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Falk, G. W. (2014). "Update on ablation for Barrett's esophagus." Curr Gastroenterol Rep 16(1): 368.
PUBLICATIONS
Abrams, J. A., H. D. Appelman, D. G. Beer, et al. (2014). "Barrett's Esophagus Translational Research Network (BETRNet): the pivotal role of multi-institutional collaboration in esophageal adenocarcinoma research." Gastroenterology 146(7): 1586-1590.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224108/
Asfaha, S., Y. Hayakawa, A. Muley, et al. (2015). "Krt19(+)/Lgr5(-) Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine." Cell Stem Cell 16(6): 627-638.
Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5(+) cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5(-) stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5(+) CBCs in the colon and intestine. In colorectal cancer models, Krt19(+) cancer-initiating cells are also radioresistant, while Lgr5(+) stem cells are radiosensitive. Moreover, Lgr5(+) stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5(+) stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19(+) stem cells are a discrete target relevant for cancer therapy.
Chandra, S., E. C. Gorospe, C. L. Leggett, et al. (2013). "Barrett's esophagus in 2012: updates in pathogenesis, treatment, and surveillance." Curr Gastroenterol Rep 15(5): 322.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815689/
Barrett's esophagus (BE) is the only established precursor lesion in the development of esophageal adenocarcinoma (EAC) and it increases the risk of cancer by 11-fold. It is regarded as a complication of gastroesophageal reflux disease. There is an ever-increasing body of knowledge on the pathogenesis, diagnosis, treatment, and surveillance of BE and its associated dysplasia. In this review, we summarize the latest advances in BE research and clinical practice in the past 2 years. It is critical to understand the molecular underpinnings of this disorder to comprehend the clinical outcomes of the disease. For clinical gastroenterologists, there is also continuous growth of endoscopic approaches which is daunting, and further improvements in the detection and treatment of BE and early EAC are anticipated. In the future, we may see the increased role of biomarkers, both molecular and imaging, in both diagnostic and therapeutic strategies for BE.
Del Portillo, A., S. M. Lagana, Y. Yao, et al. (2015). "Evaluation of Mutational Testing of Preneoplastic Barrett's Mucosa by Next-Generation Sequencing of Formalin-Fixed, Paraffin-Embedded Endoscopic Samples for Detection of Concurrent Dysplasia and Adenocarcinoma in Barrett's Esophagus." J Mol Diagn 17(4): 412-419.
http://www.sciencedirect.com/science/article/pii/S1525157815000811
Barrett's intestinal metaplasia (BIM) may harbor genomic mutations before the histologic appearance of dysplasia and cancer and requires frequent surveillance. We explored next-generation sequencing to detect mutations with the analytical sensitivity required to predict concurrent high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus by testing nonneoplastic BIM. Formalin-fixed, paraffin-embedded (FFPE) routine biopsy or endoscopic mucosal resection samples from 32 patients were tested: nonprogressors to HGD or EAC (BIM-NP) with BIM, who never had a diagnosis of dysplasia or EAC (N = 13); progressors to HGD or EAC (BIM-P) with BIM and a worse diagnosis of HGD or EAC (N = 15); and four BIM-negative samples. No mutations were detected in the BIM-NP (0 of 13) or BIM-negative samples, whereas the BIM-P samples had mutations in 6 (75%) of 8 cases in TP53, APC, and CDKN2A (P = 0.0005), detected in samples with as low as 20% BIM. We found that next-generation sequencing from routine FFPE nonneoplastic Barrett's esophagus samples can detect multiple mutations in minute areas of BIM with high analytical sensitivity. Next-generation sequencing panels for detection of TP53 and possibly combined mutations in other genes, such as APC and CDKN2A, may be useful in the clinical setting to improve dysplasia and cancer surveillance in patients with Barrett's esophagus.
Enestvedt, B. K., R. Lugo, C. Guarner-Argente, et al. (2013). "Location, location, location: does early cancer in Barrett's esophagus have a preference?" Gastrointest Endosc 78(3): 462-467.
http://www.sciencedirect.com/science/article/pii/S0016510713003829
BACKGROUND: Early cancer (high-grade dysplasia [HGD] and intramucosal carcinoma [ImCa]) associated with Barrett's esophagus (BE) may have a circumferential spatial predilection. OBJECTIVE: To describe the esophageal circumferential location of early cancer in BE. DESIGN AND SETTING: Retrospective study, single tertiary referral center. PATIENTS AND INTERVENTION: One hundred nineteen patients were referred for endoscopic eradication therapy for early cancer associated with BE. Endoscopic images and reports and pathology were reviewed. MAIN OUTCOME MEASUREMENTS: Circumferential location designation of early cancer in BE by using a clock-face orientation. RESULTS: One hundred nineteen of 131 patients referred for endoscopic eradication therapy had a location designation for their advanced histology (91.9%). There were a total of 57 patients (47.9%) with HGD and 62 patients (52.1%) with ImCa. There was a significantly higher rate of early cancer (HGD or ImCa) in the right hemisphere (12 to 6 o'clock location) compared with the left hemisphere (84.9% vs 15.1%, P < .0001). The highest percentage of early cancer was found in the 12 to 3 o'clock quadrant (64.7%); 71.9% of HGD and 58.1% of ImCa lesions were located in the 12 to 3 o'clock quadrant. LIMITATIONS: Retrospective design, single center. CONCLUSIONS: Early cancer associated with BE is far more commonly found in the right hemisphere of the esophagus (12 to 6 o'clock) with the highest rate in the 12 to 3 o'clock quadrant. These findings support enhanced scrutiny of the right hemisphere of the esophagus during surveillance and endoscopic treatment of patients with BE.
Ericksen, R. E., S. Rose, C. B. Westphalen, et al. (2014). "Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response." Gut 63(3): 385-394.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972255/
OBJECTIVE: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. DESIGN: C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. RESULTS: H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. CONCLUSIONS: Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.
Falk, G. W. (2014). "Update on ablation for Barrett's esophagus." Curr Gastroenterol Rep 16(1): 368.
http://link.springer.com/article/10.1007%2Fs11894-013-0368-7
Endoscopic ablation has dramatically changed the treatment algorithm for patients with Barrett's esophagus. Studies clearly show the benefits of this approach for patients with high-grade dysplasia and intramucosal carcinoma. Recent studies also provide evidence in support of this approach for patients with low-grade dysplasia but not for patients with nondysplastic Barrett's epithelium. Endoscopic ablation is safe and efficacious in most but not all patients and disease progression may occur during initial therapy as well as after successful completion in a small difficult to identify subset of patients. Furthermore, the past year has provided us with a better understanding of the durability of endoscopic ablation with highly variable rates of disease recurrence. Studies are underway to help determine predictors of response and recurrence.
Falk, G. W. (2015). "Barrett's oesophagus: frequency and prediction of dysplasia and cancer." Best Pract Res Clin Gastroenterol 29(1): 125-138.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352690/
The incidence of oesophageal adenocarcinoma is continuing to increase at an alarming rate in the Western world today. Barrett's oesophagus is a clearly recognized risk factor for the development of oesophageal adenocarcinoma, but the overwhelming majority of patients with Barrett's oesophagus will never develop oesophageal cancer. A number of endoscopic, histologic and epidemiologic risk factors identify Barrett's oesophagus patients at increased risk for progression to high-grade dysplasia and oesophageal adenocarcinoma. Endoscopic factors include segment length, mucosal abnormalities as seemingly trivial as oesophagitis and the 12 to 6 o'clock hemisphere of the oesophagus. Both intestinal metaplasia and low grade dysplasia, the latter only if confirmed by a pathologist with expertise in Barrett's oesophagus pathologic interpretation are the histologic risk factors for progression. Epidemiologic risk factors include ageing, male gender, obesity, and smoking. Factors that may protect against the development of adenocarcinoma include a diet rich in fruits and vegetables, and the use of proton pump inhibitors, aspirin/NSAIDs and statins.
Falk, G. W. (2015). "Endoscopic submucosal dissection for Barrett-associated neoplasia: is it ready for the endoscopist's toolbox?" Endoscopy 47(2): 97-98.
https://www.thieme-connect.com/DOI/DOI?10.1055/s-0034-1391373
Falk, G. W., N. S. Buttar, N. R. Foster, et al. (2012). "A combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E(2) in patients with Barrett's esophagus." Gastroenterology 143(4): 917-926 e911.
BACKGROUND& AIMS: Proton pump inhibitors and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barrett's esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled, phase 2 trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin (PG) E(2) in patients with BE with no dysplasia or low-grade dysplasia. METHODS: Participants were recruited through the multicenter Cancer Prevention Network and randomly assigned to groups that were given 40 mg esomeprazole twice daily in combination with an aspirin placebo once daily (arm A; n = 30), with 81 mg aspirin once daily (arm B; n = 47), or with 325 mg aspirin once daily (arm C; n = 45) for 28 days. We collected esophageal biopsy specimens before and after the intervention period to determine the absolute change in mean concentration of PGE(2) (the primary end point). RESULTS: Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentration of PGE(2) was reduced by 67.6 +/- 229.68 pg/mL in arm A, 123.9 +/- 284.0 pg/mL in arm B (P = .10 vs arm A), and 174.9 +/- 263.62 pg/mL in arm C (P = .02 vs arm A). CONCLUSIONS: In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE(2) in patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients. Clinical trial registration number NCT00474903.
Fudman, D. I., C. J. Lightdale, J. M. Poneros, et al. (2014). "Positive correlation between endoscopist radiofrequency ablation volume and response rates in Barrett's esophagus." Gastrointest Endosc 80(1): 71-77.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317349/
BACKGROUND: Radiofrequency ablation (RFA) has become an accepted form of endoscopic treatment for Barrett's esophagus (BE), yet reported response rates are variable. There are no accepted quality measures for performing RFA, and provider-level characteristics may influence RFA outcomes. OBJECTIVE: To determine whether endoscopist RFA volume is associated with rates of complete remission of intestinal metaplasia (CRIM) after RFA in patients with BE. DESIGN: Retrospective analysis of longitudinal data. SETTING: Three tertiary-care medical centers. PATIENTS: Patients with BE treated with RFA. INTERVENTION RFA MAIN OUTCOME MEASUREMENTS: For each endoscopist, we recorded RFA volume, defined as the number of unique patients treated as well as corresponding CRIM rates. We calculated a Spearman correlation coefficient relating these 2 measures. RESULTS: We identified 417 patients with BE treated with RFA who had at least 1 post-RFA endoscopy with biopsies. A total of 73% of the cases had pretreatment histology of high-grade dysplasia or adenocarcinoma. The procedures were performed by 7 endoscopists, who had a median RFA volume of 62 patients (range 20-188). The overall CRIM rate was 75.3% (provider range 62%-88%). The correlation between endoscopist RFA volume and CRIM rate was strong and significant (rho = 0.85; P = .014). In multivariable analysis, higher RFA volume was significantly associated with CRIM (P for trend .04). LIMITATIONS: Referral setting may limit generalizability. Limited number of endoscopists analyzed. CONCLUSION: Endoscopist RFA volume correlates with rates of successful BE eradication. Further studies are required to confirm these findings and to determine whether RFA volume is a valid predictor of treatment outcomes in BE.
Gorospe, E. C., M. Gupta, G. A. Prasad, et al. (2012). "Double trouble: two cases of squamous carcinoma arising from Barrett's dysplasia after endoscopic mucosal resection." Am J Gastroenterol 107(10): 1595-1596.
http://www.nature.com/ajg/journal/v107/n10/full/ajg2012232a.html
Gorospe, E. C., C. L. Leggett, G. Sun, et al. (2012). "Diagnostic performance of two confocal endomicroscopy systems in detecting Barrett's dysplasia: a pilot study using a novel bioprobe in ex vivo tissue." Gastrointest Endosc 76(5): 933-938.
BACKGROUND: There are currently 2 existing confocal laser endomicroscopy (CLE) platforms: probe-based CLE (pCLE) and endoscope-based CLE (eCLE) systems, each with its own criteria for identifying dysplasia in Barrett's esophagus (BE). The diagnostic performance of these 2 systems has not been directly compared. DESIGN: Preclinical, feasibility study. OBJECTIVES: We compared the interrater agreement and diagnostic performance of the pCLE and eCLE systems. In addition, we evaluated a new BE endomicroscopy criteria based on fluorescent glucose intensity uptake. PATIENTS: Thirteen patients with Barrett's esophagus and high-grade dysplasia or early cancer undergoing 16 EMR. INTERVENTION: CLE imaging was performed using two different probes with 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose, a fluorescent glucose analog with preferential uptake in dysplastic mucosa to supply contrast. Four quadrants were imaged per specimen with a total of 64 imaged mucosal sites presented to three gastroenterologists. MAIN OUTCOME MEASUREMENTS: Interobserver agreement and accuracy for dysplasia was assessed of images classified according to Miami criteria, stacked eCLE images classified using the Mainz criteria and a novel fluorescence intensity criteria. RESULTS: The interrater agreements were 0.17, 0.68, and 0.87 for the Miami, Mainz, and the fluorescence intensity criteria, respectively. Overall accuracy in detecting dysplasia was 37% (95% CI, 30.3-43.9), 44.3% (95% CI, 37.3-50.9), and 78.6% (95% CI, 72.2-83.3) for the Miami, Mainz, and the fluorescence intensity criteria, respectively. LIMITATIONS: This imaging technique and proposed fluorescence intensity criteria using 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose in EMR tissue will require in vivo validation and cannot be directly used with the current eCLE and pCLE clinical applications. CONCLUSIONS: In this preclinical feasibility study, the use of an eCLE system with a topical fluorescent contrast in ex vivo EMR tissue demonstrated higher interrater agreement and accuracy.
Gorospe, E. C., G. Sun and K. K. Wang (2013). "Endpoints for radiofrequency ablation in Barrett's dysplasia." Am J Gastroenterol 108(2): 197-199.
http://www.nature.com/ajg/journal/v108/n2/full/ajg2012415a.html
The need to combat the rising incidence of esophageal adenocarcinoma with its dismal prognosis has led to increasing development of many endoscopic treatments for Barrett's esophagus (BE). Radiofrequency ablation (RFA) has been shown to be a safe and effective endoscopic treatment modality for dysplastic BE. The durability of successful eradication of dysplastic BE has been reported by earlier studies with limited sample size, follow-up time, and inadequate cohort of patients with high-grade dysplasia or intramucosal cancer. In this issue, Orman and colleagues present their findings from their single center, retrospective cohort of patients who underwent RFA with post-treatment surveillance. They report a low recurrence rate of 5.2% per year. There were no clinical characteristics found to be associated with BE recurrence in terms of length of segment or degree of dysplasia. Complete eradication of dysplasia (CE-D) or intestinal metaplasia was determined after a single post-RFA endoscopic examination with biopsies. This is an area of controversy as previous studies have used a minimum of two negative examinations before CE can be claimed. There are also limitations from sampling error during surveillance biopsies and the loss of a third of all post-RFA patients during surveillance. Multicenter, prospective studies with adequate follow-up are still needed before we can draw recommendations when to adequately cease post-treatment surveillance and to identify patients with increased risk of either recurrence or progression.
Greer, K. B., C. L. Thompson, L. Brenner, et al. (2012). "Association of insulin and insulin-like growth factors with Barrett's oesophagus." Gut 61(5): 665-672.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669672/
BACKGROUND: It is postulated that high serum levels of insulin and insulin growth factor 1 (IGF-1) mediate obesity-associated carcinogenesis. The relationship of insulin, IGF-1 and IGF binding proteins (IGFBP) with Barrett's oesophagus (BO) has not been well examined. METHODS: Serum levels of insulin and IGFBPs in patients with BO were compared with two separate control groups: subjects with gastro-oesophageal reflux disease (GORD) and screening colonoscopy controls. Fasting insulin, IGF-1 and IGFBPs were assayed in the serum of BO cases (n = 135), GORD (n = 135) and screening colonoscopy (n = 932) controls recruited prospectively at two academic hospitals. Logistic regression was used to estimate the risk of BO. RESULTS: Patients in the highest tertile of serum insulin levels had an increased risk of BO compared with colonoscopy controls (adjusted OR 2.02, 95% CI 1.15 to 3.54) but not compared with GORD controls (adjusted OR 1.55, 95% CI 0.76 to 3.15). Serum IGF-1 levels in the highest tertile were associated with an increased risk of BO (adjusted OR 4.05, 95% CI 2.01 to 8.17) compared with the screening colonoscopy control group but were not significantly different from the GORD control group (adjusted OR 0.57, 95% CI 0.27 to 1.17). IGFBP-1 levels in the highest tertile were inversely associated with a risk of BO in comparison with the screening colonoscopy controls (adjusted OR 0.11, 95% CI 0.05 to 0.24) but were not significantly different from the GORD control group (adjusted OR 1.04, 95% CI 0.49 to 2.16). IGFBP-3 levels in the highest tertile were inversely associated with the risk of BO compared with the GORD controls (OR 0.36, 95% CI 0.16 to 0.81) and also when compared with the colonoscopy controls (OR 0.40, 95% CI 0.20 to 0.79). CONCLUSIONS: These results provide support for the hypothesis that the insulin/IGF signalling pathways have a role in the development of BO.
Guarner-Argente, C., T. Buoncristiano, E. E. Furth, et al. (2013). "Long-term outcomes of patients with Barrett's esophagus and high-grade dysplasia or early cancer treated with endoluminal therapies with intention to complete eradication." Gastrointest Endosc 77(2): 190-199.
http://www.sciencedirect.com/science/article/pii/S0016510712028076
BACKGROUND: Endoluminal therapy is an option for selected patients with Barrett's esophagus and high-grade dysplasia or early cancer. OBJECTIVE: To assess long-term outcomes of patients treated with endoluminal therapy with the goal of complete eradication of all dysplasia and intestinal metaplasia. DESIGN: Retrospective cohort study. PATIENTS: Selected patients referred with dysplastic Barrett's esophagus. INTERVENTION: Endoluminal therapy combining resection and photodynamic therapy, radiofrequency ablation, and/or argon plasma coagulation treatment was individualized based on patient and lesion characteristics, technique evolution, and interval response. MAIN OUTCOME MEASUREMENTS: We assessed complete eradication of dysplasia, all intestinal metaplasia, and recurrences. RESULTS: A total of 166 patients were treated and had at least 1 year of follow-up. Complete elimination of neoplasia was achieved in 157 patients (95%) and complete elimination of intestinal metaplasia in 137 patients (83%). After therapy, patients were followed for 33 (range 18-58) months. Among patients who achieved complete elimination of intestinal metaplasia, subsequent recurrent intestinal metaplasia was detected in 48 (35%) and dysplasia in 12 (9%). Among those who achieved only complete elimination of dysplasia, recurrent dysplasia was detected in 6 of 19 patients (32%). Multifocal dysplasia and patient's age were dysplasia and/or carcinoma recurrence risk factors in the multivariable and univariable analyses. Complete elimination of intestinal metaplasia was a protective factor in the univariable analysis. Retreatment achieved remission in 90% of cases. Forty-two patients (23.9%) had complications, including 21 with stricture (11.9%) and 1 treatment-related death. LIMITATIONS: Retrospective study and evolution of endoscopic modalities. CONCLUSION: Multiple-mode endoluminal therapy for Barrett's esophagus with high-grade dysplasia or early cancer with intention to complete eradication of all intestinal metaplasia was successful, with low observed recurrence of dysplasia or cancer. However, recurrence of intestinal metaplasia occurs in one-third of cases and supports continued endoscopic surveillance even after complete eradication.
Gupta, M., P. G. Iyer, L. Lutzke, et al. (2013). "Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US Multicenter Consortium." Gastroenterology 145(1): 79-86 e71.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696438/
BACKGROUND & AIMS: Radiofrequency ablation (RFA) is an established treatment for dysplastic Barrett's esophagus (BE). Although short-term end points of ablation have been ascertained, there have been concerns about recurrence of intestinal metaplasia (IM) after ablation. We aimed to estimate the incidence and identify factors that predicted the recurrence of IM after successful RFA. METHODS: We analyzed data from 592 patients with BE treated with RFA from 2003 through 2011 at 3 tertiary referral centers. Complete remission of intestinal metaplasia (CRIM) was defined as eradication of IM (in esophageal and gastroesophageal junction biopsy specimens), documented by 2 consecutive endoscopies. Recurrence was defined as the presence of IM or dysplasia after CRIM in surveillance biopsies. Two experienced gastrointestinal pathologists confirmed pathology findings. RESULTS: Based on histology analysis, before RFA, 71% of patients had high-grade dysplasia or esophageal adenocarcinoma, 15% had low-grade dysplasia, and 14% had nondysplastic BE. Of patients treated, 448 (76%) were assessed after RFA. Fifty-five percent of patients underwent endoscopic mucosal resection before RFA. The median time to CRIM was 22 months, with 56% of patients in CRIM by 24 months. Increasing age and length of BE segment were associated with longer times to CRIM. Twenty-four months after CRIM, the incidence of recurrence was 33%; 22% of all recurrences observed were dysplastic BE. There were no demographic or endoscopic factors associated with recurrence. Complications developed in 6.5% of subjects treated with RFA; strictures were the most common complication. CONCLUSIONS: Of patients with BE treated by RFA, 56% were in complete remission after 24 months. However, 33% of these patients had disease recurrence within the next 2 years. Most recurrences were nondysplastic and endoscopically manageable, but continued surveillance after RFA is essential.
Hartman, K. G., J. D. Bortner, Jr., G. W. Falk, et al. (2014). "Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems." Exp Biol Med (Maywood) 239(9): 1108-1123.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156523/
Gastrointestinal illnesses are a significant health burden for the US population, with 40 million office visits each year for gastrointestinal complaints and nearly 250,000 deaths. Acute and chronic inflammations are a common element of many gastrointestinal diseases. Inflammatory processes may be initiated by a chemical injury (acid reflux in the esophagus), an infectious agent (Helicobacter pylori infection in the stomach), autoimmune processes (graft versus host disease after bone marrow transplantation), or idiopathic (as in the case of inflammatory bowel diseases). Inflammation in these settings can contribute to acute complaints (pain, bleeding, obstruction, and diarrhea) as well as chronic sequelae including strictures and cancer. Research into the pathophysiology of these conditions has been limited by the availability of primary human tissues or appropriate animal models that attempt to physiologically model the human disease. With the many recent advances in tissue engineering and primary human cell culture systems, it is conceivable that these approaches can be adapted to develop novel human ex vivo systems that incorporate many human cell types to recapitulate in vivo growth and differentiation in inflammatory microphysiological environments. Such an advance in technology would improve our understanding of human disease progression and enhance our ability to test for disease prevention strategies and novel therapeutics. We will review current models for the inflammatory and immunological aspects of Barrett's esophagus, acute graft versus host disease, and inflammatory bowel disease and explore recent advances in culture methodologies that make these novel microphysiological research systems possible.
Hartman, K. G., J. D. Bortner, G. W. Falk, et al. (2013). "Modeling inflammation and oxidative stress in gastrointestinal disease development using novel organotypic culture systems." Stem Cell Res Ther 4 Suppl 1: S5.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983655/
Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), graft-versus-host disease (GVHD), and inflammatory bowel diseases such as ulcerative colitis and Crohn's disease are common human gastrointestinal diseases that share inflammation as a key driver for their development. A general outcome resulting from these chronic inflammatory conditions is increased oxidative stress. Oxidative stress is caused by the generation of reactive oxygen and nitrogen species that are part of the normal inflammatory response, but are also capable of damaging cellular DNA, protein, and organelles. Damage to DNA can include DNA strand breaks, point mutations due to DNA adducts, as well as alterations in methylation patterns leading to activation of oncogenes or inactivation of tumor suppressors. There are a number of significant long-term consequences associated with chronic oxidative stress, most notably cancer. Infiltrating immune cells and stromal components of tissue including fibroblasts contribute to dynamic changes occurring in tissue related to disease development. Immune cells can potentiate oxidative stress, and fibroblasts have the capacity to contribute to advanced growth and proliferation of the epithelium and any resultant cancers. Disease models for GERD, BE, GVHD, and ulcerative colitis based on three-dimensional human cell and tissue culture systems that recapitulate in vivo growth and differentiation in inflammatory-associated microphysiological environments would enhance our understanding of disease progression and improve our ability to test for disease-prevention strategies. The development of physiologically relevant, human cell-based culture systems is therefore a major focus of our research. These novel models will be of enormous value, allowing us to test hypotheses and advance our understanding of these disorders, and will have a translational impact allowing us to more rapidly develop therapeutic and chemopreventive agents. In summary, this work to develop advanced human cell-based models of inflammatory conditions will greatly improve our ability to study, prevent, and treat GERD, BE, GVHD, and inflammatory bowel disease. The work will also foster the development of novel therapeutic and preventive strategies that will improve patient care for these important clinical conditions.
Kaimakliotis, P. Z. and G. W. Falk (2014). "Radiofrequency ablation for Barrett's esophagus." Curr Opin Gastroenterol 30(4): 415-421.
http://www.ncbi.nlm.nih.gov/pubmed/24867156
PURPOSE OF REVIEW: Several studies published in the last year that have provided evidence on the efficacy, durability and safety of radiofrequency ablation (RFA) in Barrett's esophagus are highlighted in this review. RECENT FINDINGS: RFA is well tolerated and efficacious in most but not all Barrett's esophagus patients with dysplasia and esophageal adenocarcinoma (EAC). Recent reports have described highly variable rates of disease recurrence. Disease progression may occur during initial therapy or after complete eradication in a small, difficult to identify subset of patients. Studies are underway to help determine the predictors of response and recurrence. Modifications in technique and target populations have been described in the last year as well. SUMMARY: Endoscopic mucosal resection and RFA are the cornerstones in the management of dysplasia and early EAC in Barrett's esophagus patients today. Despite the encouraging data on the effectiveness and safety of RFA, recurrence and progression of disease remain an issue in a subset of patients who are treated.
Kong, J., H. Sai, M. A. Crissey, et al. (2015). "Immature myeloid progenitors promote disease progression in a mouse model of Barrett's-like metaplasia." Oncotarget 6(32): 32980-33005.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741744/
Cdx2, an intestine specific transcription factor, is expressed in Barrett's esophagus (BE). We sought to determine if esophageal Cdx2 expression would accelerate the onset of metaplasia in the L2-IL-1beta transgenic mouse model for Barrett's-like metaplasia. The K14-Cdx2::L2-IL-1beta double transgenic mice had half as many metaplastic nodules as control L2-IL-1beta mice. This effect was not due to a reduction in esophageal IL-1beta mRNA levels nor diminished systemic inflammation. The diminished metaplasia was due to an increase in apoptosis in the K14-Cdx2::L2-IL-1beta mice. Fluorescence activated cell sorting of immune cells infiltrating the metaplasia identified a population of CD11b+Gr-1+ cells that are significantly reduced in K14-Cdx2::L2-IL-1beta mice. These cells have features of immature granulocytes and have immune-suppressing capacity. We demonstrate that the apoptosis in K14-Cdx2::L2-IL-1beta mice is CD8+ T cell dependent, which CD11b+Gr-1+ cells are known to inhibit. Lastly, we show that key regulators of CD11b+Gr-1+ cell development, IL-17 and S100A9, are significantly diminished in the esophagus of K14-Cdx2::L2-IL-1beta double transgenic mice. We conclude that metaplasia development in this mouse model for Barrett's-like metaplasia requires suppression of CD8+ cell dependent apoptosis, likely mediated by immune-suppressing CD11b+Gr-1+ immature myeloid cells.
Kong, J., K. A. Whelan, D. Laczko, et al. (2015). "Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress." Mol Carcinog.
http://onlinelibrary.wiley.com/doi/10.1002/mc.22406/abstract;jsessionid=13CA5FDF00861291CB45AD28FBBB003B.f02t04
Autophagy is a highly conserved mechanism that is activated during cellular stress. We hypothesized that autophagy may be induced by acid reflux, which causes injury, and inflammation, and therefore, contributes to the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Currently, the role of autophagy in BE and EAC is poorly studied. We quantitatively define autophagy levels in human BE cell lines, a transgenic mouse model of BE, and human BE, and EAC biopsies. Human non-dysplastic BE had the highest basal number of autophagic vesicles (AVs), while AVs were reduced in normal squamous cells and dysplastic BE cells, and nearly absent in EAC. To demonstrate a functional role for autophagy in BE pathogenesis, normal squamous (STR), non-dysplastic BE (CPA), dysplastic BE (CPD), and EAC (OE19) cell lines were exposed to an acid pulse (pH 3.5) followed by incubation in the presence or absence of chloroquine, an autophagy inhibitor. Acid exposure increased reactive oxygen species (ROS) levels in STR and CPA cells. Chloroquine alone had a small impact on intracellular ROS or cell survival. However, combination of chloroquine with the acid pulse resulted in a significant increase in ROS levels at 6 h in STR and CPA cells, and increased cell death in all cell lines. These findings establish increased numbers of AVs in human BE compared to normal squamous or EAC, and suggest that autophagy functions to improve cell survival after acid reflux injury. Autophagy may thus play a critical role in BE pathogenesis and progression. (c) 2015 Wiley Periodicals, Inc.
Kumar, J. D., C. Holmberg, S. Kandola, et al. (2014). "Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells." PLoS One 9(7): e104877.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104877
Stromal cells such as myofibroblasts influence tumor progression. The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow-derived mesenchymal stromal cells (MSCs) which then colonize tumors. Using iTRAQ and LC-MS/MS we identified the adipokine, chemerin, as overexpressed in esophageal squamous cancer associated myofibroblasts (CAMs) compared with adjacent tissue myofibroblasts (ATMs). The chemerin receptor, ChemR23, is expressed by MSCs. Conditioned media (CM) from CAMs significantly increased MSC cell migration compared to ATM-CM; the action of CAM-CM was significantly reduced by chemerin-neutralising antibody, pretreatment of CAMs with chemerin siRNA, pretreatment of MSCs with ChemR23 siRNA, and by a ChemR23 receptor antagonist, CCX832. Stimulation of MSCs by chemerin increased phosphorylation of p42/44, p38 and JNK-II kinases and inhibitors of these kinases and PKC reversed chemerin-stimulated MSC migration. Chemerin stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor (MIF) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations. In a xenograft model consisting of OE21 esophageal cancer cells and CAMs, homing of MSCs administered i.v. was inhibited by CCX832. Thus, chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression.
Leggett, C. L., E. C. Gorospe, L. Lutzke, et al. (2013). "A new era: endoscopic tissue transplantation." Curr Opin Gastroenterol 29(5): 495-500.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815665/
PURPOSE OF REVIEW: To describe basic principles of tissue engineering with emphasis on the potential role of gastrointestinal endoscopy in regenerative medicine. RECENT FINDINGS: Stricturing associated with endoscopic submucosal resection and circumferential endoscopic mucosal resection can be prevented through transplantation of autologous epidermal cell sheets or seeded decellularized biological scaffolds. Lower esophageal sphincter augmentation through injection of muscle-derived cells is a novel potential treatment for gastroesophageal reflux disease. Stem cell derived tissue has been used to repair injured colon in a mouse model of colitis. A bioengineered internal anal sphincter has been successfully implanted in mice and showed preserved functionality. SUMMARY: The immediate foreseeable application of tissue engineering in gastrointestinal endoscopy is in the field of mucosal repair after acute injury. Tissue regeneration can be achieved through expansion of autologous somatic cells or by induction of multipotent or pluripotent stem cells. Advances in cellular scaffolding have made bioengineering of complex tissues a reality. Tissue engineering in endoscopy is also being pioneered by studies looking at enteral sphincter augmentation and regeneration. The availability of engineered tissue for endoscopic application will increase with advances in cell-culturing techniques.
Leggett, C. L., E. C. Gorospe and K. K. Wang (2013). "Endoscopic therapy for Barrett's esophagus and early esophageal adenocarcinoma." Gastroenterol Clin North Am 42(1): 175-185.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815664/
Endoscopic therapy for Barrett's esophagus is feasible and likely to decrease the future risk of development of esophageal adenocarcinoma. The most commonly used therapy is radiofrequency ablation, which has been shown to produce reproducible superficial injury in the esophagus. Other thermal therapies include multipolar coagulation, argon plasma coagulation, and thermal laser therapy. The other end of the ablative spectrum includes cryotherapy, which involves freezing tissue to produce mucosal necrosis. Photodynamic therapy has been used to photochemically eliminate abnormal mucosa. Endoscopic therapy has been demonstrated to be effective in high-risk situations such as Barrett's esophagus with high-grade dysplasia.
Leggett, C. L., E. M. Nelsen, J. Tian, et al. (2013). "Metabolic syndrome as a risk factor for Barrett esophagus: a population-based case-control study." Mayo Clin Proc 88(2): 157-165.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771537/
OBJECTIVES: To assess the association between Barrett esophagus (BE) and the metabolic syndrome in patients with and without reflux symptoms and to determine whether this association is reflux independent and metabolically driven. PATIENTS AND METHODS: Case patients with BE and controls were residents of Olmsted County, Minnesota (1999-2006). Two control groups (one with and one without symptoms of gastroesophageal reflux) were identified from a cohort of patients who had responded to a validated gastrointestinal symptom questionnaire. Cases and controls were individually matched by age, sex, and duration of follow-up. Controls did not have a known diagnosis of BE. The association of the metabolic syndrome and its individual components with BE was assessed using univariate and multivariate conditional logistic regression separately for each control group. RESULTS: A total of 309 patients were included (103 BE cases, 103 controls with reflux symptoms, and 103 controls without reflux symptoms). A total of 64% of cases, 47% of controls with reflux symptoms, and 50% of controls without reflux symptoms had the metabolic syndrome. The metabolic syndrome was associated with a 2-fold increased risk of BE relative to those with (odds ratio, 2.00; 95% CI, 1.10-3.65; P=.02) and without (odds ratio, 1.90; 95% CI, 1.03-3.60; P=.04) reflux symptoms. This association was independent of smoking, alcohol consumption, and body mass index and remained robust with sensitivity analysis. CONCLUSION: The metabolic syndrome is associated with BE independent of reflux symptoms, which may reflect a reflux-independent pathway of BE pathogenesis.
Leggett, C. L. and G. A. Prasad (2012). "High-grade dysplasia and intramucosal adenocarcinoma in Barrett's esophagus: the role of endoscopic eradication therapy." Curr Opin Gastroenterol 28(4): 354-361.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389732/
PURPOSE OF REVIEW: Endoscopic eradication therapy is considered a well tolerated and effective alternative to esophagectomy for a select patient population with high-grade Barrett's esophagus and intramucosal adenocarcinoma. This review highlights the available eradication techniques (resection and ablation) with emphasis on factors that influence the choice of therapy. RECENT FINDINGS: Long-term follow-up of patients treated with endoscopic eradication therapies demonstrates high rates of complete remission of dysplasia and intestinal metaplasia with overall survival comparable to patients treated surgically. Cohort studies also report that recurrence following successful ablation occurs in a significant proportion of patients, making careful surveillance an indispensable component following successful endoscopic therapy. Endoscopic eradication therapy is also effective for the treatment of recurrent dysplasia and intestinal metaplasia. Ablative therapies may lead to buried metaplasia in a small proportion of patients. The long-term clinical implications of buried metaplasia are unclear. SUMMARY: Patients undergoing endoscopic eradication therapy should be enrolled in a comprehensive surveillance and staging program that offers both resection and ablative techniques. Complete remission of dysplasia and intestinal metaplasia can be achieved in the vast majority of patients undergoing endoscopic therapy. Surveillance should continue after treatment with close monitoring for recurrent dysplasia.
Mari, L., F. Milano, K. Parikh, et al. (2014). "A pSMAD/CDX2 complex is essential for the intestinalization of epithelial metaplasia." Cell Rep 7(4): 1197-1210.
http://www.sciencedirect.com/science/article/pii/S221112471400285X
The molecular mechanisms leading to epithelial metaplasias are poorly understood. Barrett's esophagus is a premalignant metaplastic change of the esophageal epithelium into columnar epithelium, occurring in patients suffering from gastroesophageal reflux disease. Mechanisms behind the development of the intestinal subtype, which is associated with the highest cancer risk, are unclear. In humans, it has been suggested that a nonspecialized columnar metaplasia precedes the development of intestinal metaplasia. Here, we propose that a complex made up of at least two factors needs to be activated simultaneously to drive the expression of intestinal type of genes. Using unique animal models and robust in vitro assays, we show that the nonspecialized columnar metaplasia is a precursor of intestinal metaplasia and that pSMAD/CDX2 interaction is essential for the switch toward an intestinal phenotype.
Nakagawa, H., K. Whelan and J. P. Lynch (2015). "Mechanisms of Barrett's oesophagus: intestinal differentiation, stem cells, and tissue models." Best Pract Res Clin Gastroenterol 29(1): 3-16.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352719/
Barrett's oesophagus (BE) is defined as any metaplastic columnar epithelium in the distal oesophagus which replaces normal squamous epithelium and which predisposes to cancer development. It is this second requirement, the predisposition to cancer, which makes this condition both clinically highly relevant and an important area for ongoing research. While BE has been defined pathologically since the 1950's (Allison and Johnstone, Thorax 1955), and identified as a risk factor for esophageal adenocarcinoma since the 1970's (Naef A.P., et al J Thorac Cardiovasc Surg. 1975), our understanding of the molecular events giving rise to this condition remains limited. Herein we will examine what is known about the intestinal features of BE and how well it recapitulates the intestinal epithelium, including stem identity and function. Finally, we will explore laboratory models of this condition presently in use and under development, to identify new insights they may provide into this important clinical condition.
Nelsen, E. M., Y. Kirihara, N. Takahashi, et al. (2012). "Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus." Clin Gastroenterol Hepatol 10(7): 728-734; quiz e761-722.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381999/
BACKGROUND & AIMS: Increased waist circumference and visceral fat are associated with increased risk of Barrett's esophagus (BE) and esophageal adenocarcinoma. This association might be mediated by mechanical and endocrine mechanisms. We investigated the distribution of fat in subjects with BE and its association with esophageal inflammation and dysplasia. METHODS: We collected data from 50 BE cases and 50 controls (matched for age and sex, identified from a radiology trauma database) seen at the Mayo Clinic in 2009. Abdominal (subcutaneous and visceral) and gastroesophageal junction (GEJ) fat area was measured using computed tomography with standard techniques. Esophageal inflammation (based on a histologic score) and dysplasia grade were assessed from esophageal biopsies of BE cases by a gastrointestinal pathologist. Conditional logistic regression was used to assess the association of body fat depot area with BE status, esophageal inflammation, and dysplasia. RESULTS: All BE subjects had controlled reflux symptoms without esophagitis, based on endoscopy. The GEJ fat area (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.3-27.7; P = .02), visceral fat area (OR, 4.9; 95% CI, 1.0-22.8; P = .04), and abdominal circumference (OR, 9.1; 95% CI, 1.4-57.2; P = 0.02) were associated with BE, independent of body mass index (BMI). The subcutaneous fat area was not associated with BE. Visceral and GEJ fat were significantly greater in BE subjects with esophageal inflammation (compared with those without, P = .02) and high-grade dysplasia (compared with those without, P = .01), independent of BMI. CONCLUSIONS: GEJ and visceral fat are associated with BE, and with increased esophageal inflammation and high-grade dysplasia in BE subjects, independent of BMI. Visceral fat therefore might promote esophageal metaplasia and dysplasia.
Penfield, J. D., M. Anderson, L. Lutzke, et al. (2013). "The role of cellular senescence in the gastrointestinal mucosa." Gut Liver 7(3): 270-277.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661957/
Cellular senescence is a biologically irreversible state of cell-growth arrest that occurs following either a replicative or an oncogenic stimulus. This phenomenon occurs as a response to the presence of premalignant cells and appears to be an important anticancer mechanism that keeps these transformed cells at bay. Many exogenous and endogenous triggers for senescence have been recognized to act via genomic or epigenomic pathways. The most common stimulus for senescence is progressive loss of telomeric DNA, which results in the loss of chromosomal stability and eventual unregulated growth and malignancy. Senescence is activated through an interaction between the p16 and p53 tumor-suppressor genes. Senescent cells can be identified in vitro because they express senescence-associated beta-galactosidase, a marker of increased lysosomal activity. Cellular senescence plays an integral role in the prevention and development of both benign and malignant gastrointestinal diseases. The senescence cascade and the cell-cycle checkpoints that dictate the progression and maintenance of senescence are important in all types of gastrointestinal cancers, including pancreatic, liver, gastric, colon, and esophageal cancers. Understanding the pathogenic mechanisms involved in cellular senescence is important for the development of agents targeted toward the treatment of gastrointestinal tumors.
Quante, M., J. A. Abrams, Y. Lee, et al. (2012). "Barrett esophagus: what a mouse model can teach us about human disease." Cell Cycle 11(23): 4328-4338.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552915/
The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the western world and accounts for 2% of all cancer-related deaths. The precursor lesion for EAC is Barrett esophagus (BE), which is strongly associated with gastresophageal reflux disease. A major limitation to the study of EAC has been the absence of tractable and genetically modifiable preclinical models of BE. A mouse model of BE and EAC that resembles human disease could provide novel insights into the origins and molecular pathogenesis of BE. In addition, validated animal models could help stratify BE patients given the limited predictive power of current standard endoscopic measures and clinical assessment. Here, we review the findings from recently developed mouse models of BE and EAC and their impact on clinical decision making, surveillance programs and therapeutic options. The data, taken together, suggest potential origins of BE from the gastric cardia, a role of bile acid and hypergatrinemia for carcinogenesis, a growing importance for columnar-like epithelium and a critical role for Notch signaling.
Quante, M., J. A. Abrams and T. C. Wang (2013). "The rapid rise in gastroesophageal junction tumors: is inflammation of the gastric cardia the underwater iceberg?" Gastroenterology 145(4): 708-711.
http://www.gastrojournal.org/article/S0016-5085(13)01216-X/abstract
Quante, M., G. Bhagat, J. A. Abrams, et al. (2012). "Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia." Cancer Cell 21(1): 36-51.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266546/
Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1beta phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5(+) gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1beta-IL-6 signaling cascade and Dll1-dependent Notch signaling.
Singh, S., A. G. Singh, P. P. Singh, et al. (2013). "Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett's esophagus: a systematic review and meta-analysis." Clin Gastroenterol Hepatol 11(6): 620-629.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660516/
BACKGROUND & AIMS: The incidence of esophageal cancer is increasing in the United States, especially among patients with Barrett's esophagus (BE). Statins might prevent this cancer. We performed a systematic review with a meta-analysis of studies that evaluated the effect of statins on the risk of esophageal cancer. METHODS: We conducted a systematic search of Medline, Embase, and Web of Science through August 2012. Studies were included if they evaluated exposure to statins, reported the development of esophageal cancer, and reported relative risks or odds ratios (OR), or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were calculated using the random-effects model. The analysis included 13 studies (including a post hoc analysis of 22 randomized controlled trials) reporting 9285 cases of esophageal cancer among 1,132,969 patients. RESULTS: A meta-analysis of the studies showed a significant (28%) reduction in the risk of esophageal cancer among patients who took statins (adjusted OR, 0.72; 95% CI, 0.60-0.86), although there was considerable heterogeneity among studies. In analyzing a subset of patients known to have BE (5 studies, 312 esophageal adenocarcinomas [EAC] developed in 2125 patients), statins were associated with a significant (41%) decrease in the risk of EAC, after adjusting for potential confounders (adjusted OR, 0.59; 95% CI, 0.45-0.78) with consistent results among all studies. The number needed to treat with statins to prevent 1 case of EAC in patients with BE was 389. CONCLUSIONS: Based on meta-analysis of observational studies, statin use may be associated with lower risk of esophageal cancer, particularly risk of EAC in patients with BE.
Sinh, P., R. Anaparthy, P. E. Young, et al. (2015). "Clinical outcomes in patients with a diagnosis of "indefinite for dysplasia" in Barrett's esophagus: a multicenter cohort study." Endoscopy 47(8): 669-674.
https://www.thieme-connect.com/DOI/DOI?10.1055/s-0034-1391966
BACKGROUND AND STUDY AIM: Data are limited on the natural history of patients with Barrett's esophagus with a diagnosis of "indefinite for dysplasia" (IND). The aims of this study were to: (i) determine rates of progression to high grade dysplasia (HGD) or esophageal adenocarcinoma, and compare these with rates for low grade dysplasia (LGD); and (ii) determine the proportion of patients whose histological IND diagnosis changed on follow-up endoscopy. PATIENTS AND METHODS: Demographic, endoscopic, and histologic information of patients with diagnoses of IND and LGD and at least 12 months of follow-up were extracted from the database of a multicenter Barrett's esophagus study. Rates and times for progression to HGD and esophageal adenocarcinoma and regression to nondysplastic epithelium were calculated. Proportions of diagnoses upgraded to HGD/esophageal adenocarcinoma or downgraded to nondysplastic epithelium at first follow-up endoscopy were evaluated. RESULTS: Amongst 2264 patients, 83 with a diagnosis of IND (mean age 60 years, 95 % men, 95 % white; mean follow-up 5.6 years) and 79 with diagnosis of LGD were identified. In the IND group, annual incidences of esophageal adenocarcinoma and HGD were 0.21 % and 0.64 %, respectively, representing a combined incidence of 0.8 %. Mean time to progression was 4.72 years. Within the IND group 55 % patients showed regression to nondysplastic epithelium at first follow-up endoscopy and the overall regression rate was 80 %. Corresponding rates in LGD patients were similar. CONCLUSIONS: Lesions diagnosed as IND and LGD show similar biological behavior and can be treated as a single category with respect to surveillance and follow-up.
Small, A. J., J. L. Araujo, C. L. Leggett, et al. (2015). "Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett's Esophagus and Confirmed Low-Grade Dysplasia." Gastroenterology 149(3): 567-576 e563; quiz e513-564.
http://www.sciencedirect.com/science/article/pii/S0016508515005697
BACKGROUND & AIMS: Barrett's esophagus (BE) with low-grade dysplasia (LGD) can progress to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been shown to be an effective treatment for LGD in clinical trials, but its effectiveness in clinical practice is unclear. We compared the rate of progression of LGD after RFA with endoscopic surveillance alone in routine clinical practice. METHODS: We performed a retrospective study of patients who either underwent RFA (n = 45) or surveillance endoscopy (n = 125) for LGD, confirmed by at least 1 expert pathologist, from October 1992 through December 2013 at 3 medical centers in the United States. Cox regression analysis was used to assess the association between progression and RFA. RESULTS: Data were collected over median follow-up periods of 889 days (interquartile range, 264-1623 days) after RFA and 848 days (interquartile range, 322-2355 days) after surveillance endoscopy (P = .32). The annual rates of progression to HGD or EAC were 6.6% in the surveillance group and 0.77% in the RFA group. The risk of progression to HGD or EAC was significantly lower among patients who underwent RFA than those who underwent surveillance (adjusted hazard ratio = 0.06; 95% confidence interval: 0.008-0.48). CONCLUSIONS: Among patients with BE and confirmed LGD, rates of progression to a combined end point of HGD and EAC were lower among those treated with RFA than among untreated patients. Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for LGD.
Small, A. J., S. E. Sutherland, J. S. Hightower, et al. (2015). "Comparative risk of recurrence of dysplasia and carcinoma after endoluminal eradication therapy of high-grade dysplasia versus intramucosal carcinoma in Barrett's esophagus." Gastrointest Endosc 81(5): 1158-1166 e1151-1154.
http://www.sciencedirect.com/science/article/pii/S0016510714023852
BACKGROUND: Endoscopic therapy is the preferred approach for the management of Barrett's esophagus (BE) patients with high-grade dysplasia (HGD) and intramucosal carcinoma (IMC). Little is known about outcome differences in patients with HGD versus IMC. OBJECTIVE: To determine and compare the rate of recurrent dysplasia or neoplasia in patients with HGD or IMC undergoing endoscopic therapy. DESIGN: Retrospective cohort study. PATIENTS: A total of 246 BE patients with either HGD or IMC referred for endoscopic therapy. INTERVENTION: Patients underwent EMR and/or ablation therapy with the goal of complete eradication of all dysplasia/neoplasia and intestinal metaplasia (CE-IM). Patients were assigned to either the HGD or IMC group based on highest pathology grade at the start of therapy. MAIN OUTCOME MEASUREMENTS: Complete eradication and recurrence of IM and/or HGD/neoplasia were assessed among patients with HGD versus IMC. Only patients with CE-IM (documented eradication of all dysplasia/neoplasia and IM on a single endoscopy) were included for analysis of recurrence rates and risk factors. RESULTS: CE-IM was achieved in 113 of 135 patients (83.7%) with HGD and in 84 of 111 patients (75.7%) with IMC (P = .16). Overall recurrence rates of dysplasia or neoplasia after CE-IM were similar in both groups (HGD, 8.0% vs IMC, 9.5%; P = .44; relative risk, 1.2; 95% confidence interval, 0.5-3.0) and remained similar in patients with 5 years of surveillance after CE-IM (HGD, 13.5% vs IMC, 11.4%; P = .53; relative risk, 0.85; 95% confidence interval, 0.3-2.7). LIMITATIONS: Retrospective, observational study and evolution of endoscopic modalities and experience. CONCLUSION: Endoluminal therapy can successfully achieve eradication of IM and dysplasia or neoplasia in BE patients with HGD and IMC at comparable rates. There were no differences in the rates of recurrent HGD/IMC in the 2 groups.
Timmer, M. R., S. M. Brankley, E. C. Gorospe, et al. (2014). "Prediction of response to endoscopic therapy of Barrett's dysplasia by using genetic biomarkers." Gastrointest Endosc 80(6): 984-991.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311726/
BACKGROUND: Endoscopic therapy for the treatment of high-grade dysplasia (HGD) and intramucosal cancer (IMC) in Barrett's esophagus (BE) may not always result in complete remission of dysplasia (CRD). OBJECTIVE: To determine whether genetic alterations in the Barrett's mucosa can predict response to endoscopic therapy. DESIGN: Retrospective cohort study. SETTING: Tertiary-care institution. PATIENTS: Selected patients who underwent endoscopic therapy for BE containing HGD/IMC between 2003 and 2010. INTERVENTIONS: Endoscopic therapy combining mucosal resection and different ablation modalities was performed based on patient characteristics, endoscopic findings, and technique evolution. Fluorescence in situ hybridization was used to evaluate genetic alterations on baseline endoscopic cytology brushings by using probes directed to loci 8q24 (MYC), 9p21 (CDKN2A; alias P16), 17q12 (ERBB2; alias Her-2/neu), and 20q13.2 (ZNF217). MAIN OUTCOME MEASUREMENTS: Genetic biomarkers predicting achievement of CRD after endoscopic therapy. RESULTS: A total of 181 patients were included (145 men; 66 +/- 10 years of age). There were 130 patients (72%) who responded to endoscopic therapy with CRD. Multiple gains detected by fluorescence in situ hybridization was found to be a negative predictor (hazard ratio 0.57; 95% confidence interval, 0.40-0.82) after adjusting for potential clinical confounders. Similar results were found when analyses were restricted to patients (n = 66) undergoing radiofrequency ablation (hazard ratio 0.58; 95% confidence interval, 0.31-1.09). LIMITATIONS: Retrospective study, heterogeneity of treatment modalities. CONCLUSION: Patients with multiple gains detected by brush cytology specimens may have a lower response rate to endoscopic therapy. The presence of multiple gains can be an adjunct to standard histology in prognosticating BE patients with HGD/IMC undergoing endoscopic therapy.
Timmer, M. R., G. Sun, E. C. Gorospe, et al. (2013). "Predictive biomarkers for Barrett's esophagus: so near and yet so far." Dis Esophagus 26(6): 574-581.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466900/
Barrett's esophagus (BE) is the strongest risk factor for the development of esophageal adenocarcinoma. However, the risk of cancer progression is difficult to ascertain in individuals, as a significant number of patients with BE do not necessarily progress to esophageal adenocarcinoma. There are several issues with the current strategy of using dysplasia as a marker of disease progression. It is subject to sampling error during biopsy acquisition and interobserver variability among gastrointestinal pathologists. Ideal biomarkers with high sensitivity and specificity are needed to accurately detect high-risk BE patients for early intervention and appropriate cost-effective surveillance. To date, there are no available molecular tests in routine clinical practice despite known genetic and epigenetic aberrations in the Barrett's epithelium. In this review, we present potential biomarkers for the prediction of malignant progression in BE. These include markers of genomic instability, tumor suppressor loci abnormalities, epigenetic changes, proliferation markers, cell cycle predictors, and immunohistochemical markers. Further work in translating biomarkers for routine clinical use may eventually lead to accurate risk stratification.
Titi, M., A. Overhiser, O. Ulusarac, et al. (2012). "Development of subsquamous high-grade dysplasia and adenocarcinoma after successful radiofrequency ablation of Barrett's esophagus." Gastroenterology 143(3): 564-566 e561.
http://www.sciencedirect.com/science/article/pii/S0016508512006786
Patients with Barrett's esophagus are frequently treated with radiofrequency ablation (RFA). Those that undergo this procedure have a low risk of developing subsquamous intestinal metaplasia, and none have been reported to develop subsquamous dysplasia or cancer. We report the development of subsquamous neoplasia in 3 patients who were treated with RFA for Barrett's esophagus (2 developed adenocarcinoma and 1 developed high-grade dysplasia). The identification of these cases indicates the need for continued surveillance following RFA, even after complete eradication of intestinal metaplasia, and caution for widespread use of ablation, especially in patients with low-risk Barrett's esophagus.
Vega, M. E., V. Giroux, M. Natsuizaka, et al. (2014). "Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett's-like metaplasia via KLF4." Cell Cycle 13(24): 3857-3866.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614677/
Barrett's esophagus (BE) is defined as an incomplete intestinal metaplasia characterized generally by the presence of columnar and goblet cells in the formerly stratified squamous epithelium of the esophagus. BE is known as a precursor for esophageal adenocarcinoma. Currently, the cell of origin for human BE has yet to be clearly identified. Therefore, we investigated the role of Notch signaling in the initiation of BE metaplasia. Affymetrix gene expression microarray revealed that BE samples express decreased levels of Notch receptors (NOTCH2 and NOTCH3) and one of the the ligands (JAG1). Furthermore, BE tissue microarray showed decreased expression of NOTCH1 and its downstream target HES1. Therefore, Notch signaling was inhibited in human esophageal epithelial cells by expression of dominant-negative-Mastermind-like (dnMAML), in concert with MYC and CDX1 overexpression. Cell transdifferentiation was then assessed by 3D organotypic culture and evaluation of BE-lineage specific gene expression. Notch inhibition promoted transdifferentiation of esophageal epithelial cells toward columnar-like cells as demonstrated by increased expression of columnar keratins (K8, K18, K19, K20) and glandular mucins (MUC2, MUC3B, MUC5B, MUC17) and decreased expression of squamous keratins (K5, K13, K14). In 3D culture, elongated cells were observed in the basal layer of the epithelium with Notch inhibition. Furthermore, we observed increased expression of KLF4, a potential driver of the changes observed by Notch inhibition. Interestingly, knockdown of KLF4 reversed the effects of Notch inhibition on BE-like metaplasia. Overall, Notch signaling inhibition promotes transdifferentiation of esophageal cells toward BE-like metaplasia in part via upregulation of KLF4. These results support a novel mechanism through which esophageal epithelial transdifferentiation promotes the evolution of BE.
Wang, K. K. (2012). "Endoscopic vs surgical resection for Barrett's intramucosal adenocarcinoma: beyond a therapeutic equipoise." Gastroenterology 143(1): 257-259.
http://www.sciencedirect.com/science/article/pii/S0016508512007512
Wang, K. K. (2013). "The essence of management of Barrett's esophagus." Gastrointest Endosc 78(5): 702-703.
http://www.sciencedirect.com/science/article/pii/S0016510713021226
Wang, K. K., N. Okoro, G. Prasad, et al. (2011). "Endoscopic evaluation and advanced imaging of Barrett's esophagus." Gastrointest Endosc Clin N Am 21(1): 39-51.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762455/
Enhanced visualization techniques are available for Barrett's esophagus and have promise in the detection of dysplasia and cancer. Several of these techniques, such as narrow band imaging and chromoendoscopy, are being applied clinically. These techniques will allow the endoscopist to screen the surface of the Barrett's esophagus to detect areas of neoplasia. Once detected, it is hoped that either magnification techniques, such as confocal laser endomicroscopy, or spectroscopic techniques can be of value in allowing in vivo real-time diagnostic capabilities.
Whitson, M. J. and G. W. Falk (2015). "Predictors of Progression to High-Grade Dysplasia or Adenocarcinoma in Barrett's Esophagus." Gastroenterol Clin North Am 44(2): 299-315.
http://www.sciencedirect.com/science/article/pii/S0889855315000229
The prevalence of esophageal adenocarcinoma is increasing dramatically. Barrett's esophagus remains the most well-established risk factor for the development of esophageal adenocarcinoma. There are multiple clinical, endoscopic, and pathologic factors that increase the risk of neoplastic progression to high-grade dysplasia or esophageal adenocarcinoma in Barrett's esophagus. This article reviews both risk and protective factors for neoplastic progression in patients with Barrett's esophagus.
Zhao, C. M., Y. Hayakawa, Y. Kodama, et al. (2014). "Denervation suppresses gastric tumorigenesis." Sci Transl Med 6(250): 250ra115.
http://stm.sciencemag.org/content/6/250/250ra115.full
The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptor-mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer.
Zhou, J., Y. Hayakawa, T. C. Wang, et al. (2014). "RhoA mutations identified in diffuse gastric cancer." Cancer Cell 26(1): 9-11.
http://www.sciencedirect.com/science/article/pii/S1535610814002724
The diffuse-type histologic variant of gastric cancer is characterized by highly invasive growth patterns and lack of cellular cohesion. Two recent studies have identified highly recurrent mutations of the gene encoding the small GTPase RhoA and suggest that RhoA activity may have a tumor suppressive role in this disease.