|
1
|
Ghosal A, Verma S, Le IT, Lee VT, deGuzman BJ, Aklog L. Analytical Validation of a DNA Methylation Biomarker Test for the Diagnosis of Barrett's Esophagus and Esophageal Adenocarcinoma from Samples Collected Using EsoCheck ®, a Non-Endoscopic Esophageal Cell Collection Device. Diagnostics (Basel) 2024; 14:1784. [PMID: 39202271 PMCID: PMC11354049 DOI: 10.3390/diagnostics14161784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/25/2024] [Accepted: 08/09/2024] [Indexed: 09/03/2024] Open
Abstract
Barrett's esophagus (BE) is a known precursor to esophageal adenocarcinoma (EAC). Guidelines recommend BE screening in populations with multiple risk factors, for which non-endoscopic esophageal cell collection with biomarker testing is considered as an acceptable alternative to esophagogastroduodenoscopy (EGD). The aim of this study was to evaluate analytical performance characteristics of EsoGuard® (EG), a DNA methylation biomarker assay, as a laboratory-developed test (LDT) in esophageal samples collected with the swallowable EsoCheck® (EC) device. EG is a next-generation sequencing (NGS) assay that evaluates methylated vimentin (VIM) and cyclin A1 (CCNA1), clinically validated biomarkers for the detection of BE and EAC. The studies were conducted according to standards of College of American Pathology (CAP), Clinical Laboratory Improvement Amendments (CLIA), and New York (NY) state requirements for the analytical validation of molecular assays. Comparison to Sanger sequencing showed that EG was 100% accurate at all 31 CpG sites evaluated by the assay. The analytical sensitivity, specificity, and accuracy of the assay were 89%, 100%, and 96%, respectively. Intra- and inter-assay precision was 100%. The limit of detection (LOD) was 1 in 400 methylated cells, and the reference range was 84%. In summary, EsoGuard demonstrates high analytical accuracy, repeatability, and reproducibility in samples collected using the EsoCheck device.
Collapse
Affiliation(s)
- Abhisek Ghosal
- Lucid Diagnostics, 360 Madison Ave., Floor 25, New York, NY 10017, USA; (A.G.); (I.T.L.); (V.T.L.); (B.J.d.); (L.A.)
- Lucid Dx Labs, 14 Orchard Road, Lake Forest, CA 92831, USA
| | - Suman Verma
- Lucid Diagnostics, 360 Madison Ave., Floor 25, New York, NY 10017, USA; (A.G.); (I.T.L.); (V.T.L.); (B.J.d.); (L.A.)
- Lucid Dx Labs, 14 Orchard Road, Lake Forest, CA 92831, USA
- PAVmed Inc., 360 Madison Ave., Floor 25, New York, NY 10017, USA
| | - Ivy T. Le
- Lucid Diagnostics, 360 Madison Ave., Floor 25, New York, NY 10017, USA; (A.G.); (I.T.L.); (V.T.L.); (B.J.d.); (L.A.)
- Lucid Dx Labs, 14 Orchard Road, Lake Forest, CA 92831, USA
| | - Victoria T. Lee
- Lucid Diagnostics, 360 Madison Ave., Floor 25, New York, NY 10017, USA; (A.G.); (I.T.L.); (V.T.L.); (B.J.d.); (L.A.)
- PAVmed Inc., 360 Madison Ave., Floor 25, New York, NY 10017, USA
| | - Brian J. deGuzman
- Lucid Diagnostics, 360 Madison Ave., Floor 25, New York, NY 10017, USA; (A.G.); (I.T.L.); (V.T.L.); (B.J.d.); (L.A.)
- Lucid Dx Labs, 14 Orchard Road, Lake Forest, CA 92831, USA
- PAVmed Inc., 360 Madison Ave., Floor 25, New York, NY 10017, USA
| | - Lishan Aklog
- Lucid Diagnostics, 360 Madison Ave., Floor 25, New York, NY 10017, USA; (A.G.); (I.T.L.); (V.T.L.); (B.J.d.); (L.A.)
- Lucid Dx Labs, 14 Orchard Road, Lake Forest, CA 92831, USA
- PAVmed Inc., 360 Madison Ave., Floor 25, New York, NY 10017, USA
| |
Collapse
|
|
2
|
Jong MR, de Groof AJ. Advancement of artificial intelligence systems for surveillance endoscopy of Barrett's esophagus. Dig Liver Dis 2024; 56:1126-1130. [PMID: 38071181 DOI: 10.1016/j.dld.2023.11.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 06/29/2024]
Abstract
Barrett's esophagus (BE) is a precursor disease for esophageal adenocarcinoma. Timely detection and treatment has significant influence on patient outcomes. Over the last years, several artificial intelligence (AI) systems have emerged to assist the endoscopist. The primary focus of research has been computer aided detection (CADe). Several groups have succeeded in developing competitive models for neoplasia detection. Additionally, computer aided diagnosis (CADx) models have been developed for subsequent lesion characterization and assistance in clinical decision making. Future studies should focus on bridging the domain gap between academic development and integration in daily practice.
Collapse
Affiliation(s)
- M R Jong
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - A J de Groof
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
| |
Collapse
|
|
3
|
Gounella R, Granado TC, Hideo Ando Junior O, Luporini DL, Gazziro M, Carmo JP. Endoscope Capsules: The Present Situation and Future Outlooks. Bioengineering (Basel) 2023; 10:1347. [PMID: 38135938 PMCID: PMC10741108 DOI: 10.3390/bioengineering10121347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/04/2023] [Accepted: 11/20/2023] [Indexed: 12/24/2023] Open
Abstract
This paper presents new perspectives on photonic technologies for capsule endoscopy. It first presents a review of conventional endoscopy (upper endoscopy and colonoscopy), followed by capsule endoscopy (CE), as well as their techniques, advantages, and drawbacks. The technologies for CEs presented in this paper include integration with the existing endoscopic systems that are commercially available. Such technologies include narrow-band imaging (NBI), photodynamic therapy (PDT), confocal laser endomicroscopy (CLE), optical coherence tomography (OCT), and spectroscopy in order to improve the performance of the gastrointestinal (GI) tract examination. In the context of NBI, two optical filters were designed and fabricated for integration into endoscopic capsules, allowing for the visualization of light centered at the 415 nm and 540 nm wavelengths. These optical filters are based on the principle of Fabry-Perot and were made of thin films of titanium dioxide (TiO2) and silicon dioxide (SiO2). Moreover, strategies and solutions for the adaptation of ECs for PDT are also discussed.
Collapse
Affiliation(s)
- Rodrigo Gounella
- Group of Metamaterials Microwaves and Optics (GMeta), Department of Electrical Engineering (SEL), University of São Paulo (USP), Avenida Trabalhador São-Carlense, Nr. 400, Parque Industrial Arnold Schimidt, São Carlos 13566-590, Brazil; (T.C.G.); (J.P.C.)
| | - Talita Conte Granado
- Group of Metamaterials Microwaves and Optics (GMeta), Department of Electrical Engineering (SEL), University of São Paulo (USP), Avenida Trabalhador São-Carlense, Nr. 400, Parque Industrial Arnold Schimidt, São Carlos 13566-590, Brazil; (T.C.G.); (J.P.C.)
| | - Oswaldo Hideo Ando Junior
- Academic Unit of Cabo de Santo Agostinho (UACSA), Federal Rural University of Pernambuco (UFRPE), Cabo de Santo Agostinho 54518-430, Brazil;
| | - Daniel Luís Luporini
- Clinica Endoscopia São Carlos, Rua Paulino Botelho de Abreu Sampaio, 958, Centro, São Carlos 13561-060, Brazil;
| | - Mario Gazziro
- Information Engineering Group, Department of Engineering and Social Sciences (CECS), Federal University of ABC (UFABC), Av. dos Estados, 5001, Santo André 09210-580, Brazil;
| | - João Paulo Carmo
- Group of Metamaterials Microwaves and Optics (GMeta), Department of Electrical Engineering (SEL), University of São Paulo (USP), Avenida Trabalhador São-Carlense, Nr. 400, Parque Industrial Arnold Schimidt, São Carlos 13566-590, Brazil; (T.C.G.); (J.P.C.)
| |
Collapse
|
|
4
|
Nguyen T, Mills JC, Cho CJ. The coordinated management of ribosome and translation during injury and regeneration. Front Cell Dev Biol 2023; 11:1186638. [PMID: 37427381 PMCID: PMC10325863 DOI: 10.3389/fcell.2023.1186638] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/06/2023] [Indexed: 07/11/2023] Open
Abstract
Diverse acute and chronic injuries induce damage responses in the gastrointestinal (GI) system, and numerous cell types in the gastrointestinal tract demonstrate remarkable resilience, adaptability, and regenerative capacity in response to stress. Metaplasias, such as columnar and secretory cell metaplasia, are well-known adaptations that these cells make, the majority of which are epidemiologically associated with an elevated cancer risk. On a number of fronts, it is now being investigated how cells respond to injury at the tissue level, where diverse cell types that differ in proliferation capacity and differentiation state cooperate and compete with one another to participate in regeneration. In addition, the cascades or series of molecular responses that cells show are just beginning to be understood. Notably, the ribosome, a ribonucleoprotein complex that is essential for translation on the endoplasmic reticulum (ER) and in the cytoplasm, is recognized as the central organelle during this process. The highly regulated management of ribosomes as key translational machinery, and their platform, rough endoplasmic reticulum, are not only essential for maintaining differentiated cell identity, but also for achieving successful cell regeneration after injury. This review will cover in depth how ribosomes, the endoplasmic reticulum, and translation are regulated and managed in response to injury (e.g., paligenosis), as well as why this is essential for the proper adaptation of a cell to stress. For this, we will first discuss how multiple gastrointestinal organs respond to stress through metaplasia. Next, we will cover how ribosomes are generated, maintained, and degraded, in addition to the factors that govern translation. Finally, we will investigate how ribosomes and translation machinery are dynamically regulated in response to injury. Our increased understanding of this overlooked cell fate decision mechanism will facilitate the discovery of novel therapeutic targets for gastrointestinal tract tumors, focusing on ribosomes and translation machinery.
Collapse
Affiliation(s)
- Thanh Nguyen
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Jason C. Mills
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Charles J. Cho
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| |
Collapse
|
|
5
|
Shibli F, Fass OZ, Teramoto OM, Remes-Troche JM, Rangan V, Kurin M, Fass R. Esophageal Hypocontractile Disorders and Hiatal Hernia Size Are Predictors for Long Segment Barrett's Esophagus. J Neurogastroenterol Motil 2023; 29:31-37. [PMID: 36606434 PMCID: PMC9837537 DOI: 10.5056/jnm21255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 07/22/2022] [Accepted: 08/06/2022] [Indexed: 01/07/2023] Open
Abstract
Background/Aims Presently, there is paucity of information about clinical predictors, especially esophageal motor abnormalities, for long segment Barrett's esophagus (LSBE) as compared with short segment Barrett's esophagus (SSBE). The aims of this study are to compare the frequency of esophageal function abnormalities between patients with LSBE and those with SSBE and to determine their clinical predictors. Methods This was a multicenter cohort study that included all patients with a diagnosis of BE who underwent high-resolution esophageal manometry. Motility disorders were categorized as hypercontractile disorders or hypocontractile disorders and their frequency was compared between patients with LSBE and those with SSBE. Multivariable logistic regression modeling was used to calculate the odds of being diagnosed with LSBE relative to SSBE for demographics, comorbidities, medication use, endoscopic findings, and the type of motility disorders. Results A total of 148 patients with BE were identified, of which 89 (60.1%) had SSBE and 59 (39.9%) LSBE. Patients with LSBE had a significantly larger hiatal hernia and higher likelihood of erosive esophagitis than patients with SSBE (P = 0.002). Patients with LSBE had a significantly lower mean LES resting pressure, distal contractile integral, distal latency, and significantly higher failed swallows and hypocontractile motility disorders than those with SSBE (P < 0.05). Hiatal hernia and hypocontractile motility disorder increased the odds of LSBE by 38.0% and 242.0%, as opposed to SSBE. Conclusions The presence of a hypocontractile motility disorder increased the risk for LSBE. Furthermore, the risk for LSBE was directly associated with the length of the hiatal hernia.
Collapse
Affiliation(s)
- Fahmi Shibli
- Department of Medicine, Division of Gastroenterology and Hepatology, Esophageal and Swallowing Center, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Ofer Z Fass
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Oscar Matsubara Teramoto
- Department of Gastroenterology, ABC Medical Center PMG, Santa Fe, Contadero, Cuajimalpa de Morelos, Mexico
| | - José M Remes-Troche
- Deapartment of Digestive Physiology and Motility Laboratory, Medical Biological Research Institute, University of Veracruz, Veracruz, Mexico
| | - Vikram Rangan
- Department of Medicine, Division of Gastroenterology and Hepatology, Digestive Disease Center, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA
| | - Michael Kurin
- Department of Medicine, Division of Gastroenterology and Hepatology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Ronnie Fass
- Department of Medicine, Division of Gastroenterology and Hepatology, Esophageal and Swallowing Center, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| |
Collapse
|
|
6
|
Copetti H, Copetti L, Copetti L, Felin GD, Felin GD, Felin CD, Felin FD, Chiesa V. RISK OF PRENEOPLASTIC LESIONS IN MUCOSAL PROJECTIONS OF DIFFERENT SIZES OF THE COLUMNAR EPITHELIUM IN THE LOWER ESOPHAGUS. ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA : ABCD = BRAZILIAN ARCHIVES OF DIGESTIVE SURGERY 2022; 35:e1674. [PMID: 36102485 PMCID: PMC9462856 DOI: 10.1590/0102-672020220002e1674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 05/28/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Barrett's esophagus is an acquired condition that predisposes to the development of esophageal adenocarcinoma. AIMS The aim of this study was to establish an association between the endoscopic and the histopathological findings regarding differently sized endoscopic columnar epithelial mucosa projections in the low esophagus, under 3.0 cm in the longitudinal extent. METHODS This is a prospective study, including 1262 patients who were submitted to upper gastrointestinal endoscopy in the period from July 2015 to June 2017. The suspicious projections were measured and subdivided into three groups according to the sizes encountered (Group I: <0.99 cm; Group II: 1.0-1.99 cm; and Group III: 2.0-2.99 cm), and biopsies were then performed. RESULTS There was a general prevalence of suspicious lesions of 6.42% and of confirmed Barrett's lesions of 1.17%, without a general significant statistical difference among groups. However, from Groups I and II to Group III, the differences were significant, showing that the greater the lesion, the higher the probability of Barrett's esophagus diagnosis. The absolute number of Barrett's lesions was 7, 9, and 6 for Groups I, II, and III, respectively. CONCLUSIONS The findings led to the conclusion that even projections under 3.0 cm present a similar possibility of evolution to Barrett's esophagus. If, on the one hand, short segments are more prevalent, on the other hand, the long segments have the higher probability of Barrett's esophagus diagnosis, which is why biopsies are required in all suspicious segments.
Collapse
Affiliation(s)
- Hairton Copetti
- Universidade Federal de Santa Maria – Santa Maria (RS), Brazil
| | | | - Laura Copetti
- Universidade Federal de Santa Maria – Santa Maria (RS), Brazil
| | | | | | | | | | - Vitória Chiesa
- Universidade Federal de Ciências da Saúde de Porto Alegre – Porto Alegre (RS), Brazil
| |
Collapse
|
|
7
|
Fu S, Xu M, Zhou H, Wang Y, Tan Y, Liu D. Metabolic syndrome is associated with higher rate of gastroesophageal reflux disease: a meta-analysis. Neurogastroenterol Motil 2022; 34:e14234. [PMID: 34378835 DOI: 10.1111/nmo.14234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/05/2021] [Accepted: 07/17/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Gastroesophageal reflux disease (GERD) seriously lowers the quality of life of patients, and its prevalence has gradually increased in recent years. Some studies have showed that metabolic syndrome (MetS) is related to GERD, but the results remain controversial. This study explored the relationship between MetS and GERD through systematic retrieval and analysis of published studies. METHODS Retrieve related research from PubMed, Web of Science, and Cochrane Library. Including cohort studies that compare the prevalence of GERD between patients with MetS and patients without, and case-control studies or cross-sectional studies that compare the prevalence of MetS between patients with GERD and patients without. In addition to analyzing the relationship between MetS and GERD, individual metabolic components are also analyzed. Use a random effects model (DerSimmonian and Laird) to merge the odd ratio (OR). Cochran's Q test and Higgins' I-squared statistic were performed to assess heterogeneity. Publication bias was assessed by Egger's test. KEY RESULTS A total of 103,048 patients from 15 studies were included. The combined results suggest that MetS is a risk factor of GERD (OR: 1.66, 95%CI: 1.38-1.99). Among the individual metabolic components, abdominal obesity (OR: 1.42, 95%CI: 1.22-1.64), hypertriglyceridemia (OR: 1.50, 95%CI: 1.27-1.78), hyperglycemia (OR: 1.31, 95%CI: 1.07-1.61), and hypertension (OR: 1.19, 95%CI: 1.07-1.33) are risk factors of GERD. CONCLUSIONS AND INFERENCES MetS is a risk factor of GERD, and among the abnormal metabolic components that establish the diagnosis of MetS, abdominal obesity, hypertriglyceridemia, hyperglycemia, and hypertension are risk factors of GERD.
Collapse
Affiliation(s)
- Shifeng Fu
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Mengmeng Xu
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Hejun Zhou
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Yongjun Wang
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Yuyong Tan
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Deliang Liu
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| |
Collapse
|
|
8
|
Garg V, Narang P, Taneja R. Antacids revisited: review on contemporary facts and relevance for self-management. J Int Med Res 2022; 50:3000605221086457. [PMID: 35343261 PMCID: PMC8966100 DOI: 10.1177/03000605221086457] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Heartburn and acid regurgitation are the typical symptoms of gastroesophageal reflux. Despite the availability of several treatment options, antacids remain the mainstay treatment for gastroesophageal reflux-related symptoms based on their efficacy, safety, and over-the-counter availability. Antacids are generally recommended for adults and children at least 12 years old, and the FDA recommends antacids as the first-line treatment for heartburn in pregnancy. This narrative review summarizes the mechanism, features, and limitations related to different antacid ingredients and techniques available to study the acid neutralization and buffering capacity of antacid formulations. Using supporting clinical evidence for different antacid ingredients, it also discusses the importance of antacids as OTC medicines and first-line therapies for heartburn, particularly in the era of the COVID-19 pandemic, in which reliance on self-care has increased. The review will also assist pharmacists and other healthcare professionals in helping individuals with heartburn to make informed self-care decisions and educating them to ensure that antacids are used in an optimal, safe, and effective manner.
Collapse
Affiliation(s)
- Vandana Garg
- Medical Innovation Director, GSK Consumer Healthcare Pte Ltd., Singapore
| | - Prashant Narang
- Medical Affairs Director, GSK Consumer Healthcare Pte Ltd., Gurugram (Haryana), India
| | - Ritu Taneja
- Senior Director, Innovation and Localization Lead, GSK Consumer Healthcare Pte Ltd., Singapore
| |
Collapse
|
|
9
|
Odze RD, Goldblum J, Kaul V. Role of Wide-Area Transepithelial Sampling With 3D Computer-Assisted Analysis in the Diagnosis and Management of Barrett's Esophagus. Clin Transl Gastroenterol 2021; 12:e00422. [PMID: 34874019 PMCID: PMC8751778 DOI: 10.14309/ctg.0000000000000422] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022] Open
Abstract
Barrett's esophagus (BE) is a premalignant condition in which cancer prevention is performed by endoscopic surveillance combined with Seattle protocol mucosal biopsies. The Seattle protocol has significant limitations, including a high rate of sampling error due to the focality of dysplasia/carcinoma, low endoscopist adherence to the protocol, and a high degree of variability in pathologic interpretation. These factors all contribute to a high incidence of cancers missed within 1 year of surveillance endoscopy. Wide-area transepithelial sampling with computer-assisted three-dimensional analysis (WATS3D) is a relatively new technique that minimizes sampling error by using a brush biopsy device that extensively samples "at risk" mucosa and helps pathologists diagnose dysplasia/neoplasia by generating three-dimensional images of whole crypts using a neural network-based software program. Several large prospective trials (involving both academic and community practices) have shown significantly increased rates of detection of dysplasia and intestinal metaplasia in both screening and surveillance in patients with BE when used as an adjunct to Seattle protocol-based forceps biopsies. The WATS3D diagnostic platform was included in the most recent American Society for Gastrointestinal Endoscopy Barrett's guideline as an adjunct to forceps biopsies (conditional recommendation and low quality of evidence). This review summarizes the scientific and pathologic basis of WATS3D technology, its potential impact on BE surveillance and management, and its limitations and future directions.
Collapse
Affiliation(s)
| | - John Goldblum
- Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Vivek Kaul
- Division of Gastroenterology and Hepatology, University of Rochester Medical Center, Rochester, New York, USA
| |
Collapse
|
|
10
|
Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells. Cancers (Basel) 2021; 13:cancers13112806. [PMID: 34199909 PMCID: PMC8200109 DOI: 10.3390/cancers13112806] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Inflammation caused by acidic reflux contributes to disease progression in Barrett’s esophagus. Little is known, whether esophageal cancer cells are influenced by acidic reflux and whether reflux influences cancer cell physiology, targeting the Nrf2/Kepa1- and the NFκB-pathway. The understanding mechanisms of the acidic susceptibility in cells from advanced stages of Barrett’s esophagus will provide further evidence, whether it should be prevented during chemotherapy for EAC treatment. Abstract Chronic acid reflux causes cellular damage and inflammation in the lower esophagus. Due to these irritating insults, the squamous epithelium is replaced by metaplastic epithelium, which is a risk factor for the development of esophageal adenocarcinoma (EAC). In this study, we investigated the acid susceptibility in a Barrett’s cell culture in vitro model, using six cell lines, derived from squamous epithelium (EPC1 and EPC2), metaplasia (CP-A), dysplasia (CP-B), and EAC (OE33 and OE19) cells. Cells exposed to acidic pH showed a decreased viability dependent on time, pH, and progression status in the Barrett’s sequence, with the highest acid susceptibility in the squamous epithelium (EPC1 and EPC2), and the lowest in EAC cells. Acid pulsing was accompanied with an activation of the Nrf2/Keap1- and the NFκB-pathway, resulting in an increased expression of HO1—independent of the cellular context. OE33 showed a decreased responsiveness towards 5-FU, when the cells were grown in acidic conditions (pH 6 and pH 5.5). Our findings suggest a strong damage of squamous epithelium by gastroesophageal reflux, while Barrett’s dysplasia and EAC cells apparently exert acid-protective features, which lead to a cellular resistance against acid reflux.
Collapse
|
|
11
|
Global burden and epidemiology of Barrett oesophagus and oesophageal cancer. Nat Rev Gastroenterol Hepatol 2021; 18:432-443. [PMID: 33603224 DOI: 10.1038/s41575-021-00419-3] [Citation(s) in RCA: 184] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/14/2021] [Indexed: 02/07/2023]
Abstract
Oesophageal cancer is a global health problem; in 2018 there were more than 572,000 people newly diagnosed with oesophageal cancer worldwide. There are two main histological subtypes of oesophageal cancer, oesophageal adenocarcinoma (EAC) and oesophageal squamous cell carcinoma (ESCC), and there has been a dramatic shift in its epidemiology. While the incidence of EAC and its precursor lesion, Barrett oesophagus, has increased in Western populations over the past four decades, the incidence of ESCC has declined in most parts of the world over the same period. ESCC still accounts for the vast majority of all oesophageal cancer cases diagnosed worldwide each year. Prognosis for patients with oesophageal cancer is strongly related to stage at diagnosis. As most patients are diagnosed with late-stage disease, overall 5-year survival for oesophageal cancer remains <20%. Knowledge of epidemiology and risk factors for oesophageal cancer is essential for public health and clinical decisions about risk stratification, screening and prevention. The goal of this Review is to establish the current epidemiology of oesophageal cancer, with a particular focus on the Western world and the increasing incidence of EAC and Barrett oesophagus.
Collapse
|
|
12
|
Key molecules involved in the Th17/Treg balance are associated with the pathogenesis of reflux esophagitis and Barrett's esophagus. Esophagus 2021; 18:388-397. [PMID: 32920737 DOI: 10.1007/s10388-020-00773-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 08/24/2020] [Indexed: 02/03/2023]
Abstract
BACKGROUND Reflux esophagitis (RE) impairs the squamous epithelium that normally lines the esophagus, and contributes to the replacement of the damaged squamous lining by the intestinal metaplasia of Barrett's esophagus (BE), which is considered as a precursor of esophageal adenocarcinoma. This study aimed to investigate the changes in the balance of Th17/Treg and the related key molecules in the pathogenesis of RE and BE and evaluate the diagnostic and predictive value of the molecules in patients with these diseases. METHODS The proportions of Th17 and Treg in RE and BE patients were estimated using flow cytometric analysis. Key molecules involving in the Th17/Treg balance, including RORγt, Foxp3, IL-17, IL-6, IL-10, and TGF-β, were measured using quantitative real-time PCR (qRT-PCR) and ELISA analyses. The diagnostic and predictive value of the Th17/Treg ratio and its key regulators was evaluated using a receiver operating characteristic assay (ROC). In addition, the Spearman correlation analysis explored the relationship between the Th17/Treg ratio and the clinical characteristics. RESULTS An increased ratio of Th17/Treg was observed in RE and BE compared with the normal controls, and the proportion of Th17/Treg in BE was further increased compared with RE patients. Moreover, the expression levels of RORγt, IL-17, IL-6, and TGF-β were elevated, while the levels of Foxp3 and IL-10 were reduced in patients when compared to the controls. Compared with the RE groups, the levels of IL-17 were significantly higher in BE patients, while the Foxp3 levels were significant decreased. In addition, the Th17/Treg ratio also showed high diagnostic significance and considerable predictive value for the clinical outcomes in patients with RE and BE. CONCLUSION The balance of Th17/Treg was impaired in patients with RE and BE. Th17/Treg may be involved in the development of both RE and BE through regulating the release of inflammatory cytokines, but the concrete mechanisms maybe different in the two diseases. The imbalance of Th17/Treg ratio and the related key molecules had a certain clinical diagnosis and prediction potential for RE and BE.
Collapse
|
|
13
|
Masoudi SF, Baratian S, Asadi S, Rasouli FS. Dose reduction in HDR brachytherapy of esophageal cancer using gold and gold alloy plaques: a Monte Carlo study. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2021; 60:115-124. [PMID: 33389051 DOI: 10.1007/s00411-020-00885-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 11/30/2020] [Indexed: 06/12/2023]
Abstract
In this work, the use of gold and gold alloy plaques is proposed for the first time, to reduce the dose to healthy organs in brachytherapy with Ir-192 sources. For dose simulations in tumour and healthy tissue, the MCNPX Monte Carlo code was used. The radiation source implemented in those simulations was benchmarked with well-known TG-43 criteria of dose rate constant, air-kerma strength, radial dose function, and 2D anisotropy function. For various arrangements of iridium sources and plaques of gold and gold alloy of various thicknesses, the dose distributions in an esophagus tumour and in surrounding healthy organs were simulated. The results showed that while the dose to the tumour is not much affected by the presence of gold plaques with a thickness of 3.5 mm in an optimized 192Ir sources' configuration, a relative reduction in average organ dose of 64%, 65%, 73%, 67%, and 35% was observed, for esophagus, thyroid, heart, stomach, and liver, respectively. Moreover, it was found that a gold plaque leads to smaller doses to healthy organs than a gold alloy plaque. It is concluded that gold plaques can be used to improve the treatment of esophageal cancer by HDR brachytherapy and to protect surrounding non-target organs.
Collapse
Affiliation(s)
- S Farhad Masoudi
- Department of Physics, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran.
| | - Shokoufeh Baratian
- Department of Physics, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
| | - Somayeh Asadi
- Department of Mechanical Engineering, Politecnico Di Milano, Milan, Italy
| | - Fatemeh S Rasouli
- Department of Physics, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
| |
Collapse
|
|
14
|
Okereke IC, Miller AL, Jupiter DC, Hamilton CF, Reep GL, Krill T, Andersen CR, Pyles RB. Microbiota Detection Patterns Correlate With Presence and Severity of Barrett's Esophagus. Front Cell Infect Microbiol 2021; 11:555072. [PMID: 33708643 PMCID: PMC7942024 DOI: 10.3389/fcimb.2021.555072] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 01/05/2021] [Indexed: 01/10/2023] Open
Abstract
Background The microbiome has been increasingly associated with different disease processes, but its role in esophagus is largely unknown. Our goal was to determine the associations of the esophageal microbiota with Barrett’s esophagus. Methods A total of 74 patients were included in this prospective study, including 34 patients with Barrett’s esophagus and 40 patients without Barrett’s esophagus. Esophageal swabs were obtained from the uvula, and mucosal biopsies were obtained from the proximal esophagus and distal esophagus in each patient. The microbiome of each sample was assessed using a customized Esophageal Microbiome qPCR array (EMB). For each clinical sample, we completed a detection/non-detection analysis for each organism in the EMB. The limit of detection (LOD) for each target was established by analysis of plasmid dilutions. Results Average age was 60.2 years. There were significantly different microbial detection patterns in patients with Barrett’s esophagus compared to the control population. There were a greater number of organisms which had different likelihoods of detection in the distal esophagus, compared to the proximal esophagus or uvula. In addition, as the length of the Barrett’s column increased, multiple organisms were less likely to be detected. This decreased likelihood occurred only in the distal esophagus. Beside Barrett’s esophagus, no other demographic factors were associated with differences in detection patterns. Conclusions Microbial community structures differ between patients with and without Barrett’s esophagus. Certain organisms are less likely to be detected as the severity of Barrett’s esophagus worsens. These results suggest that particular organisms may have a protective effect against the development of Barrett’s esophagus.
Collapse
Affiliation(s)
- Ikenna C Okereke
- Division of Cardiothoracic Surgery, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Aaron L Miller
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX , United States
| | - Daniel C Jupiter
- Department of Preventive Medicine and Population Health, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Catherine F Hamilton
- Division of Cardiothoracic Surgery, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Gabriel L Reep
- Division of Gastroenterology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Timothy Krill
- Division of Gastroenterology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Clark R Andersen
- Department of Preventive Medicine and Population Health, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Richard B Pyles
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX , United States
| |
Collapse
|
|
15
|
Bornschein J, Quante M, Jansen M. The complexity of cancer origins at the gastro-oesophageal junction. Best Pract Res Clin Gastroenterol 2021; 50-51:101729. [PMID: 33975686 DOI: 10.1016/j.bpg.2021.101729] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/08/2021] [Indexed: 01/31/2023]
Abstract
Chronic acid-biliary reflux and Helicobacter pylori infection are instrumental environmental drivers of cancer initiation and progression in the upper gastrointestinal tract. Remarkably, although these environmental carcinogens are quite dissimilar, the tumour progression cascade these carcinogens engender is highly comparable. For this reason, studies of malignant progression occurring at the anatomic borderland between the oesophagus and the stomach have traditionally lumped junctional adenocarcinomas with either oesophageal adenocarcinoma or gastric adenocarcinoma. Whilst studies have revealed remarkable epidemiological and genetic similarities of these cancers and their associated premalignant conditions, these works have also revealed some key differences. This highlights that further scientific effort demands a dedicated focus on the understanding of the cell-cell interaction between the epithelium and the local microenvironment in this anatomic region. We here review available evidence with regards to tumour progression occurring at the gastro-oesophageal junction and contrast it with available data on cancer evolution in the metaplastic oesophagus and distal stomach.
Collapse
Affiliation(s)
- Jan Bornschein
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom and NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
| | - Michael Quante
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Germany
| | | |
Collapse
|
|
16
|
Singer ME, Smith MS. Wide Area Transepithelial Sampling with Computer-Assisted Analysis (WATS 3D) Is Cost-Effective in Barrett's Esophagus Screening. Dig Dis Sci 2021; 66:1572-1579. [PMID: 32578042 PMCID: PMC8053177 DOI: 10.1007/s10620-020-06412-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 06/12/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Wide area transepithelial sampling with three-dimensional computer-assisted analysis (WATS3D) is an adjunct to the standard random 4-quadrant forceps biopsies (FB, "Seattle protocol") that significantly increases the detection of Barrett's esophagus (BE) and associated neoplasia in patients undergoing screening or surveillance. AIMS To examine the cost-effectiveness of adding WATS3D to the Seattle protocol in screening patients for BE. METHODS A decision analytic model was used to compare the effectiveness and cost-effectiveness of two alternative BE screening strategies in chronic gastroesophageal reflux disease patients: FB with and without WATS3D. The reference case was a 60-year-old white male with gastroesophageal reflux disease (GERD). Effectiveness was measured by the number needed to screen to avert one cancer and one cancer-related death, and quality-adjusted life years (QALYs). Cost was measured in 2019 US$, and the incremental cost-effectiveness ratio (ICER) was measured in $/QALY using thresholds for cost-effectiveness of $100,000/QALY and $150,000/QALY. Cost was measured in 2019 US$. Cost and QALYs were discounted at 3% per year. RESULTS Between 320 and 337 people would need to be screened with WATS3D in addition to FB to avert one additional cancer, and 328-367 people to avert one cancer-related death. Screening with WATS3D costs an additional $1219 and produced an additional 0.017 QALYs, for an ICER of $71,395/QALY. All one-way sensitivity analyses resulted in ICERs under $84,000/QALY. CONCLUSIONS Screening for BE in 60-year-old white male GERD patients is more cost-effective when WATS3D is used adjunctively to the Seattle protocol than with the Seattle protocol alone.
Collapse
Affiliation(s)
- Mendel E. Singer
- Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH USA
| | - Michael S. Smith
- Division of Gastroenterology and Hepatology, Mount Sinai West and Mount Sinai Morningside Hospitals, Icahn School of Medicine at Mount Sinai, Ambulatory Care Center, 13th Floor, 440 W 114th St., New York, NY 10025 USA
| |
Collapse
|
|
17
|
Loomans-Kropp HA, Chaloux M, Richmond E, Umar A. Association of Common Use Pharmaceuticals in Reducing Risk of Esophageal Adenocarcinoma: A SEER-Medicare Analysis. Cancer Prev Res (Phila) 2020; 14:195-204. [PMID: 32998939 DOI: 10.1158/1940-6207.capr-20-0274] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 08/15/2020] [Accepted: 09/17/2020] [Indexed: 12/24/2022]
Abstract
Barrett's esophagus (BE), a recognized risk factor for esophageal adenocarcinoma (EAC), is routinely managed with proton pump inhibitors (PPIs) when symptomatic. Several lines of evidence suggest that PPIs may prevent malignant transformation. Chronic use of other common drugs, namely, statins nonsteroidal anti-inflammatory drugs (NSAIDs) and metformin, may also interfere with BE carcinogenesis, but confirmatory evidence is lacking. We identified 1,943 EAC cases and 19,430 controls (matched 10:1) between 2007 and 2013 that met our specified inclusion criteria in the SEER-Medicare database. Conditional logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (95% CI). Wald χ2 tests were used to assess significance of covariates. Compared with controls, EAC cases had a higher prevalence of BE (26.2%). Use of PPIs, NSAIDs, statins, or metformin reduced the odds of EAC (PPIs: 0.10; 95% CI, 0.09-0.12; NSAIDs: 0.62; 95% CI, 0.51-0.74; statins: 0.15; 95% CI, 0.13-0.17; metformin: 0.76; 95% CI, 0.62-0.93). When stratified by BE, these associations persisted, though no association was found between NSAID use and EAC risk for participants with BE. Dual use of PPIs with NSAIDs or statins, and NSAID, statin, or metformin use alone also showed significant EAC risk reduction among all participants and those without BE. Use of PPIs alone and with NSAIDs, statins, or metformin was associated with reduced risk of EAC; however, a history of BE may diminish drug efficacy. These results indicate that common pharmacologic agents alone or in combination may decrease EAC development.Prevention Relevance: The use of common drugs, such as proton pump inhibitors, statins, non-steroidal anti-inflammatory drugs, or metformin, may reduce one's risk of developing esophageal adenocarcinoma. These results suggest that repurposing agents often used for common chronic conditions may be a new strategy for cancer prevention efforts.
Collapse
Affiliation(s)
- Holli A Loomans-Kropp
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, NCI, Bethesda, Maryland. .,Gastrointestinal and Other Cancers Research Group, Division of Cancer Prevention, NCI, Bethesda, Maryland
| | | | - Ellen Richmond
- Gastrointestinal and Other Cancers Research Group, Division of Cancer Prevention, NCI, Bethesda, Maryland
| | - Asad Umar
- Gastrointestinal and Other Cancers Research Group, Division of Cancer Prevention, NCI, Bethesda, Maryland
| |
Collapse
|
|
18
|
Sali R, Moradinasab N, Guleria S, Ehsan L, Fernandes P, Shah TU, Syed S, Brown DE. Deep Learning for Whole-Slide Tissue Histopathology Classification: A Comparative Study in the Identification of Dysplastic and Non-Dysplastic Barrett's Esophagus. J Pers Med 2020; 10:E141. [PMID: 32977465 PMCID: PMC7711456 DOI: 10.3390/jpm10040141] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 11/16/2022] Open
Abstract
The gold standard of histopathology for the diagnosis of Barrett's esophagus (BE) is hindered by inter-observer variability among gastrointestinal pathologists. Deep learning-based approaches have shown promising results in the analysis of whole-slide tissue histopathology images (WSIs). We performed a comparative study to elucidate the characteristics and behaviors of different deep learning-based feature representation approaches for the WSI-based diagnosis of diseased esophageal architectures, namely, dysplastic and non-dysplastic BE. The results showed that if appropriate settings are chosen, the unsupervised feature representation approach is capable of extracting more relevant image features from WSIs to classify and locate the precursors of esophageal cancer compared to weakly supervised and fully supervised approaches.
Collapse
Affiliation(s)
- Rasoul Sali
- Department of Systems and Information Engineering, University of Virginia, Charlottesville, VA 22904, USA; (R.S.); (N.M.)
| | - Nazanin Moradinasab
- Department of Systems and Information Engineering, University of Virginia, Charlottesville, VA 22904, USA; (R.S.); (N.M.)
| | - Shan Guleria
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA;
| | - Lubaina Ehsan
- School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; (L.E.); (P.F.)
| | - Philip Fernandes
- School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; (L.E.); (P.F.)
| | - Tilak U. Shah
- Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA 23249, USA;
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA 23219, USA
| | - Sana Syed
- School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; (L.E.); (P.F.)
| | - Donald E. Brown
- Department of Systems and Information Engineering, University of Virginia, Charlottesville, VA 22904, USA; (R.S.); (N.M.)
- School of Data Science, University of Virginia, Charlottesville, VA 22904, USA
| |
Collapse
|
|
19
|
Lazăr DC, Avram MF, Faur AC, Goldiş A, Romoşan I, Tăban S, Cornianu M. The Impact of Artificial Intelligence in the Endoscopic Assessment of Premalignant and Malignant Esophageal Lesions: Present and Future. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:364. [PMID: 32708343 PMCID: PMC7404688 DOI: 10.3390/medicina56070364] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 07/13/2020] [Accepted: 07/16/2020] [Indexed: 02/07/2023]
Abstract
In the gastroenterology field, the impact of artificial intelligence was investigated for the purposes of diagnostics, risk stratification of patients, improvement in quality of endoscopic procedures and early detection of neoplastic diseases, implementation of the best treatment strategy, and optimization of patient prognosis. Computer-assisted diagnostic systems to evaluate upper endoscopy images have recently emerged as a supporting tool in endoscopy due to the risks of misdiagnosis related to standard endoscopy and different expertise levels of endoscopists, time-consuming procedures, lack of availability of advanced procedures, increasing workloads, and development of endoscopic mass screening programs. Recent research has tended toward computerized, automatic, and real-time detection of lesions, which are approaches that offer utility in daily practice. Despite promising results, certain studies might overexaggerate the diagnostic accuracy of artificial systems, and several limitations remain to be overcome in the future. Therefore, additional multicenter randomized trials and the development of existent database platforms are needed to certify clinical implementation. This paper presents an overview of the literature and the current knowledge of the usefulness of different types of machine learning systems in the assessment of premalignant and malignant esophageal lesions via conventional and advanced endoscopic procedures. This study makes a presentation of the artificial intelligence terminology and refers also to the most prominent recent research on computer-assisted diagnosis of neoplasia on Barrett's esophagus and early esophageal squamous cell carcinoma, and prediction of invasion depth in esophageal neoplasms. Furthermore, this review highlights the main directions of future doctor-computer collaborations in which machines are expected to improve the quality of medical action and routine clinical workflow, thus reducing the burden on physicians.
Collapse
Affiliation(s)
- Daniela Cornelia Lazăr
- Department V of Internal Medicine I, Discipline of Internal Medicine IV, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timișoara, Romania; (D.C.L.); (I.R.)
| | - Mihaela Flavia Avram
- Department of Surgery X, 1st Surgery Discipline, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timișoara, Romania
| | - Alexandra Corina Faur
- Department I, Discipline of Anatomy and Embriology, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timișoara, Romania;
| | - Adrian Goldiş
- Department VII of Internal Medicine II, Discipline of Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timișoara, Romania;
| | - Ioan Romoşan
- Department V of Internal Medicine I, Discipline of Internal Medicine IV, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timișoara, Romania; (D.C.L.); (I.R.)
| | - Sorina Tăban
- Department II of Microscopic Morphology, Discipline of Pathology, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timișoara, Romania; (S.T.); (M.C.)
| | - Mărioara Cornianu
- Department II of Microscopic Morphology, Discipline of Pathology, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timișoara, Romania; (S.T.); (M.C.)
| |
Collapse
|
|
20
|
Johncilla M, Odze RD, Agoston AT. Role of submucosal glands in the development and progression of carcinoma in Barrett's oesophagus. Pathology 2020; 52:310-317. [PMID: 32122647 DOI: 10.1016/j.pathol.2019.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 12/09/2019] [Accepted: 12/19/2019] [Indexed: 11/29/2022]
Abstract
Oesophageal submucosal glands secrete mucins and other chemicals that are believed to serve as protectants of the mucosal surface from luminal noxious agents, either ingested or refluxed. Changes in the type, distribution or number of submucosal glands may contribute to, or be associated with, the development of Barrett's oesophagus and progression to cancer. The aim of this study was to investigate the anatomical, morphological and immunohistochemical characteristics of submucosal glands in Barrett's oesophagus-associated neoplasia in 64 oesophageal resections for Barrett's oesophagus-associated adenocarcinoma and 32 squamous cell carcinomas (as a control group). Gland density was not significantly different between the oesophageal adenocarcinoma (0.91/cm) and squamous cell carcinoma (0.81/cm) groups (p=0.7). In the oesophageal adenocarcinoma group, glands underlying Barrett's oesophagus-associated neoplastic epithelium showed a significant decrease in the percentage of mucinous acini and a significant increase in the percentage of atrophic acini compared to glands underlying epithelium without dysplasia or carcinoma (74% vs 83%, p=0.03; and 24% vs 14%, p=0.01). There was also an increase in the percentage of glands with moderate to severe inflammation underlying neoplastic epithelium compared to glands underlying epithelium without dysplasia or carcinoma (53% vs 33%, p=0.001). None of these differences was seen in the squamous cell carcinoma group. The immunohistochemical characteristics of the different histological subtypes were also distinct. Atrophic and oncocytic acini were diffusely and strongly positive for CK7, SOX2, SOX9 and CK5/6 (a progenitor cell phenotype) while mucinous acini showed weak or moderate staining for those markers. Our results suggest that submucosal glands play a role in the progression of neoplasia, possibly by offering less protection to the mucosal surface of the oesophageal epithelium from chemical injury.
Collapse
Affiliation(s)
- Melanie Johncilla
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
| | - Robert D Odze
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Agoston T Agoston
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
21
|
Kaul V, Bittner K, Ullah A, Kothari S. Liquid nitrogen spray cryotherapy-based multimodal endoscopic management of dysplastic Barrett's esophagus and early esophageal neoplasia: retrospective review and long-term follow-up at an academic tertiary care referral center. Dis Esophagus 2020; 33:5697877. [PMID: 31909783 PMCID: PMC7150654 DOI: 10.1093/dote/doz095] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Endoscopic eradication therapy of dysplastic Barrett's esophagus (BE) and early esophageal neoplasia has emerged as an effective treatment option. Data for the role of spray cryotherapy (SCT) in this setting is relatively limited. OBJECTIVE To evaluate the safety and long-term outcomes of SCT-based multimodal therapy in the management of dysplastic BE and early esophageal neoplasia. DESIGN Single-center, retrospective, cohort study. SETTING Academic, tertiary care center between August 2008 and February 2019. METHODS A retrospective chart review was conducted of the prospectively maintained endoscopic cryotherapy database at our center. Fifty-seven patients were identified who underwent SCT treatment for dysplastic BE and esophageal or Gastro-esophageal (GE) junction adenocarcinoma during the study period. Primary outcome was complete eradication of intestinal metaplasia (CE-IM); secondary outcome was complete eradication of dysplasia (CE-D). RESULTS A total of 171 SCT procedures were performed in 57 patients. The majority of patients were male (89.5%) with long-segment BE (93%; mean segment length 6.2 cm). Complete follow-up data was available for 56 of these 57 patients. 43.9% (25/57) of patients underwent radiofrequency ablation (RFA) during the course of treatment (e.g. after initiating SCT). 33.3% of patients (19/57) were RFA failures prior to SCT. Additionally, 68.4% (39/57) of patients underwent endoscopic resection (EMR) prior to SCT as part of our multimodal approach to treatment of BE dysplasia/neoplasia. Four patients (7%) are currently undergoing active ablation and/or EMR treatment. CE-IM was achieved in 75% (39/52) of patients, and CE-D in 98.1% (51/52). Mean duration of overall follow-up was 4.8 years, with mean CE-IM durability of 2.6 years. LIMITATIONS Single-center only, retrospective study design. CONCLUSION SCT-based multimodal endoscopic therapy can achieve very high CE-IM (75%) and CE-D (>98%) rates in a high-risk population with esophageal dysplasia and/or neoplasia.
Collapse
Affiliation(s)
- Vivek Kaul
- Division of Gastroenterology and Hepatology, University of Rochester Medical Center and Strong Memorial Hospital, Rochester, NY, USA,Address correspondence to: Vivek Kaul, MD, FACG, FASGE, AGAF, Segal-Watson Professor of Medicine, Chief, Division of Gastroenterology and Hepatology, University of Rochester Medical Center and Strong Memorial Hospital, 601 Elmwood Avenue, Box 646, Rochester, NY 14642, USA;
| | - Krystle Bittner
- Division of Gastroenterology and Hepatology, University of Rochester Medical Center and Strong Memorial Hospital, Rochester, NY, USA
| | - Asad Ullah
- Division of Gastroenterology and Hepatology, University of Rochester Medical Center and Strong Memorial Hospital, Rochester, NY, USA
| | - Shivangi Kothari
- Division of Gastroenterology and Hepatology, University of Rochester Medical Center and Strong Memorial Hospital, Rochester, NY, USA
| |
Collapse
|
|
22
|
Specific DNA methylation markers in the diagnosis and prognosis of esophageal cancer. Aging (Albany NY) 2019; 11:11640-11658. [PMID: 31834866 PMCID: PMC6932928 DOI: 10.18632/aging.102569] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 11/23/2019] [Indexed: 12/14/2022]
Abstract
The early diagnosis and accurate prognosis prediction of esophageal cancer is an essential part of improving survival. However, these diseases lack effective and specific markers. A total of 1,744 samples of HumanMethylation450 data were integrated to identify and validate specific methylation markers for esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) as well as for Barrett's esophagus (BE) using The Cancer Genome Atlas and the Gene Expression Omnibus. The diagnostic and prognostic methylation classifiers were constructed by moderated t-statistics and the least absolute shrinkage and selection operator method. The diagnostic methylation classifier using 12 CpG sites was constructed in training set (377 samples) that could effectively discriminate samples of BE, EAC, and ESCC from normal tissue (AUC = 0.992), which achieved highly predictive ability in both internal (187 samples, AUC = 0.990) and external validation (184 samples, AUC = 0.978). The prognostic methylation classifier with 3 CpG and 2 CpG sites for EAC and ESCC respectively, could accurately estimate the prognosis of an individual patient and improved the predictive ability of the tumor node metastasis staging system. Overall, our study systematically analyzed large-scale methylation data and provided promising markers for the diagnosis and prognosis of esophageal cancer.
Collapse
|
|
23
|
Mukaisho KI, Kanai S, Kushima R, Nakayama T, Hattori T, Sugihara H. Barretts's carcinogenesis. Pathol Int 2019; 69:319-330. [PMID: 31290583 PMCID: PMC6851828 DOI: 10.1111/pin.12804] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 03/22/2019] [Indexed: 12/14/2022]
Abstract
Barrett's esophagus is considered a precancerous lesion of esophageal adenocarcinoma (EAC). Long‐segment Barrett's esophagus, which is generally associated with intestinal metaplasia, has a higher rate of carcinogenesis than short‐segment Barrett's esophagus, which is mainly composed of cardiac‐type mucosa. However, a large number of cases reportedly develop EAC from the cardiac‐type mucosa which has the potential to involve intestinal phenotypes. There is no consensus regarding whether the definition of Barrett's epithelium should include intestinal metaplasia. Basic researches using rodent models have provided information regarding the origins of Barrett's epithelium. Nevertheless, it remains unclear whether differentiated gastric columnar epithelium or stratified esophageal squamous epithelium undergo transdifferentiation into the intestinal‐type columnar epithelium, transcommittment into the columnar epithelium, or whether the other pathways exist. Reflux of duodenal fluid including bile acids into the stomach may occur when an individual lies down after eating, which could cause the digestive juices to collect in the fornix of the stomach. N‐nitroso‐bile acids are produced with nitrites that are secreted from the salivary glands, and bile acids can drive expression of pro‐inflammatory cytokines via EGFR or the NF‐κB pathway. These steps may contribute significantly to carcinogenesis.
Collapse
Affiliation(s)
- Ken-Ichi Mukaisho
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Shunpei Kanai
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Ryoji Kushima
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Takahisa Nakayama
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Takanori Hattori
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Hiroyuki Sugihara
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| |
Collapse
|
|
24
|
Christman EM, Chandrakesan P, Weygant N, Maple JT, Tierney WM, Vega KJ, Houchen CW. Elevated doublecortin-like kinase 1 serum levels revert to baseline after therapy in early stage esophageal adenocarcinoma. Biomark Res 2019; 7:5. [PMID: 30899515 PMCID: PMC6408757 DOI: 10.1186/s40364-019-0157-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/27/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) incidence has been increasing in the United States for greater than 30 years. For the majority of EAC patients, treatment is limited and prognosis poor. Doublecortin like kinase-1 (DCLK1) is a cancer stem cell marker with elevated expression in BE patients with high grade dysplasia and/or EAC. This prospective cohort study was designed to compare serum DCLK1 levels before and after EAC treatment with endoscopic mucosal resection (EMR) and/or radio-frequency ablation (RFA). METHODS Barrett's esophagus patients with low or high-grade dysplasia (n = 9) and EAC patients (Stage I/II) eligible for treatment were enrolled (n = 14). Serum was obtained at enrollment and at end of treatment (EoT) where possible (n = 6). Normal control samples (n = 5) were obtained from patients with normal upper endoscopies. Serum was analyzed for DCLK1 protein content by ELISA. Kruskal-Wallis, Mann Whitney U, Pearson correlation, and Receiver Operating Characteristic tests were used to analyze the data. RESULTS Serum DCLK1 levels were increased by > 50% in Barrett's Esophagus (n = 9) and EAC patients (n = 14) vs controls (n = 5, p = 0.0007). These levels were reduced > 50% at EoT compared to EAC (p = 0.033). Although age was significantly lower in controls, this factor was not statistically related to DCLK1 serum levels (p = 0.66). CONCLUSIONS EAC treatment results in significantly decreased serum DCLK1 levels, suggesting that DCLK1 may be useful as a non-invasive disease regression biomarker following treatment. IMPACT Biomarkers for EAC therapeutic response have been poorly studied and no reliable marker has been discovered thus far. These results demonstrate that DCLK1 may have potential as a circulating biomarker of the response to therapy in EAC, which could be used to improve patient outcomes.
Collapse
Affiliation(s)
- Emily M. Christman
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - Parthasarathy Chandrakesan
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
- Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK USA
| | - Nathaniel Weygant
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - John T. Maple
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - William M. Tierney
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - Kenneth J. Vega
- Department of Medicine, Division of Gastroenterology and Hepatology, Augusta University-Medical College of Georgia, 1120 15th Street, AD 2226, Augusta, GA 30912 USA
| | - Courtney W. Houchen
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
- Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK USA
| |
Collapse
|
|
25
|
Li K, Liang W, Mavadia-Shukla J, Park HC, Li D, Yuan W, Wan S, Li X. Super-achromatic optical coherence tomography capsule for ultrahigh-resolution imaging of esophagus. JOURNAL OF BIOPHOTONICS 2019; 12:e201800205. [PMID: 30302923 PMCID: PMC6416074 DOI: 10.1002/jbio.201800205] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/08/2018] [Indexed: 05/19/2023]
Abstract
Endoscopic optical coherence tomography (OCT) is a noninvasive technology allowing for imaging of tissue microanatomies of luminal organs in real time. Conventional endoscopic OCT operates at 1300 nm wavelength region with a suboptimal axial resolution limited to 8-20 μm. In this paper, we present the first ultrahigh-resolution tethered OCT capsule operating at 800 nm and offering about 3- to 4-fold improvement of axial resolution (plus enhanced imaging contrast). The capsule uses diffractive optics to manage chromatic aberration over a full ~200 nm spectral bandwidth centering around 830 nm, enabling to achieve super-achromaticity and an axial resolution of ~2.6 μm in air. The performance of the OCT capsule is demonstrated by volumetric imaging of swine esophagus ex vivo and sheep esophagus in vivo, where fine anatomic structures including the sub-epithelial layers are clearly identified. The ultrahigh resolution and excellent imaging contrast at 800 nm of the tethered capsule suggest the potential of the technology as an enabling tool for surveillance of early esophageal diseases on awake patients without the need for sedation.
Collapse
Affiliation(s)
| | - Wenxuan Liang
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA 21205
| | - Jessica Mavadia-Shukla
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA 21205
| | - Hyeon-Cheol Park
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA 21205
| | - Dawei Li
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA 21205
| | - Wu Yuan
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA 21205
| | - Suiren Wan
- School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China 210096
| | - Xingde Li
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA 21205
| |
Collapse
|
|
26
|
Smith MS, Ikonomi E, Bhuta R, Iorio N, Kataria RD, Kaul V, Gross SA. Wide-area transepithelial sampling with computer-assisted 3-dimensional analysis (WATS) markedly improves detection of esophageal dysplasia and Barrett's esophagus: analysis from a prospective multicenter community-based study. Dis Esophagus 2018; 32:5239642. [PMID: 30541019 PMCID: PMC6403460 DOI: 10.1093/dote/doy099] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/05/2018] [Accepted: 09/27/2018] [Indexed: 02/06/2023]
Abstract
The 4-quadrant forceps biopsy (FB) protocol for identifying Barrett's esophagus (BE) and esophageal dysplasia (ED) suffers from poor sensitivity due to significant sampling error. We investigated the benefit of wide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS) used adjunctively to the combination of random and targeted FB in the detection of ED, and as a secondary outcome, BE. In this multicenter prospective trial, community endoscopists at 21 sites utilized WATS as an adjunct to both targeted and random FB in patients undergoing BE screening and surveillance. Investigators alternated taking FB and WATS samples first. WATS specimens were analyzed at CDx Diagnostics (Suffern, NY) while FB samples were analyzed by each site's regular pathologists. Data were de-identified and then aggregated for analysis. Of 12,899 patients enrolled, FB identified 88 cases of ED, and WATS detected an additional 213 cases missed by FB. These 213 cases represented an absolute increase of 1.65%, raising the yield from 0.68% to 2.33%. Adding WATS to FB increased the overall detection of ED by 242% (95% CI: 191%-315%). Fewer than 61 patients needed to be tested with WATS to identify an additional case of ED. The combination of random and targeted FB identified 1,684 cases of BE, and WATS detected an additional 2,570 BE cases. The absolute incremental yield of adding WATS to FB is 19.9%, increasing the rate of detection from 13.1% to 33%. Adding WATS to FB increased the overall detection of BE by 153% (95% CI: 144-162%). The number needed to test with WATS in order to detect an additional case of BE was 5. Whether FB or WATS was done first did not impact the results. In this study, comprised of the largest series of patients evaluated with WATS, adjunctive use of the technique with targeted and random FB markedly improved the detection of both ED and BE. These results underscore the shortcomings of FB in detecting BE-associated neoplasia, which can potentially impact the management and clinical outcomes of these patients.
Collapse
Affiliation(s)
- M S Smith
- Gastroenterology and Hepatology, Mount Sinai West & Mount Sinai St. Luke's Hospitals, New York, NY, USA,Address correspondence to: Michael S. Smith, MD, MBA, Gastroenterology and Hepatology, Mount Sinai West & Mount Sinai St. Luke's Hospitals, 1111 Amsterdam Avenue, S&R Building, 13th Floor, New York, NY 10025, USA.
| | - E Ikonomi
- Gastroenterology and Hepatology, Hahnemann University Hospital, Philadelphia, PA, USA
| | - R Bhuta
- Gastroenterology, Temple University Hospital, Philadelphia, PA, USA
| | - N Iorio
- Gastroenterology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - R D Kataria
- Gastroenterology, Temple University Hospital, Philadelphia, PA, USA
| | - V Kaul
- Gastroenterology, University of Rochester Medical Center, Rochester, NY, USA
| | - S A Gross
- Gastroenterology, New York University Langone Medical Center, New York, NY, USA
| | | |
Collapse
|
|
27
|
Chilukuri P, Gromski MA, Johnson CS, Ceppa DKP, Kesler KA, Birdas TJ, Rieger KM, Fatima H, Kessler WR, Rex DK, Al-Haddad M, DeWitt JM. Impact of the development of an endoscopic eradication program for Barrett's esophagus with high grade dysplasia or early adenocarcinoma on the frequency of surgery. Endosc Int Open 2018; 6:E1085-E1092. [PMID: 30211296 PMCID: PMC6133650 DOI: 10.1055/a-0640-3030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 03/12/2018] [Indexed: 11/20/2022] Open
Abstract
Background and aims The impact of the advent of an institutional endoscopic eradication therapy (EET) program on surgical practice for Barrett's esophagus (BE)-associated high grade dysplasia (HGD) or suspected T1a esophageal adenocarcinoma (EAC) is unknown. The aims of this study are to evaluate the different endoscopic modalities used during development of our EET program and factors associated with the use of EET or surgery for these patients after its development. Methods Patients who underwent primary endoscopic or surgical treatment for BE-HGD or early EAC at our hospital between January 1992 and December 2014 were retrospectively identified. They were categorized by their initial modality of treatment during the first year, and the impact over time for choice of therapy was assessed by multivariable logistic regression. Results We identified 386 patients and 80 patients who underwent EET and surgery, respectively. EET included single modality therapy in 254 (66 %) patients and multimodal therapy in 132 (34 %) patients. Multivariable logistic regression showed that, for each subsequent study year, EET was more likely to be performed in patients who were older ( P = 0.0009), with shorter BE lengths ( P < 0.0001), and with a pretreatment diagnosis of HGD ( P = 0.0054) compared to surgical patients. The diagnosis of EAC did not increase the utilization of EET compared to surgery as time progressed ( P = 0.8165). Conclusion The introduction of an EET program at our hospital increased the odds of utilizing EET versus surgery over time for initial treatment of patients who were older, had shorter BE lengths or the diagnosis of BE-HGD, but not in patients with EAC.
Collapse
Affiliation(s)
- Prianka Chilukuri
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mark A. Gromski
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Duy Khanh P. Ceppa
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kenneth A. Kesler
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Thomas J. Birdas
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Karen M. Rieger
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Hala Fatima
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - William R. Kessler
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Douglas K. Rex
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mohammad Al-Haddad
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - John M. DeWitt
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA,Corresponding author John M. DeWitt, MD Indiana University School of Medicine550 University BlvdSuite 4100IndianapolisIN 46202-5250USA+1-317-948-8144
| |
Collapse
|
|
28
|
Abstract
The incidence of esophageal adenocarcinoma (EAC) and its precursor lesion Barrett's esophagus (BE) has been increasing steadily in the western world in recent decades. Understanding the cellular origins of BE and the conditions responsible for their malignant transformation would greatly facilitate risk assessment and identification of patients at risk of progression, but this topic remains a source of debate. Here, we review recent findings that have provided support for the gastroesophageal junction (GEJ) as the main source of stem cells that give rise to BE and EAC. These include both gastric cardia cells and transitional basal cells. Furthermore, we discuss the role of chronic injury and inflammation in a tumor microenvironment as a major factor in promoting stem cell expansion and proliferation as well as transformation of the GEJ-derived stem cells and progression to EAC. We conclude that there exists a large amount of empirical support for the GEJ as the likely source of BE stem cells. While BE seems to resemble a successful adaptation to esophageal damage, carcinogenesis appears as a consequence of natural selection at the level of GEJ stem cells, and later glands, that expand into the esophagus wherein the local ecology creates the selective landscape for cancer progression.
Collapse
|
|
29
|
Abstract
INTRODUCTION Surveillance patterns in Barrett's esophagus (BE) are not well characterized. Guidelines published between 2002 and 2008 recommended surveillance esophagogastroduodenoscopy (sEGD) at 3-year intervals for nondysplastic BE (NDBE). We assessed guideline adherence in incident NDBE in a Veterans Affairs (VA)-based study. METHODS At a single VA center, we identified incident cases of biopsy-confirmed NDBE between January, 2006 and December, 2008. We excluded patients aged 76 years and above and those who developed BE-associated dysplasia or cancer during follow-up. All sEGDs through October, 2014 were documented. Our primary criteria classified cases as guideline adherent if a sEGD was performed within 6 months of each expected 3-year surveillance interval; in cases with ≥2 sEGDs, 1 sEGD >6 months, and ≤1 year outside an interval was allowed if the average interval was between 2.5 and 3.5 years. Comorbidity, primary care encounters, presence of long-segment BE (LSBE), endoscopist recommendations, and Charlson comorbidity index (CCI) were assessed. RESULTS We identified 110 patients (96.4% male, 93.6% white) with mean age 58.9±8.5 years at index EGD. Median follow-up was 6.7 years (range, 3.7 to 8.6). Thirty-three (30.0%) cases were guideline adherent; 77 (70.0%) cases were nonadherent, including 52 (47.3%) with irregular surveillance and 25 (22.7%) with no surveillance. Forty cases (14 adherent) had 1 sEGD, 36 (18 adherent) had 2, 8 (1 adherent) had 3, and 1 nonadherent case had 4. Adherent cases were significantly older (61.5 vs. 57.9 y, P=0.04), and tended to have more LSBE (33.3% vs. 20.8%, P=0.16). There were no differences between adherent and nonadherent cases in annual primary care encounters (72.7% vs. 66.2%, P=0.66), CCI≥4 (15.2% vs. 15.6%, P=0.95), biopsy-positive sEGDs (75.8% vs. 76.6%, P=0.92), and any recommendation for subsequent surveillance (81.8% vs. 77.9%, P=0.65). A logistic regression model using age, CCI, and LSBE showed an independent association between adherence and older age (P=0.03). CONCLUSIONS In a single-center VA cohort, sEGD of NDBE was mostly nonadherent to guidelines. Adherent cases were older at baseline with a trend toward more LSBE. A larger study is needed to identify medical and social factors associated with adherence or nonadherence to surveillance.
Collapse
|
|
30
|
Cabibi D, Caruso S, Bazan V, Castiglia M, Bronte G, Ingrao S, Fanale D, Cangemi A, Calò V, Listì A, Incorvaia L, Galvano A, Pantuso G, Fiorentino E, Castorina S, Russo A. Analysis of tissue and circulating microRNA expression during metaplastic transformation of the esophagus. Oncotarget 2018; 7:47821-47830. [PMID: 27374102 PMCID: PMC5216981 DOI: 10.18632/oncotarget.10291] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 05/05/2016] [Indexed: 12/19/2022] Open
Abstract
Genetic changes involved in the metaplastic progression from squamous esophageal mucosa toward Barrett's metaplasia and adenocarcinoma are almost unknown. Several evidences suggest that some miRNAs are differentially expressed in Barrett's esophagus (BE) and esophageal adenocarcinoma. Among these, miR-143, miR-145, miR-194, miR-203, miR-205, miR-215 appear to have a key role in metaplasia and neoplastic progression. The aim of this study was to analyze deregulated miRNAs in serum and esophageal mucosal tissue biopsies to identify new biomarkers that could be associated with different stages of esophageal disease. Esophageal mucosal tissue biopsies and blood samples were collected and analyzed for BE diagnosis. Quantitative Real-time PCR was used to compare miRNA expression levels in serum and 60 disease/normal-paired tissues from 30 patients diagnosed with esophagitis, columnar-lined oesophagus (CLO) or BE. MiRNA expression analysis showed that miR-143, miR-145, miR-194 and miR-215 levels were significantly higher, while miR-203 and miR-205 were lower in BE tissues compared with their corresponding normal tissues. Esophageal mucosa analysis of patients with CLO and esophagitis showed that these miRNAs were similarly deregulated but to a lesser extent keeping the same trend and CLO appeared as intermediate step between esophagitis and BE. Analysis on circulating miRNA levels confirmed that miR-194 and miR-215 were significantly upregulated in both BE and CLO compared to esophagitis, while miR-143 was significantly upregulated only in the Barrett group. These findings suggest that miRNAs may be involved in neoplastic/metaplastic progression and miRNA analysis might be useful for progression risk prediction as well as for monitoring of BE/CLO patients.
Collapse
Affiliation(s)
- Daniela Cabibi
- Department of Science for Promotion of Health and Mother and Child Care, Section of Human Pathology, University of Palermo, 90127 Palermo, Italy
| | - Stefano Caruso
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Viviana Bazan
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Marta Castiglia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Giuseppe Bronte
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Sabrina Ingrao
- Department of Science for Promotion of Health and Mother and Child Care, Section of Human Pathology, University of Palermo, 90127 Palermo, Italy
| | - Daniele Fanale
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Antonina Cangemi
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Valentina Calò
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Angela Listì
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Lorena Incorvaia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Antonio Galvano
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Gianni Pantuso
- Department of Surgical, Oncological and Oral Sciences, Section of Surgical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Eugenio Fiorentino
- Department of Surgical, Oncological and Oral Sciences, Section of Surgical Oncology, University of Palermo, 90127 Palermo, Italy
| | - Sergio Castorina
- Fondazione Mediterranea, "G.B. Morgagni", Department of Biomedical and Biotechnological Sciences, University of Catania, 95100 Catania, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
| |
Collapse
|
|
31
|
Predictive Biomarkers of Gastroesophageal Reflux Disease and Barrett's Esophagus in World Trade Center Exposed Firefighters: a 15 Year Longitudinal Study. Sci Rep 2018; 8:3106. [PMID: 29449669 PMCID: PMC5814524 DOI: 10.1038/s41598-018-21334-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 02/02/2018] [Indexed: 12/12/2022] Open
Abstract
Gastroesophageal reflux disease (GERD) and Barrett’s Esophagus (BE), which are prevalent in the World Trade Center (WTC) exposed and general populations, negatively impact quality of life and cost of healthcare. GERD, a risk factor of BE, is linked to obstructive airways disease (OAD). We aim to identify serum biomarkers of GERD/BE, and assess the respiratory and clinical phenotype of a longitudinal cohort of never-smoking, male, WTC-exposed rescue workers presenting with pulmonary symptoms. Biomarkers collected soon after WTC-exposure were evaluated in optimized predictive models of GERD/BE. In the WTC-exposed cohort, the prevalence of BE is at least 6 times higher than in the general population. GERD/BE cases had similar lung function, DLCO, bronchodilator response and long-acting β-agonist use compared to controls. In confounder-adjusted regression models, TNF-α ≥ 6 pg/mL predicted both GERD and BE. GERD was also predicted by C-peptide ≥ 360 pg/mL, while BE was predicted by fractalkine ≥ 250 pg/mL and IP-10 ≥ 290 pg/mL. Finally, participants with GERD had significantly increased use of short-acting β-agonist compared to controls. Overall, biomarkers sampled prior to GERD/BE presentation showed strong predictive abilities of disease development. This study frames future investigations to further our understanding of aerodigestive pathology due to particulate matter exposure.
Collapse
|
|
32
|
Increased detection of Barrett's esophagus-associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial. Gastrointest Endosc 2018; 87:348-355. [PMID: 28757316 DOI: 10.1016/j.gie.2017.07.039] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 07/18/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Wide-area transepithelial sampling (WATS) with computer-assisted 3-dimensional analysis is a sampling technique that combines abrasive brushing of the Barrett's esophagus (BE) mucosa followed by neural network analysis to highlight abnormal-appearing cells. METHODS We performed a randomized trial of referred BE patients undergoing surveillance at 16 medical centers. Subjects received either biopsy sampling followed by WATS or WATS followed by biopsy sampling. The primary outcome was rate of detection of high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) using WATS in conjunction with biopsy sampling compared with biopsy sampling alone using standard histopathologic criteria. Secondary aims included evaluating neoplasia detection rates based on the procedure order (WATS vs biopsy sampling first), of each procedure separately, and the additional time required for WATS. RESULTS One hundred sixty patients (mean age, 63.4 years; 76% men; 95% white) completed the trial. The median circumferential and maximal BE extents were 1.0 cm (interquartile range: .0-5.0) and 4.0 cm (interquartile range, 2.0-8.0), respectively. The diagnostic yield for biopsy sampling alone was as follows: HGD/EAC, 7 (4.4%); low-grade dysplasia (LGD), 28 (17.5%); nondysplastic BE (NDBE), 106 (66.25%); and no BE, 19 (11.9%). The addition of WATS to biopsy sampling yielded an additional 23 cases of HGD/EAC (absolute increase, 14.4%; 95% confidence interval, 7.5%-21.2%). Among these 23 patients, 11 were classified by biopsy sampling as NDBE and 12 as LGD/indefinite for dysplasia (IND); 14 received biopsy sampling first and 9 WATS first (not significant) and most (n = 21; 91.7%) had a prior dysplasia history. WATS added an average of 4.5 minutes to the procedure. CONCLUSION Results of this multicenter, prospective, randomized trial demonstrate that the use of WATS in a referral BE population increases the detection of HGD/EAC. (Clinical trial registration number: NCT03008980.).
Collapse
|
|
33
|
Li J, Ye D, Wang L, Peng Y, Li Q, Deng H, Zhou C. Role of MLH1 methylation in esophageal cancer carcinogenesis and its clinical significance. Onco Targets Ther 2018; 11:651-663. [PMID: 29440913 PMCID: PMC5798571 DOI: 10.2147/ott.s154999] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The mutL homolog-1 (MLH1) is a DNA mismatch repair gene and has been reported to be frequently methylated in numerous cancers. However, the association between MLH1 methylation and esophageal cancer (EC), as well as its clinical significance, remains unclear. Hence, we conducted a systematic meta-analysis based on 19 articles (including 1384 ECs, 345 premalignant lesions, and 1244 healthy controls). Our analysis revealed that the frequency of MLH1 methylation was significantly elevated during EC carcinogenesis. In addition, we observed that MLH1 promoter methylation was associated with age (odds ratio [OR]=1.79; 95% CI =1.20-2.66), advanced tumor grade (OR=3.7; 95% CI =2.37-5.77), lymph node metastasis (OR=2.65; 95% CI =1.81-3.88), distant metastasis (OR=7.60; 95% CI =1.23-47.19), advanced clinical stage (OR=4.46; 95% CI =2.88-6.91), and poor prognosis in EC patients (hazard ratio =1.64, 95% CI =1.00-2.69). The pooled sensitivity, specificity, and area under the curve of MLH1 methylation in EC patients versus healthy individuals were 0.15, 0.99, and 0.77, respectively. Our findings indicate that MLH1 methylation is involved in the carcinogenesis, progression, and metastasis of EC. Moreover, methylated MLH1 could be a potential diagnostic and prognostic biomarker for EC.
Collapse
Affiliation(s)
- Jinyun Li
- Department of Oncology and Hematology, Affiliated Hospital of Ningbo University
| | - Dong Ye
- Department of Otorhinolaryngology – Head and Neck Surgery
| | - Lei Wang
- Department of General Surgery, Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Yingying Peng
- Department of General Surgery, Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Qun Li
- Department of Otorhinolaryngology – Head and Neck Surgery
| | - Hongxia Deng
- Department of Otorhinolaryngology – Head and Neck Surgery
| | | |
Collapse
|
|
34
|
Hou Y, Hu Q, Huang J, Xiong H. Omeprazole Inhibits Cell Proliferation and Induces G0/G1 Cell Cycle Arrest through Up-regulating miR-203a-3p Expression in Barrett's Esophagus Cells. Front Pharmacol 2018; 8:968. [PMID: 29375376 PMCID: PMC5767174 DOI: 10.3389/fphar.2017.00968] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 12/19/2017] [Indexed: 12/21/2022] Open
Abstract
Existing data suggest that proton pump inhibitors (PPIs), particularly omeprazole, have significant anti-tumor action in monotherapy and or combination chemotherapy. Hedgehog (Hh) signaling pathway represents a leading candidate as a molecular mediator of Barrett's esophagus (BE). Studies have indicated reduced miRNAs in BE progression, however, little is known about the latent anti-neoplasm effects of miRNAs in BE cells. Here, we investigated whether omeprazole could inhibit BE progression by regulating Hh pathway and explored the promising Hh-targeted miRNAs in BE cells. We conducted qRT-PCR and immunoblotting assay to evaluate the effects of omeprazole on the expression of Hh signaling components and miR-203a-3p in CP-A and CP-B cells. The promising target genes of miR-203a-3p were predicted by bioinformatics methods, and verified by luciferase assays and qRT-PCR. The effects of omeprazole on BE cell proliferation and cell cycle distribution were determined. The overexpression or silencing of miR-203a-3p was performed to test its anti-proliferative effects. Finally, rescue experiments that miR-203a-3p inhibitor alleviated the effects of omeprazole on decreasing the levels of Gli1 mRNA, protein and luciferase were performed. Mechanistic studies showed that omeprazole could inhibit the expression of Gli1 and the nuclear localization of Gli1. Moreover, we determined that omeprazole could selectively up-regulated the expression of miR-203a-3p, and Gli1 was a bona fide target of miR-203a-3p. miR-203a-3p inhibitor alleviated the suppressing effects of omeprazole on Gli1 luciferase activity, mRNA and protein level. The functional assay suggested that omeprazole could dose-dependently inhibit BE cell growth and induce cell cycle arrest in G0/G1 phase. Additionally, overexpression and silencing of miR-203a-3p in BE cells disrupted cell cycle progress, resulting in suppressing and accelerating cell proliferation, respectively. Taken together, these data provide a novel mechanism of potentially anti-neoplastic effects for omeprazole through modulation of miR-203a-3p expression and thus suppressing Hh/Gli1 signaling in BE cells.
Collapse
Affiliation(s)
- Yichao Hou
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qiang Hu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jiao Huang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Hua Xiong
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| |
Collapse
|
|
35
|
Knight BC, Devitt PG, Watson DI, Smith LT, Jamieson GG, Thompson SK. Long-term Efficacy of Laparoscopic Antireflux Surgery on Regression of Barrett's Esophagus Using BRAVO Wireless pH Monitoring: A Prospective Clinical Cohort Study. Ann Surg 2017; 266:1000-1005. [PMID: 27735829 DOI: 10.1097/sla.0000000000002019] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To assess the long-term efficacy of antireflux surgery on Barrett's esophagus (BE) using BRAVO wireless pH monitoring. BACKGROUND BE is associated with chronic gastroesophageal reflux and esophageal cancer. Till date, studies have failed to demonstrate that preventing gastroesophageal reflux with antireflux surgery halts the progression of BE, often because of difficulties in objectively proving an effective antireflux barrier. METHODS Since 1991, all patients undergoing antireflux surgery across 2 hospital sites have been followed in a prospective database. Patients with BE and at least 5 years follow up after antireflux surgery were identified. All patients completed a clinical outcome questionnaire and underwent endoscopic assessment and histological evaluation of their BE. Fourty-eight hours pH monitoring was then performed with the wireless BRAVO system. RESULTS A total of 50 patients (40 males:10 females) were included in the study, with an average follow up of 11.9 years. Approximately, 92% (46/50) reported their outcome of surgery as "excellent" or "good" and 86% (43/50) reported "none" or "mild" symptoms. Histological regression of BE was seen in 41% (20/49). Lower esophageal acid exposure (percentage time pH < 4) was significantly greater in those with no pathological regression (P = 0.008). Moreover, 64% (32/50) showed endoscopic reduction in the length of BE. Acid exposure was also significantly less in the group showing endoscopic reduction of BE (%time pH < 4, 0.2 vs 3.6, P = 0.007). CONCLUSIONS Antireflux surgery is safe and effective in patients with Barrett's esophagus. An intact fundoplication, as assessed with BRAVO wireless pH monitoring, suggests that antireflux surgery may halt the progression of Barrett's esophagus, and this might reduce the risk of cancer development.
Collapse
Affiliation(s)
- Benjamin C Knight
- *Discipline of Surgery, University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia, Australia †Department of Surgery, Flinders University, Flinders Medical Center, Bedford Park, South Australia, Australia
| | | | | | | | | | | |
Collapse
|
|
36
|
Li N, Petrick JL, Steck SE, Bradshaw PT, McClain KM, Niehoff NM, Engel LS, Shaheen NJ, Corley DA, Vaughan TL, Gammon MD. Dietary sugar/starches intake and Barrett's esophagus: a pooled analysis. Eur J Epidemiol 2017; 32:1007-1017. [PMID: 28864851 DOI: 10.1007/s10654-017-0301-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 08/23/2017] [Indexed: 02/07/2023]
Abstract
Barrett's esophagus (BE) is the key precursor lesion of esophageal adenocarcinoma, a lethal cancer that has increased rapidly in westernized countries over the past four decades. Dietary sugar intake has also been increasing over time, and may be associated with these tumors by promoting hyperinsulinemia. The study goal was to examine multiple measures of sugar/starches intake in association with BE. This pooled analysis included 472 BE cases and 492 controls from two similarly conducted case-control studies in the United States. Dietary intake data, collected by study-specific food frequency questionnaires, were harmonized across studies by linking with the University of Minnesota Nutrient Database, and pooled based on study-specific quartiles. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, total energy intake, study indicator, body mass index, frequency of gastro-esophageal reflux, and fruit/vegetable intake. In both studies, intake of sucrose (cases vs. controls, g/day: 36.07 vs. 33.51; 36.80 vs. 35.06, respectively) and added sugar (46.15 vs. 41.01; 44.18 vs. 40.68, respectively) were higher in cases than controls. BE risk was increased 79% and 71%, respectively, for associations comparing the fourth to the first quartile of intake of sucrose (ORQ4vs.Q1 = 1.79, 95% CI = 1.07-3.02, P trend = 0.01) and added sugar (ORQ4vs.Q1 = 1.71, 95% CI = 1.05-2.80, P trend = 0.15). Intake of sweetened desserts/beverages was associated with 71% increase in BE risk (ORQ4vs.Q1 = 1.71, 95% CI = 1.07-2.73, P trend = 0.04). Limiting dietary intake of foods and beverages that are high in added sugar, especially refined table sugar, may reduce the risk of developing BE.
Collapse
Affiliation(s)
- Nan Li
- Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, CB# 7435, Chapel Hill, NC, 27599-7435, USA.
| | - Jessica Leigh Petrick
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Susan Elizabeth Steck
- Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USA
| | | | - Kathleen Michele McClain
- Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, CB# 7435, Chapel Hill, NC, 27599-7435, USA
| | - Nicole Michelle Niehoff
- Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, CB# 7435, Chapel Hill, NC, 27599-7435, USA
| | - Lawrence Stuart Engel
- Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, CB# 7435, Chapel Hill, NC, 27599-7435, USA
| | - Nicholas James Shaheen
- Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, CB# 7435, Chapel Hill, NC, 27599-7435, USA.,Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Douglas Allen Corley
- Division of Research and San Francisco Medical Center, Kaiser Permanente, Northern California, Oakland, CA, USA
| | | | - Marilie Denise Gammon
- Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, CB# 7435, Chapel Hill, NC, 27599-7435, USA
| |
Collapse
|
|
37
|
Souza RF. Reflux esophagitis and its role in the pathogenesis of Barrett's metaplasia. J Gastroenterol 2017; 52:767-776. [PMID: 28451845 PMCID: PMC5488728 DOI: 10.1007/s00535-017-1342-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 04/11/2017] [Indexed: 02/04/2023]
Abstract
Reflux esophagitis damages the squamous epithelium that normally lines the esophagus, and promotes replacement of the damaged squamous lining by the intestinal metaplasia of Barrett's esophagus, the precursor of esophageal adenocarcinoma. Therefore, to prevent the development of Barrett's metaplasia and esophageal adenocarcinoma, the pathogenesis of reflux esophagitis must be understood. We have reported that reflux esophagitis, both in a rat model and in humans, develops as a cytokine-mediated inflammatory injury (i.e., cytokine sizzle), not as a caustic chemical injury (i.e., acid burn), as traditionally has been assumed. Moreover, reflux induces activation of hypoxia inducible factor (HIF)-2α, which enhances the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) causing increases in pro-inflammatory cytokines and in migration of T lymphocytes, an underlying molecular mechanism for this cytokine-mediated injury. In some individuals, reflux esophagitis heals with Barrett's metaplasia. A number of possibilities exist for the origin of the progenitor cells that give rise to this intestinal metaplasia including those of the esophagus, the proximal stomach, or the bone marrow. However, intestinal cells are not normally found in the esophagus, the stomach, or the bone marrow. Thus, the development of Barrett's intestinal metaplasia must involve some molecular reprogramming of key developmental transcription factors within the progenitor cell, a process termed transcommitment, which may be initiated by the noxious components of the gastric refluxate. This review will highlight recent studies on the pathogenesis of reflux esophagitis and on reflux-related molecular reprogramming of esophageal squamous epithelial cells in the pathogenesis of Barrett's metaplasia.
Collapse
Affiliation(s)
- Rhonda F. Souza
- Center for Esophageal Research, Baylor Scott and White Research Institute, Dallas, TX, USA
| |
Collapse
|
|
38
|
The Role of Acid Suppression in Barrett's Esophagus. Am J Med 2017; 130:525-529. [PMID: 28159599 DOI: 10.1016/j.amjmed.2016.12.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/22/2016] [Accepted: 12/23/2016] [Indexed: 02/08/2023]
Abstract
In recent years, proton pump inhibitors (PPIs) have come under great scrutiny due to possible adverse, long-term side effects. At the same time, Barrett's esophagus, a premalignant condition in the esophagus, continues to be a disease whose course is thought to be improved by the use of PPIs. We review the impact of proton pump therapy on the esophagus and on Barrett's mucosa. In analyzing changes on a cellular level, we explore the effect of mixed gastric refluxate and the complex cascade that ensues with esophageal exposure of these contents. Because the incidence of esophageal adenocarcinoma is on the rise, we explore other factors that may contribute to the progression of Barrett's from non-dysplastic mucosa to esophageal adenocarcinoma. By revisiting the need for adequate acid suppression in Barrett's and increasing our understanding of other possible factors that may have an effect of Barrett's progression, we hope to support our multifaceted approach to acid suppression in patients with Barrett's esophagus.
Collapse
|
|
39
|
Letsolo BT, Jones RE, Rowson J, Grimstead JW, Keith WN, Jenkins GJS, Baird DM. Extensive telomere erosion is consistent with localised clonal expansions in Barrett's metaplasia. PLoS One 2017; 12:e0174833. [PMID: 28362812 PMCID: PMC5375150 DOI: 10.1371/journal.pone.0174833] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 03/15/2017] [Indexed: 12/24/2022] Open
Abstract
Barrett's oesophagus is a premalignant metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma. However, only a minor fraction of Barrett's oesophagus patients progress to adenocarcinoma and it is thus essential to determine bio-molecular markers that can predict the progression of this condition. Telomere dysfunction is considered to drive clonal evolution in several tumour types and telomere length analysis provides clinically relevant prognostic and predictive information. The aim of this work was to use high-resolution telomere analysis to examine telomere dynamics in Barrett's oesophagus. Telomere length analysis of XpYp, 17p, 11q and 9p, chromosome arms that contain key cancer related genes that are known to be subjected to copy number changes in Barrett's metaplasia, revealed similar profiles at each chromosome end, indicating that no one specific telomere is likely to suffer preferential telomere erosion. Analysis of patient matched tissues (233 samples from 32 patients) sampled from normal squamous oesophagus, Z-line, and 2 cm intervals within Barrett's metaplasia, plus oesophago-gastric junction, gastric body and antrum, revealed extensive telomere erosion in Barrett's metaplasia to within the length ranges at which telomere fusion is detected in other tumour types. Telomere erosion was not uniform, with distinct zones displaying more extensive erosion and more homogenous telomere length profiles. These data are consistent with an extensive proliferative history of cells within Barrett's metaplasia and are indicative of localised clonal growth. The extent of telomere erosion highlights the potential of telomere dysfunction to drive genome instability and clonal evolution in Barrett's metaplasia.
Collapse
Affiliation(s)
- Boitelo T. Letsolo
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - Rhiannon E. Jones
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - Jan Rowson
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - Julia W. Grimstead
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - W. Nicol Keith
- Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Gareth J. S. Jenkins
- GI Cancer Group, School of Medicine, Swansea University, Swansea, United Kingdom
| | - Duncan M. Baird
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| |
Collapse
|
|
40
|
Bishayee A, Haskell Y, Do C, Siveen KS, Mohandas N, Sethi G, Stoner GD. Potential Benefits of Edible Berries in the Management of Aerodigestive and Gastrointestinal Tract Cancers: Preclinical and Clinical Evidence. Crit Rev Food Sci Nutr 2017; 56:1753-75. [PMID: 25781639 DOI: 10.1080/10408398.2014.982243] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Epidemiological reports as well as experimental studies have demonstrated the significant health benefits provided by regular berry consumption. Berries possess both prophylactic and therapeutic potential against several chronic illnesses, such as cardiovascular, neurodegenerative, and neoplastic diseases. Berries owe their health benefits to phytoconstituents, such as polyphenolic anthocyanins, ellagic acid, and a diverse array of phytochemicals bestowed with potent antioxidant and anti-inflammatory effects as well as the ability to engage a multitude of signaling pathways. This review highlights the principal chemical constituents present in berries and their primary molecular targets. The article presents and critically analyzes the chemopreventive and therapeutic potential of berry extracts, fractions, and bioactive components on various cancers of the gastrointestinal tract (GIT), including esophageal, stomach, intestinal, and colorectal cancers as well as cancers of the upper aerodigestive tract, such as oral cancer. The current status of clinical studies evaluating berry products in several aforementioned cancers is presented. Various emerging issues including dose-ranging and dosage forms, the role of synergy and the usage of combination therapy as well as other relevant areas essential for the development of berry phytoconstituents as mainstream chemopreventive and therapeutic agents against aerodigestive and GIT cancers are critically discussed.
Collapse
Affiliation(s)
- Anupam Bishayee
- a Department of Pharmaceutical Sciences , College of Pharmacy, Larkin Health Sciences Institute , Miami , Florida USA
| | - Yennie Haskell
- b Department of Pharmaceutical Sciences , College of Pharmacy, Northeast Ohio Medical University , Rootstown , Ohio USA
| | - Chau Do
- b Department of Pharmaceutical Sciences , College of Pharmacy, Northeast Ohio Medical University , Rootstown , Ohio USA
| | - Kodappully Sivaraman Siveen
- c Department of Pharmacology , Yong Loo Lin School of Medicine, National University of Singapore , Singapore
| | - Nima Mohandas
- d School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University , Western Australia , Australia
| | - Gautam Sethi
- c Department of Pharmacology , Yong Loo Lin School of Medicine, National University of Singapore , Singapore.,d School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University , Western Australia , Australia
| | - Gary D Stoner
- e Division of Hematology and Oncology , Department of Medicine, Medical College of Wisconsin , Milwaukee , Wisconsin USA
| |
Collapse
|
|
41
|
Abstract
Changes in cell identity occur in adult mammalian organisms but are rare and often linked to disease. Research in the last few decades has thrown light on how to manipulate cell fate, but the conversion of a particular cell type into another within a living organism (also termed in vivo transdifferentiation) has only been recently achieved in a limited number of tissues. Although the therapeutic promise of this strategy for tissue regeneration and repair is exciting, important efficacy and safety concerns will need to be addressed before it becomes a reality in the clinical practice. Here, we review the most relevant in vivo transdifferentiation studies in adult mammalian animal models, offering a critical assessment of this potentially powerful strategy for regenerative medicine.
Collapse
|
|
42
|
Kaz AM, Wong CJ, Varadan V, Willis JE, Chak A, Grady WM. Global DNA methylation patterns in Barrett's esophagus, dysplastic Barrett's, and esophageal adenocarcinoma are associated with BMI, gender, and tobacco use. Clin Epigenetics 2016; 8:111. [PMID: 27795744 PMCID: PMC5082363 DOI: 10.1186/s13148-016-0273-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 09/29/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The risk of developing Barrett's esophagus (BE) and/or esophageal adenocarcinoma (EAC) is associated with specific demographic and behavioral factors, including gender, obesity/elevated body mass index (BMI), and tobacco use. Alterations in DNA methylation, an epigenetic modification that can affect gene expression and that can be influenced by environmental factors, is frequently present in both BE and EAC and is believed to play a role in the formation of BE and its progression to EAC. It is currently unknown whether obesity or tobacco smoking influences the risk of developing BE/EAC via the induction of alterations in DNA methylation. To investigate this possibility, we assessed the genome-wide methylation status of 81 esophageal tissues, including BE, dysplastic BE, and EAC epithelia using HumanMethylation450 BeadChips (Illumina). RESULTS We found numerous differentially methylated loci in the esophagus tissues when comparing males to females, obese to lean individuals, and smokers to nonsmokers. Differences in DNA methylation between these groups were seen in a variety of functional genomic regions and both within and outside of CpG islands. Several cancer-related pathways were found to have differentially methylated genes between these comparison groups. CONCLUSIONS Our findings suggest obesity and tobacco smoking may influence DNA methylation in the esophagus and raise the possibility that these risk factors affect the development of BE, dysplastic BE, and EAC through influencing the epigenetic status of specific loci that have a biologically plausible role in cancer formation.
Collapse
Affiliation(s)
- Andrew M. Kaz
- Gastroenterology Section, VA Puget Sound Health Care System, Seattle, WA 98108 USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195 USA
| | - Chao-Jen Wong
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA
| | - Vinay Varadan
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106 USA
| | - Joseph E. Willis
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA
| | - Amitabh Chak
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106 USA
- Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA
| | - William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195 USA
| |
Collapse
|
|
43
|
DNA methylation profiling of esophageal adenocarcinoma using Methylation Ligation-dependent Macroarray (MLM). Biochem Biophys Res Commun 2016; 479:231-237. [PMID: 27634218 DOI: 10.1016/j.bbrc.2016.09.049] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 09/11/2016] [Indexed: 02/08/2023]
Abstract
Most types of cancer cells are characterized by aberrant methylation of promoter genes. In this study, we described a rapid, reproducible, and relatively inexpensive approach allowing the detection of multiple human methylated promoter genes from many tissue samples, without the need of bisulfite conversion. The Methylation Ligation-dependent Macroarray (MLM), an array-based analysis, was designed in order to measure methylation levels of 58 genes previously described as putative biomarkers of cancer. The performance of the design was proven by screening the methylation profile of DNA from esophageal cell lines, as well as microdissected formalin-fixed and paraffin-embedded (FFPE) tissues from esophageal adenocarcinoma (EAC). Using the MLM approach, we identified 32 (55%) hypermethylated promoters in EAC, and not or rarely methylated in normal tissues. Among them, 21promoters were found aberrantly methylated in more than half of tumors. Moreover, seven of them (ADAMTS18, APC, DKK2, FOXL2, GPX3, TIMP3 and WIF1) were found aberrantly methylated in all or almost all the tumor samples, suggesting an important role for these genes in EAC. In addition, dysregulation of the Wnt pathway with hypermethylation of several Wnt antagonist genes was frequently observed. MLM revealed a homogeneous pattern of methylation for a majority of tumors which were associated with an advanced stage at presentation and a poor prognosis. Interestingly, the few tumors presenting less methylation changes had a lower pathological stage. In conclusion, this study demonstrated the feasibility and accuracy of MLM for DNA methylation profiling of FFPE tissue samples.
Collapse
|
|
44
|
Lash RH, Deas TM, Wians FH. Healthcare Cost of Over-Diagnosis of Low-Grade Dysplasia in Barrett's Esophagus. Adv Ther 2016; 33:684-97. [PMID: 26942725 DOI: 10.1007/s12325-016-0308-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Published reports have demonstrated that many Barrett's esophagus patients are over-diagnosed as low-grade dysplasia (BE-LGD). We performed an analysis of the surveillance and treatment costs associated with the over-diagnosis of BE-LGD. METHODS As the principal cost variables, we used endoscopic and histologic procedures performed during the recommended surveillance intervals for patients with BE-LGD, the national average Medicare reimbursement for the Current Procedural Terminology codes of the procedures performed, and a spreadsheet-based tool we created to determine the overall healthcare cost associated with the over-diagnosis of BE-LGD in the US population. RESULTS The average excess cost (range) for every patient in the US who is over-diagnosed with BE-LGD is estimated to be $5557 ($3115 to $8072). The principal contributors to the excess cost of over-diagnosis of BE-LGD in these patients are: endoscopy ($2626 to $4639), pathologist biopsy review ($275 to $2185), and esophagogastroduodenoscopy-guided endoscopic ablation ($214 to $1249). CONCLUSIONS The healthcare cost of over-diagnosis of BE-LGD is significant. To reduce the overall healthcare cost impact of over-diagnosis of BE-LGD, strict adherence to the recommendations of the American Gastroenterological Association, American College of Gastroenterology, and American Society for Gastrointestinal Endoscopy that pathology review of all BE biopsy specimens be performed by a gastrointestinal pathologist is warranted.
Collapse
Affiliation(s)
| | - Thomas M Deas
- North Texas Specialty Physicians, Ft. Worth, TX, USA
| | - Frank H Wians
- Department of Pathology, Texas Tech University Health Sciences Center, El Paso, TX, USA
| |
Collapse
|
|
45
|
Sun X, Elston R, Falk GW, Grady WM, Faulx A, Mittal SK, Canto MI, Shaheen NJ, Wang JS, Iyer PG, Abrams JA, Willis JE, Guda K, Markowitz S, Barnholtz-Sloan JS, Chandar A, Brock W, Chak A. Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas. Mol Genet Genomic Med 2016; 4:407-19. [PMID: 27468417 PMCID: PMC4947860 DOI: 10.1002/mgg3.211] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 01/27/2016] [Accepted: 02/02/2016] [Indexed: 12/20/2022] Open
Abstract
Background Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC). Methods We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model‐based and model‐free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model‐based linkage analysis. Model‐based and model‐free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome‐wide associations were also tested in these families. Results Linkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female‐affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported. Conclusion Our linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC.
Collapse
Affiliation(s)
- Xiangqing Sun
- Department of Epidemiology and Biostatistics Case Western Reserve University Cleveland Ohio
| | - Robert Elston
- Department of Epidemiology and BiostatisticsCase Western Reserve UniversityClevelandOhio; Case Comprehensive Cancer CenterCase Western Reserve University School of MedicineClevelandOhio
| | - Gary W Falk
- University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania
| | - William M Grady
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashington; Gastroenterology DivisionUniversity of Washington School of MedicineSeattleWashington
| | - Ashley Faulx
- Division of Gastroenterology and HepatologyUniversity Hospitals Case Medical CenterCase Western Reserve University School of MedicineClevelandOhio; Division of Gastroenterology and HepatologyLouis Stokes Veterans Administration Medical CenterCase Western Reserve University School of MedicineClevelandOhio
| | - Sumeet K Mittal
- Department of Surgery Creighton University School of Medicine Omaha Nebraska
| | - Marcia I Canto
- Division of Gastroenterology Johns Hopkins Medical Institutions Baltimore Maryland
| | - Nicholas J Shaheen
- Center for Esophageal Diseases & Swallowing University of North Carolina at Chapel Hill School of Medicine Chapel Hill North Carolina
| | - Jean S Wang
- Division of Gastroenterology Washington University School of Medicine St. Louis Missouri
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology Mayo Clinic Rochester Minnesota
| | - Julian A Abrams
- Department of Medicine Columbia University Medical Center New York New York
| | - Joseph E Willis
- Department of Pathology University Hospitals Case Medical Center Case Western Reserve University School of Medicine Cleveland Ohio
| | - Kishore Guda
- Division of General Medical Sciences (Oncology) Case Comprehensive Cancer Center Cleveland Ohio
| | - Sanford Markowitz
- Department of Medicine and Case Comprehensive Cancer Center Case Medical Center Case Western Reserve University Cleveland Ohio
| | - Jill S Barnholtz-Sloan
- Department of Epidemiology and BiostatisticsCase Western Reserve UniversityClevelandOhio; Case Comprehensive Cancer CenterCase Western Reserve University School of MedicineClevelandOhio
| | - Apoorva Chandar
- Division of Gastroenterology and Hepatology University Hospitals Case Medical Center Case Western Reserve University School of Medicine Cleveland Ohio
| | - Wendy Brock
- Division of Gastroenterology and Hepatology University Hospitals Case Medical Center Case Western Reserve University School of Medicine Cleveland Ohio
| | - Amitabh Chak
- Case Comprehensive Cancer CenterCase Western Reserve University School of MedicineClevelandOhio; Division of Gastroenterology and HepatologyUniversity Hospitals Case Medical CenterCase Western Reserve University School of MedicineClevelandOhio
| |
Collapse
|
|
46
|
Riley CA, Marino MJ, Hawkey N, Lawlor CM, McCoul ED. Sinonasal Tract Inflammation as a Precursor to Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis. Otolaryngol Head Neck Surg 2016; 154:810-6. [PMID: 26908557 DOI: 10.1177/0194599816629436] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 01/07/2016] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Chronic inflammation has been described as a precursor to the development of malignancy in several disease states. However, the relationship of sinonasal tract inflammation to nasopharyngeal carcinoma (NPC) remains poorly defined. DATA SOURCES Systematic review of primary studies identified through PubMed, EMBASE, MEDLINE, and Cochrane. METHODS REVIEW Systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. MEDLINE, EMBASE, and Cochrane databases were queried for English-language studies published between 1980 and 2015. Studies were excluded that did not provide quantitative data on sinonasal tract inflammation such as chronic rhinosinusitis (CRS), allergic rhinitis (AR), or human papillomavirus (HPV) status and NPC. An itemized assessment of the risk of bias was conducted for each included study. RESULTS Of the 325 studies identified during systematic review, 5 met the criteria for analysis. The level of evidence of those studies was generally low. There was an increased risk of NPC in patients with a previous diagnosis of CRS or AR. Meta-analysis demonstrated an odds ratio (95% confidence interval [CI]) of 2.35 (2.00-2.76) for all studies. Subgroup analysis of patients with sinonasal inflammation had an odds ratio of 2.39 (95% CI, 2.20-2.60). Patients with AR had an odds ratio of 2.29 (95% CI, 2.06-2.54), while those with CRS had an odds ratio of 2.70 (95% CI, 1.98-3.70). CONCLUSIONS This systematic review and meta-analysis suggests an association between previous sinonasal inflammatory disease and subsequent NPC. Prospective studies are needed to further examine this relationship.
Collapse
Affiliation(s)
- Charles A Riley
- Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Michael J Marino
- Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Nathan Hawkey
- Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Claire M Lawlor
- Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Edward D McCoul
- Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine, New Orleans, Louisiana, USA Department of Otorhinolaryngology, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| |
Collapse
|
|
47
|
Thrift AP. Esophageal Adenocarcinoma: The Influence of Medications Used to Treat Comorbidities on Cancer Prognosis. Clin Gastroenterol Hepatol 2015; 13:2225-32. [PMID: 25835331 DOI: 10.1016/j.cgh.2015.03.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 03/23/2015] [Accepted: 03/25/2015] [Indexed: 02/07/2023]
Abstract
Esophageal adenocarcinoma has undergone a continuous rise in incidence since the early 1970s and is the fastest rising cancer among white men in the United States. Epidemiologic studies have demonstrated that medications commonly used to treat multiple chronic conditions (for example, aspirin, non-aspirin nonsteroidal anti-inflammatory drugs, and statins) as well as powerful acid suppressants such as proton pump inhibitors are associated with a reduced risk of esophageal adenocarcinoma. The chemopreventive potential of these classes of medications appears to be especially applicable to persons with Barrett's esophagus, the only known premalignant condition for esophageal adenocarcinoma. However, it is not known whether these medications also influence cancer recurrence and cancer-specific mortality in persons diagnosed with esophageal adenocarcinoma. This is an important question because most patients with esophageal adenocarcinoma have 1 or more comorbid conditions at the time of their cancer diagnosis and are receiving medication to treat these conditions. This article summarizes the evidence on the associations between 4 commonly used classes of medications and (1) risk of developing esophageal adenocarcinoma and Barrett's esophagus and (2) risk of cancer recurrence and cancer-specific mortality in patients with esophageal adenocarcinoma.
Collapse
Affiliation(s)
- Aaron P Thrift
- Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
| |
Collapse
|
|
48
|
Yu M, O'Leary RM, Kaz AM, Morris SM, Carter KT, Chak A, Chandar A, Willis JE, Moinova HR, Markowitz SD, Brenner DE, Anandabapasathy S, Westerhoff M, Wong CJ, Shaheen NJ, Chen Y, Barnholtz-Sloan JS, Grady WM. Methylated B3GAT2 and ZNF793 Are Potential Detection Biomarkers for Barrett's Esophagus. Cancer Epidemiol Biomarkers Prev 2015; 24:1890-7. [PMID: 26545406 DOI: 10.1158/1055-9965.epi-15-0370] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 09/30/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Barrett's esophagus (BE) is a preneoplastic condition in which normal esophageal squamous epithelium (SQ) is replaced by specialized intestinal metaplasia. It is the presumed precursor for esophageal adenocarcinoma (EAC) as well as the strongest risk factor for this cancer. Unfortunately, many patients with BE go undiagnosed under the current BE screening guidelines. The development of noninvasive and accurate BE detection assays could potentially identify many of these undiagnosed BE patients. METHODS DNA methylation is a common epigenetic alteration in BE. Therefore, we conducted a genome-wide methylation screen to identify potential BE biomarkers. Samples from SQ (N = 12), stomach (N = 28), and BE (N = 29) were analyzed and methylation levels at over 485,000 CpG sites were compared. Pyrosequencing assays were used to validate the results and MethyLight assays were developed to detect the methylated alleles in endoscopic brushings. RESULTS We discovered two genes, B3GAT2 and ZNF793, that are aberrantly methylated in BE. Clinical validation studies confirmed B3GAT2 and ZNF793 methylation levels were significantly higher in BE samples (median = 32.5% and 33.1%, respectively) than in control tissues (median = 2.29% and 2.52%, respectively; P < 0.0001 for both genes). Furthermore, gene-specific MethyLight assays could accurately detect BE (P < 0.0001 for both) in endoscopic brushing samples. CONCLUSION B3GAT2 and ZNF793 are hypermethylated in BE, and the methylation status of these genes can be used to detect BE in tissue samples. IMPACT These findings support the development of methylated B3GAT2 and ZNF793 as biomarkers for noninvasive assays for the detection of BE.
Collapse
Affiliation(s)
- Ming Yu
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Rachele M O'Leary
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Andrew M Kaz
- Research and Development Service, VA Puget Sound Health Care System, Seattle, Washington. Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Shelli M Morris
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Kelly T Carter
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Amitabh Chak
- Division of Gastroenterology, University Hospitals Case Medical Center, Cleveland, Ohio. Division of Oncology, University Hospitals Case Medical Center, Cleveland, Ohio
| | - Apoorva Chandar
- Division of Gastroenterology, University Hospitals Case Medical Center, Cleveland, Ohio. Division of Oncology, University Hospitals Case Medical Center, Cleveland, Ohio
| | - Joseph E Willis
- Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio
| | - Helen R Moinova
- Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio
| | - Sanford D Markowitz
- Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio. Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - Dean E Brenner
- University of Michigan Medical Center, Ann Arbor, Michigan
| | | | - Maria Westerhoff
- Department of Anatomic Pathology, University of Washington School of Medicine, Seattle, Washington
| | - Chao-Jen Wong
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Nicholas J Shaheen
- Division of Gastroenterology & Hepatology, University of North Carolina Hospitals, Chapel Hill, North Carolina
| | - Yanwen Chen
- Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - Jill S Barnholtz-Sloan
- Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - William M Grady
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
| |
Collapse
|
|
49
|
Shiozaki A, Fujiwara H, Konishi H, Kinoshita O, Kosuga T, Morimura R, Murayama Y, Komatsu S, Kuriu Y, Ikoma H, Nakanishi M, Ichikawa D, Okamoto K, Sakakura C, Otsuji E. Laparoscopic transhiatal approach for resection of an adenocarcinoma in long-segment Barrett’s esophagus. World J Gastroenterol 2015; 21:8974-8980. [PMID: 26269688 PMCID: PMC4528041 DOI: 10.3748/wjg.v21.i29.8974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 04/03/2015] [Accepted: 05/21/2015] [Indexed: 02/06/2023] Open
Abstract
Barrett’s esophagus (BE) is a precursor of esophageal adenocarcinoma and is associated with gastroesophageal reflux disease, which is often preceded by a hiatal hernia. We describe a case of esophageal adenocarcinoma arising in long-segment BE (LSBE) associated with a hiatal hernia that was successfully treated with a laparoscopic transhiatal approach (LTHA) without thoracotomy. The patient was a 42-year-old male who had previously undergone laryngectomy and tracheal separation to avoid repeated aspiration pneumonitis. An ulcerative lesion was found in a hiatal hernia by endoscopy and superficial esophageal cancer was also detected in the lower thoracic esophagus. The histopathological diagnosis of biopsy samples from both lesions was adenocarcinoma. There were difficulties with the thoracic approach because the patient had severe kyphosis and muscular contractures from cerebral palsy. Therefore, we performed subtotal esophagectomy by LTHA without thoracotomy. Using hand-assisted laparoscopic surgery, the esophageal hiatus was divided and carbon dioxide was introduced into the mediastinum. A hernial sac was identified on the cranial side of the right crus of the diaphragm and carefully separated from the surrounding tissues. Abruption of the thoracic esophagus was performed up to the level of the arch of the azygos vein via LTHA. A cervical incision was made in the left side of the permanent tracheal stoma, the cervical esophagus was divided, and gastric tube reconstruction was performed via a posterior mediastinal route. The operative time was 175 min, and there was 61 mL of intra-operative bleeding. A histopathological examination revealed superficial adenocarcinoma in LSBE. Our surgical procedure provided a good surgical view and can be safely applied to patients with a hiatal hernia and kyphosis.
Collapse
|
|
50
|
Abstract
Although there are many unanswered questions with Barrett esophagus, we can safely say that the incidence is increasing, chemoprevention strategies for the prevention of Barrett metaplasia and its progression to adenocarcinoma may be in the offing, surveillance should be considered for all patients who are discovered to have Barrett esophagus, RFA is the treatment of choice for those with HGD and strongly considered in those with LGD, EMR should be the treatment of choice for patients with nodular high-grade Barrett esophagus, and, finally, vagal-sparing esophagectomy reserved for patients with persistent HGD or a strong suspicion of carcinoma, with consideration of a concomitant fundoplication.
Collapse
Affiliation(s)
- Mark Splittgerber
- Division of General Surgery, University of South Florida, Tampa, FL, USA
| | - Vic Velanovich
- Division of General Surgery, University of South Florida, Tampa, FL, USA.
| |
Collapse
|