of 13 patients (21% of 47 total) had buried glands with advanced pathology (HGD or IMC), whereas 3 of 13 (6% of 47 total) had specialized intestinal metaplasia without dysplasia., Limitations: A single-center, modest study population size., Conclusions: Our results revealed a significant prevalence of buried Barrett's epithelium with or without dysplasia under squamous mucosa (squamocolumnar junction) on initial mucosectomy specimens. Given the neoplastic potential of BE, the presence of these subsquamous BE glands may affect the extent and adequacy of mucosal resection margins. Based on these findings, surveillance biopsies and ablative therapy should extend to 1 cm proximal to the endoscopically determined squamocolumnar junction.

The management of Barrett esophagus is evolving with the emergence of new endoscopic technologies. Traditionally, patients with high-grade dysplasia or cancer were referred for esophagectomy. However, with the advent of endoscopic ablative therapies for Barrett esophagus, the treatment paradigm has shifted. Patients with high-grade dysplasia and intramucosal carcinoma are increasingly offered esophagus-sparing therapies. Endoscopic ablative therapies can be categorized into tissue-acquiring and non-tissue-acquiring modalities. Visible lesions in the setting of dysplasia should be treated with a tissue-acquiring modality to stage and resect the lesion appropriately. One or more modalities may be used to eradicate the entire region of affected esophagus totally. Total eradication treats all of the at-risk epithelium and, therefore, treats any metachronous or synchronous lesions. Success of treatment may be gauged by complete remission of cancer, dysplasia, or Barrett esophagus. In addition to procedure-related complications, the risk of residual Barrett esophagus or subsquamous Barrett esophagus remains to be addressed. Endoscopic surveillance and acid suppression is still currently required after ablation.

Background & Aims: Recent studies have claimed long neoplasia-free survival rates with endoscopic mucosal resection of high-grade dysplasia (HGD) in Barrett's esophagus (BE). However, reports have contended that approximately 40% of patients who have esophagectomy for HGD have occult invasive cancer. The aim of this study was to use explicit criteria to determine the true prevalence of invasive adenocarcinoma in reports of patients who had esophagectomy for HGD in BE., Methods: Studies reporting rates of esophageal cancer in patients who underwent esophagectomy for HGD in BE were gathered using MEDLINE and PUBMED. We defined invasive esophageal adenocarcinoma (IEAC) as tumor with submucosal invasion or beyond. Intramucosal carcinoma (IMC) was not considered IEAC., Results: Twenty-three articles were selected for analysis. Most investigators reported rates of invasive cancer in the esophagectomy specimen, and the pooled average was 39.9% among the 441 patients who underwent an esophagectomy for HGD. Reported rates varied from 0% to 73%. A total of 267 patients had American Joint Committee on Cancer stage 0 postoperatively, 132 patients had stage I, 23 patients had stage IIa, 10 patients had stage IIb, and 9 patients had stage III. Fourteen studies provided differentiation between intramucosal and submucosal invasion. Among 213 patients, only 12.7% had IEAC, whereas 87.3% had HGD or IMC. The IEAC rate of 11% among patients with visible lesions is greater than the rate of 3% among patients with no visible lesion., Conclusions: By using strict pathologic definitions of invasive disease, the present study indicates the true prevalence of IEAC in BE and HGD may have been overestimated significantly. Separating IMC from IEAC is clinically relevant because endoscopic techniques potentially may treat IMC.