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Gensthaler L, Schoppmann SF. New Developments in Anti-Reflux Surgery: Where Are We Now? Visc Med 2024; 40:250-255. [PMID: 39398392 PMCID: PMC11466450 DOI: 10.1159/000538117] [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: 01/30/2024] [Accepted: 02/28/2024] [Indexed: 10/15/2024] Open
Abstract
Background Gastroesophageal reflux disease is one of the most common chronic diseases, affecting up to 28% of the western population. Therapeutic management ranges from conservative measures to endoscopic or surgical interventions. Laparoscopic Nissen fundoplication (LNF) still is considered as gold standard, but alternative procedures have been developed and evaluated within the past years. Summary Magnetic sphincter augmentation (MSA), which aims to be a less disruptive and possibly more standardized laparoscopic procedure than LNF, shows satisfying results regarding short- and long-term follow-up as well as comorbidities. Alternatives, such as the RefluxStop™ procedure or Transoral incisionless fundoplication (TIF), combined with laparoscopic hiatal hernia repair (cTIF) show promising results for short-term follow-up, nevertheless further studies regarding long-term follow-up are necessary. Key Message Although there definitely are upcoming and promising trends in upper GI surgery, LNF still represents today's gold standard and MSA is an equivalent alternative. RefluxStop™ and cTIF show promising results, nevertheless, further studies are necessary.
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Affiliation(s)
- Lisa Gensthaler
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Sebastian F Schoppmann
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
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Mikolasevic I, Poropat G, Filipec Kanizaj T, Skenderevic N, Zelic M, Matasin M, Vranic L, Kresovic A, Hauser G. Association between Gastroesophageal Reflux Disease and Elastographic Parameters of Liver Steatosis and Fibrosis: Controlled Attenuation Parameter and Liver Stiffness Measurements. Can J Gastroenterol Hepatol 2021; 2021:6670065. [PMID: 33688490 PMCID: PMC7925017 DOI: 10.1155/2021/6670065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
AIM Our aim was to investigate the association among elastographic parameters of liver steatosis and fibrosis, controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), with gastroesophageal reflux disease (GERD). METHODS In this prospective, cross-sectional study, we have evaluated 937 patients with one or more components of the metabolic syndrome who had an esophagogastroduodenoscopy (EGD) due to GERD symptoms. In all patients, a laboratory analysis, an abdominal ultrasound, and FibroScan measurements were done. GERD was defined by EGD. RESULTS The mean body mass index (BMI) of the study population was 30.95 ± 5.45 kg/m2. The prevalence of increased CAP was 82.6% (774/937). Patients with increased CAP were younger, were more obese, had higher prevalence of hypertension, diabetes, and dyslipidemia, and had higher values of aminotransferases. Similar results of higher prevalence in patients with elevated CAP were observed with GERD, hiatal hernia, and insufficient cardia (defined as deficient or absent closure of the gastric inlet in relation to the esophagus). Additionally, patients with elevated CAP had a higher prevalence of GERD grades B and C in comparison to those without elevated CAP. Consequently, patients who did not have elevated CAP had a higher prevalence of GERD grade A. Even though we have found an upward trend in the prevalence of GERD, hiatal hernia, and insufficient cardia, there was no significant difference between subjects with fibrosis (F) 1-2 and F3-4 stage of fibrosis or F1 and F2-4. In a binary logistic regression, a significant positive association with GERD was obtained for CAP. Furthermore, a significant positive association with hiatal hernia was obtained for BMI and CAP. Finally, a significant positive association with hiatal hernia was obtained with CAP in multivariate analysis. CONCLUSION To the best of our knowledge, our study is the first to reveal a positive association between CAP as a surrogate marker of liver steatosis and GERD after adjustments for other clinical variables.
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Affiliation(s)
- Ivana Mikolasevic
- Department of Gastroenterology, Clinical Hospital Center Rijeka, Rijeka, Croatia
- Department of Gastroenterology, University Hospital Merkur, Zagreb, Croatia
- Faculty of Medicine, Rijeka, Croatia
| | - Goran Poropat
- Department of Gastroenterology, Clinical Hospital Center Rijeka, Rijeka, Croatia
- Faculty of Medicine, Rijeka, Croatia
| | - Tajana Filipec Kanizaj
- Department of Gastroenterology, University Hospital Merkur, Zagreb, Croatia
- Faculty of Medicine, Zagreb, Croatia
| | - Nadija Skenderevic
- Department of Gastroenterology, University Hospital Merkur, Zagreb, Croatia
| | - Marko Zelic
- Faculty of Medicine, Rijeka, Croatia
- Faculty of Health Studies, Rijeka, Croatia
- Department of Abdominal Surgery, Clinical Hospital Centre Rijeka, Croatia
| | | | - Luka Vranic
- Department of Gastroenterology, Clinical Hospital Center Rijeka, Rijeka, Croatia
- Faculty of Medicine, Rijeka, Croatia
| | - Andrea Kresovic
- Department of Gastroenterology, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Goran Hauser
- Department of Gastroenterology, Clinical Hospital Center Rijeka, Rijeka, Croatia
- Faculty of Medicine, Rijeka, Croatia
- Faculty of Health Studies, Rijeka, Croatia
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Development and Pilot Testing of Decision Aid for Shared Decision Making in Barrett's Esophagus With Low-Grade Dysplasia. J Clin Gastroenterol 2021; 55:36-42. [PMID: 32040049 DOI: 10.1097/mcg.0000000000001319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
GOALS To develop an encounter decision aid [Barrett's esophagus Choice (BE-Choice)] for patients and clinicians to engage in shared decision making (SDM) for management of BE with low-grade dysplasia (BE-LGD) and assess its impact on patient-important outcomes. BACKGROUND Currently, there are 2 strategies for management of BE-LGD-endoscopic surveillance and ablation. SDM can help patients decide on their preferred management option. STUDY Phase-I: Patients and clinicians were engaged in a user-centered design approach to develop BE-Choice. Phase-I included review of evidence on BE-LGD management, observation of usual care (UC), creation, field-testing, and iterative development of BE-Choice in clinical settings. Phase-II: Impact of BE-Choice on patient-important outcomes (patient knowledge, decisional conflict, and patient involvement in decision making) was assessed using a controlled before-after study design (UC vs. BE-Choice). RESULTS Phase-I: Initial prototype was designed with observation of 8 clinical encounters. With field-testing, 3 successive iterations were made before finalizing BE-Choice. BE-Choice was paper based and fulfilled the qualifying criteria of International patient decision aid standards. Phase II: 29 patients were enrolled, 8 to UC and 21 to BE-Choice. Compared with UC, use of BE-Choice improved patient knowledge (90.4% vs. 70.5%; P=0.03), decisional comfort (89.6 vs. 71.9; P=0.01), and patient involvement (OPTION score: 27.1 vs. 19.2; P=0.01). CONCLUSIONS BE-Choice is a feasible and effective decision aid to promote SDM in the management of BE-LGD. On pilot testing, BE-Choice had promising impact on patient-important outcomes. A larger multicenter trial is needed to confirm our results and promote widespread use of BE-Choice.
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Xia Y, Fang Y, Zhang H, Shen C, Wang P, Yan W, Li J, Xu Y, Shao S, Zhang Y, Yu X, Peng Z, Peng G, Chen W, Fang D. Role of Kruppel-Like Factor 5 in Deoxycholic Acid-Mediated Intestinal Transdifferentiation of Esophageal Squamous Epithelium. J Cancer 2019; 10:5597-5607. [PMID: 31632504 PMCID: PMC6775683 DOI: 10.7150/jca.30050] [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: 09/18/2018] [Accepted: 05/26/2019] [Indexed: 12/15/2022] Open
Abstract
Barrett's esophagus (BE) is an acquired condition in which normal squamous epithelium is replaced with metaplastic columnar epithelium as a consequence of gastroesophageal reflux disease. BE is known as a precursor of esophageal adenocarcinoma. Currently, the molecular mechanism underlying epithelial metaplasia in BE patients remains unknown. Therefore, we investigated the role of Krüppel-like factor 5 (KLF5) signaling in the initiation of BE-associated metaplasia. Sprague-Dawley (SD) rats were used to create a surgical model of bile reflux injury. Immunohistochemistry was performed to analyze human and mouse esophageal specimens. Human esophageal squamous epithelial (HET-1A) cells were treated with bile acid and used in transfection experiments. Quantitative real-time PCR and western blot analysis were performed to detect the expression of KLF5, CDX2, MUC2 and villin. Epithelial tissue from both the rat BE model and human BE patients strongly expressed KLF5, CDX2, MUC2, and villin. Bile acid treatment also increased the expression of KLF5, CDX2, MUC2 and villin in esophageal epithelial cells in a time-dependent manner. Moreover, siRNA-mediated knockdown of KLF5 blocked the expression of CDX2, MUC2 and villin, but transfection of a KLF5 expression vector into esophageal epithelial cells promoted their transdifferentiation into columnar-like cells, as demonstrated by increased expression of the intestinal markers CDX2, MUC2 and villin. Thus, in addition to its function as a transcription factor, KLF5 may be linked to an increased risk of BE development.
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Affiliation(s)
- Yiju Xia
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Yu Fang
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Haoxiang Zhang
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Caifei Shen
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Pu Wang
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Wu Yan
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Jingwen Li
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Yin Xu
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Shunzi Shao
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Yafei Zhang
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Xiaona Yu
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Zhihong Peng
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Guiyong Peng
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Wensheng Chen
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
| | - Dianchun Fang
- Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
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Markoš P, Brčić I, Brčić L, Jakić-Razumović J, Pulanić R. Microsatellite instability in metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus: a retrospective study. Croat Med J 2018; 59:100-107. [PMID: 29972732 PMCID: PMC6045894 DOI: 10.3325/cmj.2018.59.100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 05/01/2018] [Indexed: 12/24/2022] Open
Abstract
AIM To analyze the loss of mismatch repair (MMR) system protein expression in metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus (BE). METHODS This study retrospectively analyzed the data from 70 patients with pathohistological diagnosis of BE or esophageal adenocarcinoma (EAC) treated at the Clinical Department of Pathology and Cytology, University Hospital Center Zagreb, from January 2009 to January 2011. Patients were divided into three groups: BE without dysplasia (22 patients), BE with dysplasia (37 patients), and EAC (11 patients). Immunohistochemical expression of MutL homologue 1 (MLH1), MutS homologue 2 (MSH2), postmeiotic segregation increased 2 (PMS2), and MutS homologue 6 (MSH6) of DNA MMR system was measured and compared with tumor protein p53 expression. RESULTS A total of 81.8% and 81.8% patients with EAC, 32.4% and 35.1% patients with dysplasia, and 50% and 54.5% patients without dysplasia had loss of MLH1 and PMS2 expression, respectively. Patients with EAC and patients with dysplasia did not have loss of MSH2 and MSH6 expression, and 18.2% patients without dysplasia had loss of MSH2 and MSH6 expression. There was a strong positive correlation between MLH1 and PMS2 expression (Spearman ρ 0.97; P<0.001) and between MSH2 and MSH6 expression (Spearman ρ 0.90, P<0.001) in the entire sample and in all BE groups. No significant correlations of MLH1 and PMS2 with p53 expression were found, except in dysplasia group (φ 0.402, P=0.030 for MSH1; φ 0.371, P=0.042 for PMS2). CONCLUSION Although we demonstrated considerable loss of MLH1 and PMS2 expression in BE-associated carcinoma sequence, due to the retrospective study design and low number of patients we cannot conclude that MLH1 and PMS2 can be used as biomarkers for patient surveillance and therapy-making decisions. Oxford Centre for Evidence-based Medicine level of evidence: 3.
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Affiliation(s)
- Pave Markoš
- Pave Markoš, Division of Gastroenterology and Hepatology, University Hospital Center Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia,
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Mikolašević I, Bokun T, Filipec Kanižaj T. Gastroesophageal reflux disease, Barrett esophagus, and esophageal adenocarcinoma - where do we stand? Croat Med J 2018; 59:97-99. [PMID: 29972731 PMCID: PMC6045895 DOI: 10.3325/cmj.2018.59.97] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Ivana Mikolašević
- Ivana Mikolašević, Department of Gastroenterology, University Hospital Center Rijeka, University of Rijeka School of Medicine, Rijeka, Croatia,
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7
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Wang L, Jin JQ, Zhou Y, Tian Z, Jablons DM, He B. Gli is activated and promotes epithelial-mesenchymal transition in human esophageal adenocarcinoma. Oncotarget 2017; 9:853-865. [PMID: 29416661 PMCID: PMC5787518 DOI: 10.18632/oncotarget.22856] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 11/09/2017] [Indexed: 02/07/2023] Open
Abstract
Esophageal adenocarcinoma (EAC) accounts for the most esophageal cancer cases in the US, and is notoriously aggressive. This study examines the role of Sonic Hedgehog (SHh)/Gli signaling in the regulation of epithelial-mesenchymal transition (EMT), a process tied to invasion and metastasis, in EAC. Gli/EMT protein expression levels were examined by western blot in paired EAC patient tissues (n = 24) and cell lines (OE19, OE33). Functional analyses were performed (siRNA, treatment with Gli-inhibitor, AKT-inhibitor, and N-Shh recombinant proteins) to investigate SHh/Gli signaling and EMT, cell cycle, and prognostic markers in EAC cell lines. MTS, luciferase reporter, qRT-PCR, western blot, wound healing, and transwell assays were executed to analyze pathway activity, cell migration, and invasion. Aberrant Gli1/2 expression was found in EAC patient tissues, and was significantly associated with increased EMT and AKT pathway activity. Stimulation of SHh/Gli resulted in EMT signaling, including expression of E-cadherin, N-cadherin, Vimentin, β-catenin, Snail, and Slug, as well as cell cycle progression at mRNA and protein levels in EAC cell lines. Gli inhibition via small molecule administration and siRNA significantly reduced EMT, decreasing cell mobility and invasion. Both Gli and AKT inhibition rescued E-cadherin expression and suppressed AKT phosphorylation. This study provides evidence for a strong association between aberrant Gli1/2 expression and AKT/EMT markers in EAC; activated SHh/Gli signaling may be a critical component in promoting cell survival, metastases, and resistance to chemotherapy, and represents a promising avenue to target tumor proliferation and mobility.
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Affiliation(s)
- Lei Wang
- Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China.,Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA
| | - Joy Q Jin
- Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA
| | - Yong Zhou
- Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.,Department of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Ziqiang Tian
- Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China
| | - David M Jablons
- Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA
| | - Biao He
- Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA
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Krill JT, Naik RD, Higginbotham T, Slaughter JC, Holzman MD, Francis DO, Garrett CG, Vaezi MF. Association Between Response to Acid-Suppression Therapy and Efficacy of Antireflux Surgery in Patients With Extraesophageal Reflux. Clin Gastroenterol Hepatol 2017; 15:675-681. [PMID: 27840185 DOI: 10.1016/j.cgh.2016.10.031] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 10/12/2016] [Accepted: 10/27/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The effectiveness of antireflux surgery (ARS) varies among patients with extraesophageal manifestations of gastroesophageal reflux disease (GERD). By studying a cohort of patients with primary extraesophageal symptoms and abnormal physiologic markers for GERD, we aimed to identify factors associated with positive outcomes from surgery, and compare outcomes to those with typical esophageal manifestations of GERD. METHODS We performed a retrospective cohort study to compare adult patients with extraesophageal and typical reflux symptoms who underwent de novo ARS from 2004 through 2012 at a tertiary care center. All 115 patients (79 with typical GERD and 36 with extraesophageal manifestations of GERD) had evidence of abnormal distal esophageal acid exposure based on pH testing or endoscopy. The principle outcome was time to primary symptom recurrence after surgery, based on patient reports of partial or total recurrence of symptoms at follow-up visits. Patients were followed up for a median duration of 66 months (interquartile range, 52-77 mo). RESULTS The median time to recurrence of symptoms in the overall cohort was 68 months (11.5 months in the extraesophageal cohort vs >132 months in the typical cohort). Symptom recurrence after ARS was associated with having primarily extraesophageal symptoms (adjusted hazard ratio, 2.34; 95% confidence interval, 1.31-4.17) and poor preoperative symptom response to acid-suppression therapy (AST) (hazard ratio, 3.85; 95% confidence interval, 2.05-7.22). Patients with primary extraesophageal symptoms who had a full or partial preoperative AST response experienced lower rates of symptom recurrence compared to patients with poor AST response (P < .01). The rate of symptom recurrence was lowest among patients with primary typical reflux symptoms who had a partial or full symptom response to AST (P < .01). The severity of acid reflux on pH testing, symptom indices, severity of esophagitis, and hiatal hernia size were not associated with symptom response. CONCLUSIONS In a retrospective study, we found the effectiveness of ARS to be less predictable in patients with extraesophageal symptoms of GERD than in patients with typical GERD. Response to AST before surgery was associated with ARS effectiveness in patients with extraesophageal reflux symptoms. Caution should be exercised when advocating ARS for patients with extraesophageal symptoms that do not respond to AST.
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Affiliation(s)
- Joseph T Krill
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rishi D Naik
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Tina Higginbotham
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee
| | - James C Slaughter
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Michael D Holzman
- Department of General Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David O Francis
- Vanderbilt Voice Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - C Gaelyn Garrett
- Vanderbilt Voice Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Michael F Vaezi
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee.
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Feng C, Luo Y, Nian Y, Liu D, Yin X, Wu J, Di J, Zhang R, Zhang J. Diallyl Disulfide Suppresses the Inflammation and Apoptosis Resistance Induced by DCA Through ROS and the NF-κB Signaling Pathway in Human Barrett’s Epithelial Cells. Inflammation 2017; 40:818-831. [DOI: 10.1007/s10753-017-0526-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Kusaka G, Uno K, Iijima K, Shimosegawa T. Role of nitric oxide in the pathogenesis of Barrett’s-associated carcinogenesis. World J Gastrointest Pathophysiol 2016; 7:131-137. [PMID: 26909236 PMCID: PMC4753179 DOI: 10.4291/wjgp.v7.i1.131] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 09/01/2015] [Accepted: 11/11/2015] [Indexed: 02/06/2023] Open
Abstract
Barrett’s esophagus (BE), a premalignant condition to Barrett’s adenocarcinoma (BAC), is closely associated with chronic inflammation due to gastro-esophageal reflux. Caudal type homeobox 2 (CDX2), a representative marker of BE, is increased during the metaplastic and neoplastic transformation of BE. Nitric oxide (NO) has been proposed to be a crucial mediator of Barrett’s carcinogenesis. We previously demonstrated that CDX2 might be induced directly under stimulation of large amounts of NO generated around the gastro-esophageal junction (GEJ) by activating epithelial growth factor receptor in a ligand-independent manner. Thus, we reviewed recent developments on the role of NO in Barrett’s carcinogenesis. Notably, recent studies have reported that microbial communities in the distal esophagus are significantly different among groups with a normal esophagus, reflux esophagitis, BE or BAC, despite there being no difference in the bacterial quantity. Considering that microorganism components can be one of the major sources of large amounts of NO, these studies suggest that the bacterial composition in the distal esophagus might play an important role in regulating NO production during the carcinogenic process. Controlling an inflammatory reaction due to gastro-esophageal reflux or bacterial composition around the GEJ might help prevent the progression of Barrett’s carcinogenesis by inhibiting NO production.
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11
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Guan X, Yi Y, Huang Y, Hu Y, Li X, Wang X, Fan H, Wang G, Wang D. Revealing potential molecular targets bridging colitis and colorectal cancer based on multidimensional integration strategy. Oncotarget 2015; 6:37600-12. [PMID: 26461477 PMCID: PMC4741951 DOI: 10.18632/oncotarget.6067] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Accepted: 09/24/2015] [Indexed: 02/05/2023] Open
Abstract
Chronic inflammation may play a vital role in the pathogenesis of inflammation-associated tumors. However, the underlying mechanisms bridging ulcerative colitis (UC) and colorectal cancer (CRC) remain unclear. Here, we integrated multidimensional interaction resources, including gene expression profiling, protein-protein interactions (PPIs), transcriptional and post-transcriptional regulation data, and virus-host interactions, to tentatively explore potential molecular targets that functionally link UC and CRC at a systematic level. In this work, by deciphering the overlapping genes, crosstalking genes and pivotal regulators of both UC- and CRC-associated functional module pairs, we revealed a variety of genes (including FOS and DUSP1, etc.), transcription factors (including SMAD3 and ETS1, etc.) and miRNAs (including miR-155 and miR-196b, etc.) that may have the potential to complete the connections between UC and CRC. Interestingly, further analyses of the virus-host interaction network demonstrated that several virus proteins (including EBNA-LP of EBV and protein E7 of HPV) frequently inter-connected to UC- and CRC-associated module pairs with their validated targets significantly enriched in both modules of the host. Together, our results suggested that multidimensional integration strategy provides a novel approach to discover potential molecular targets that bridge the connections between UC and CRC, which could also be extensively applied to studies on other inflammation-related cancers.
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Affiliation(s)
- Xu Guan
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ying Yi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yan Huang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yongfei Hu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xiaobo Li
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Xishan Wang
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huihui Fan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Guiyu Wang
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dong Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
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Schwacke J, Millar TP, Hammond CE, Saha A, Hoffman BJ, Romagnuolo J, Hill EG, Smolka AJ. Discrimination of normal and esophageal cancer plasma proteomes by MALDI-TOF mass spectrometry. Dig Dis Sci 2015; 60:1645-54. [PMID: 25577268 DOI: 10.1007/s10620-014-3513-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 12/29/2014] [Indexed: 12/09/2022]
Abstract
BACKGROUND Most patients presenting with symptoms of esophageal cancer (EC) have advanced disease. Even with resection, the cure rate is extremely low due to local recurrence and metastatic disease. Early detection and effective therapeutic intervention are essential to improve survival. AIMS This study tested the hypothesis that the presence of EC modulates concentrations of specific plasma proteins and peptides, potentially allowing discrimination between EC and controls based on mass spectrometric analysis of the respective plasma proteomes. METHODS Blood samples from 79 esophageal cancer patients and 40 age-matched normal subjects were processed to plasma, and protein/peptide sub-fractions were isolated using HIC8 or WAX-derivatized superparamagnetic beads. Triplicate matrix-assisted laser desorption time-of-flight mass spectra were acquired for specific plasma fractions from each subject. RESULTS HIC8 and WAX-derivatized plasma eluates yielded 79 and 77 candidate features, respectively, and a Random Forest algorithm identified a subset of features whose peak intensities allowed discrimination between cancer patients and controls. Areas under the curve in receiver operating characteristic curves for HIC8 spectra were 0.88 and 0.83 for WAX spectra. The combined feature set discriminated EC from control plasma with 79 % sensitivity and 79 % specificity, with positive and negative test likelihood ratios of >14 and 0.17, respectively. CONCLUSIONS These data lay the foundation for the development of a clinically useful test for esophageal cancer based on statistical analysis of proteomic spectra of patient plasma samples. This approach will be validated by analysis of larger patient cohorts, development of cancer-specific classifiers, and assessment of racial origin imbalances.
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Esmaillzadeh A, Keshteli AH, Tabesh M, Feizi A, Adibi P. Smoking status and prevalence of upper gastrointestinal disorders. Digestion 2015; 89:282-90. [PMID: 25034636 DOI: 10.1159/000358169] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 12/20/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Lifestyle and environmental factors affecting upper gastrointestinal (GI) disorders are different in developing countries than those in developed nations. OBJECTIVE This study aimed to examine the association between smoking status and upper GI disorders among a large group of the Iranian adult population. METHODS This cross-sectional study was conducted among 1,933 adult men in Isfahan, Iran. Smoking status was assessed by a self-administered questionnaire. Required information on GI health was collected through the use of the validated ROME III questionnaire. Individuals who reported having heartburn sometimes, often, or always in the last 3 months were considered as having epidemiologic gastroesophageal reflux disease (GERD), and those who reported having heartburn often or always were considered as having clinical GERD. Subjects who reported having functional dyspepsia (FD) symptoms (based on the ROME III criteria) sometimes, often, or always in the last 3 months were considered as having epidemiologic FD, and those who reported having these disorders often or always were considered as having clinical FD. RESULTS Smoking was prevalent among 7.8% of the study population. FD and GERD was prevalent among 12.6% (n = 244) and 22.3% (n = 432), respectively. Smoking was not associated with GERD by either the epidemiologic or clinical definition. Although the association between smoking and FD (epidemiologic definition) was not statistically significant, smokers had an 83% higher risk of suffering from clinical FD compared with nonsmokers after taking potential confounders into account [odds ratio (OR) = 1.83, 95% CI: 1.12-3.00; p = 0.01]. Smokers had a 57% higher risk for epidemiologic postprandial fullness (OR = 1.57, 95% CI: 1.05-2.33; p = 0.02) and a 92% higher risk for clinical epigastric pain compared with nonsmokers (OR = 1.92, 95% CI: 1.02-3.62; p = 0.04). We found no significant association between smoking and severity of upper GI disorders. CONCLUSION This large population-based study indicated that smoking was not associated with GERD and epidemiologic FD. However, smoking was significantly associated with clinical FD, postprandial fullness, and epigastric pain.
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Affiliation(s)
- Ahmad Esmaillzadeh
- Food Security Research Center, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
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Kirtane TS, Wagh MS. Endoscopic Optical Coherence Tomography (OCT): Advances in Gastrointestinal Imaging. Gastroenterol Res Pract 2014; 2014:376367. [PMID: 24719611 PMCID: PMC3955614 DOI: 10.1155/2014/376367] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 12/21/2013] [Indexed: 12/20/2022] Open
Abstract
In the rapidly evolving field of endoscopic gastrointestinal imaging, Optical Coherence Tomography (OCT) has found many diverse applications. We present the current status of OCT and its practical applications in imaging normal and abnormal mucosa in the esophagus, stomach, small and large intestines, and biliary and pancreatic ducts. We highlight technical aspects and principles of imaging, assess published data, and suggest future directions for OCT-guided evaluation and therapy.
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Affiliation(s)
- Tejas S. Kirtane
- Department of Medicine, Washington Hospital Center, 110 Irving St NW, Washington, DC 20010, USA
| | - Mihir S. Wagh
- Division of Gastroenterology, University of Florida, 1600 SW Archer Road, P.O. Box 100214, Gainesville, FL 32610, USA
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15
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Dewalt RI, Kesler KA, Hammoud ZT, Baldridge L, Hattab EM, Jalal SI. Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair. LUNG CANCER-TARGETS AND THERAPY 2014; 5:11-20. [PMID: 28210138 PMCID: PMC5217507 DOI: 10.2147/lctt.s57594] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Esophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues. METHODS We analyzed the expression of genes involved in homologous recombination (HR), nonhomologous end-joining, and nucleotide excision repair (NER) pathways in 12 EAC tumor samples with their matched normal counterparts. These pathways were chosen because they are the main pathways involved in the repair of platinum- or ionizing-radiation-induced damage. In addition, abnormalities in these pathways have not been well characterized in EAC. RESULTS We identified increased expression of at least one HR gene in eight of the EAC tumor samples. Alterations in the expression of EME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples. In addition, all EAC samples revealed decreased expression of at least one of numerous NER genes including XPC, XPA, DDB2, XPF, and XPG. CONCLUSION Our study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration of EME1 upregulation in any cancer. These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC.
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Affiliation(s)
| | - Kenneth A Kesler
- Cardiothoracic Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - LeeAnn Baldridge
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Eyas M Hattab
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Shadia I Jalal
- Division of Hematology/Oncology, Department of Medicine; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA
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Infiltration of Tumor-associated Macrophages is Increased in the Epithelial and Stromal Compartments of Endometrial Carcinomas. Int J Gynecol Pathol 2013; 32:576-84. [DOI: 10.1097/pgp.0b013e318284e198] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Fei L, Rossetti G, Moccia F, Marra T, Guadagno P, Docimo L, Cimmino M, Napolitano V, Docimo G, Napoletano D, Guerriero L, Pascotto B. Is the advanced age a contraindication to GERD laparoscopic surgery? Results of a long term follow-up. BMC Surg 2013; 13 Suppl 2:S13. [PMID: 24267613 PMCID: PMC3851262 DOI: 10.1186/1471-2482-13-s2-s13] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background In this prospective non randomized observational cohort study we have
evaluated the influence of age on outcome of laparoscopic total
fundoplication for GERD. Methods Six hundred and twenty consecutive patients underwent total laparoscopic
fundoplication for GERD. Five hundred and twenty-four patients were younger
than 65 years (YG), and 96 patients were 65 years or older (EG). The
following parameters were considered in the preoperative and postoperative
evaluation: presence, duration, and severity of GERD symptoms, presence of a
hiatal hernia, manometric and 24 hour pH-monitoring data, duration of
operation, incidence of complications and length of hospital stay. Results Elderly patients more often had atypical symptoms of GERD and at manometric
evaluation had a higher rate of impaired esophageal peristalsis in
comparison with younger patients. The duration of the operation was similar
between the two groups. The incidence of intraoperative and postoperative
complications was low and the difference was not statistically significant
between the two groups. An excellent outcome was observed in 93.0% of young
patients and in 88.9% of elderly patients (p = NS). Conclusions Laparoscopic antireflux surgery is a safe and effective treatment for GERD
even in elderly patients, warranting low morbidity and mortality rates and a
significant improvement of symptoms comparable to younger patients.
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18
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Bajpai M, Kessel R, Bhagat T, Nischal S, Yu Y, Verma A, Das KM. High resolution integrative analysis reveals widespread genetic and epigenetic changes after chronic in-vitro acid and bile exposure in Barrett's epithelium cells. Genes Chromosomes Cancer 2013; 52:1123-32. [PMID: 24123713 DOI: 10.1002/gcc.22106] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 07/31/2013] [Accepted: 08/01/2013] [Indexed: 12/12/2022] Open
Abstract
Barrett's epithelium (BE) is a premalignant condition resulting from chronic gastroesophageal reflux that may progress to esophageal adenocarcinoma (EAC). Early intervention holds promise in preventing BE progression. However, identification of high-risk BE patients remains challenging due to inadequate biomarkers for early diagnosis. We investigated the effect of prolonged chronic acid and bile exposure on transcriptome, methylome, and mutatome of cells in an in-vitro BE carcinogenesis (BEC) model. Twenty weeks acid and bile exposed cells from the BEC model (BEC20w) were compared with their naïve predecessors HiSeq Illumina based RNA sequencing was performed on RNA from both the cells for gene expression and mutational analysis. HELP Tagging Assay was performed for DNA methylation analysis. Ingenuity pathway, Gene Ontology, and KEGG PATHWAY analyses were then performed on datasets. Widespread aberrant genetic and epigenetic changes were observed in the BEC20w cells. Combinatorial analyses revealed 433 from a total of 863 downregulated genes had accompanying hypermethylation of promoters. Simultaneously, 690 genes from a total of 1,492 were upregulated with accompanying promoter hypomethylation. In addition, 763 mutations were identified on 637 genes. Ingenuity pathway analysis, Gene Ontology, and KEGG PATHWAY analyses associated the genetic and epigenetic changes in BEC20w cells with cellular and biological functions. Integration of high resolution comparative analyses of naïve BAR-T and BEC20w cells revealed striking genetic and epigenetic changes induced by chronic acid and bile exposure that may disrupt normal cellular functions and promote carcinogenesis. This novel study reveals several potential targets for future biomarkers and therapeutic development.
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Affiliation(s)
- Manisha Bajpai
- Division of Gastroenterology and Hepatology, Department of Medicine, RUTGERS Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
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Godoy MCB, Bruzzi JF, Viswanathan C, Truong MT, Guimarães MD, Hofstetter WL, Erasmus JJ, Marom EM. Multimodality imaging evaluation of esophageal cancer: staging, therapy assessment, and complications. ACTA ACUST UNITED AC 2013; 38:974-93. [DOI: 10.1007/s00261-013-9986-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Chen Z, Saad R, Jia P, Peng D, Zhu S, Washington MK, Zhao Z, Xu Z, El-Rifai W. Gastric adenocarcinoma has a unique microRNA signature not present in esophageal adenocarcinoma. Cancer 2013; 119:1985-93. [PMID: 23456798 DOI: 10.1002/cncr.28002] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 01/02/2013] [Accepted: 01/03/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs) play critical roles in tumor development and progression. The finding that a single miRNA can regulate hundreds of genes places miRNAs at critical hubs of signaling pathways. For the current study, the authors investigated the miRNA expression profile of gastric adenocarcinomas and compared it with esophageal adenocarcinomas to better identify a unique miRNA signature of gastric adenocarcinoma. METHODS miRNA expression profiles were obtained using 2 different proprietary microarray platforms on primary gastric adenocarcinoma tissue samples. The cross comparison of results identified 17 up-regulated miRNAs and 12 down-regulated miRNAs that overlapped in both platforms. Quantitative real-time polymerase chain reaction was performed for independent validation of a representative set of 8 miRNAs in gastric and esophageal adenocarcinomas compared with normal gastric mucosa or esophageal mucosa, respectively. RESULTS The deregulation of miR-146b-5p, miR-375, miR-148a, miR-31, and miR-451 was associated significantly with gastric adenocarcinomas. Conversely, deregulation of miR-21 (up-regulation) and miR-133b (down-regulation) was detectable in both gastric and esophageal adenocarcinomas. It was noteworthy that miR-200a was significantly down-regulated in gastric adenocarcinoma samples (P = .04) but was up-regulated in esophageal adenocarcinoma samples (P = .001). In addition, the expression level of miR-146b-5p displayed a strong correlation with the tumor stage of gastric cancer. CONCLUSIONS Gastric adenocarcinoma displayed a unique miRNA signature that distinguished it from esophageal adenocarcinoma. This specific signature may reflect differences in the etiology and/or molecular signaling in these 2 closely related cancers. The current findings suggest important miRNA candidates that can be investigated for their biological functions and for their possible diagnostic, prognostic, and therapeutic role in gastric adenocarcinoma.
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Affiliation(s)
- Zheng Chen
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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21
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Chen X, Jiang K, Fan Z, Liu Z, Zhang P, Zheng L, Peng N, Tong J, Ji G. Aberrant expression of Wnt and Notch signal pathways in Barrett's esophagus. Clin Res Hepatol Gastroenterol 2012; 36:473-83. [PMID: 22889748 DOI: 10.1016/j.clinre.2012.06.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 05/30/2012] [Accepted: 06/06/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Specialized intestinal metaplasia (SIM) mucosa observed in Barrett's esophagus (BE) has been a hot research topic due to the close relationship with adenocarcinoma of esophagus (ACE). Earlier studies found that SIM mucosa was similar to normal intestinal epithelium on morphology and histology. The signal pathway involved in conformation of intestinal epithelium may be a critical initiator for BE. METHODS The expressions of key regulators (Tcf4, Cdx2, Hes1 and Math1) in Wnt and Notch signal pathways were measured in 41 paired esophageal biopsies. Cell morphological changes in normal esophagus were compared among groups treated by acid, bile acid and the mixture of both media. RESULTS The expression levels of regulators (Tcf4, Cdx2, Hes1 and Math1) were found significantly increased in SIM, C ≥ 3Mn and high-grade dysplasia (HGD) groups. Distinct ultrastructure changes and highly expressed key regulators were also detected at the seventh day for group treated by 400 μmol bile acid. CONCLUSIONS Aberrant expressed regulators in Wnt and Notch pathways were observed in BE tissue and normal esophageal cells treated by acid, bile acid and the mixture of both media. This study provided preliminary data to understand the mechanism of BE conformation.
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Affiliation(s)
- Xia Chen
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, 121, Jing Jiayuan, Nanjing 210011, China
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22
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Zhou C, Tsai TH, Lee HC, Kirtane T, Figueiredo M, Tao YK, Ahsen OO, Adler DC, Schmitt JM, Huang Q, Fujimoto JG, Mashimo H. Characterization of buried glands before and after radiofrequency ablation by using 3-dimensional optical coherence tomography (with videos). Gastrointest Endosc 2012; 76:32-40. [PMID: 22482920 PMCID: PMC3396122 DOI: 10.1016/j.gie.2012.02.003] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Accepted: 02/03/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Radiofrequency ablation (RFA) is an endoscopic technique used to eradicate Barrett's esophagus (BE). However, such ablation can commonly lead to neosquamous epithelium overlying residual BE glands not visible by conventional endoscopy and may evade detection on random biopsy samples. OBJECTIVE To demonstrate the capability of endoscopic 3-dimensional optical coherence tomography (3D-OCT) for the identification and characterization of buried glands before and after RFA therapy. DESIGN Cross-sectional study. SETTING Single teaching hospital. PATIENTS Twenty-six male and 1 female white patients with BE undergoing RFA treatment. INTERVENTIONS 3D-OCT was performed at the gastroesophageal junction in 18 patients before attaining complete eradication of intestinal metaplasia (pre-CE-IM group) and in 16 patients after CE-IM (post-CE-IM group). MAIN OUTCOME MEASUREMENTS Prevalence, size, and location of buried glands relative to the squamocolumnar junction. RESULTS 3D-OCT provided an approximately 30 to 60 times larger field of view compared with jumbo and standard biopsy and sufficient imaging depth for detecting buried glands. Based on 3D-OCT results, buried glands were found in 72% of patients (13/18) in the pre-CE-IM group and 63% of patients (10/16) in the post-CE-IM group. The number (mean [standard deviation]) of buried glands per patient in the post-CE-IM group (7.1 [9.3]) was significantly lower compared with the pre-CE-IM group (34.4 [44.6]; P = .02). The buried gland size (P = .69) and distribution (P = .54) were not significantly different before and after CE-IM. LIMITATIONS A single-center, cross-sectional study comparing patients at different time points in treatment. Lack of 1-to-1 coregistered histology for all OCT data sets obtained in vivo. CONCLUSION Buried glands were frequently detected with 3D-OCT near the gastroesophageal junction before and after radiofrequency ablation.
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Affiliation(s)
- Chao Zhou
- Department of Electrical Engineering and Computer Science, Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Vandernoot I, Sartelet H, Abu-Khudir R, Chanoine JP, Deladoëy J. Evidence for calcitonin-producing cells in human lingual thyroids. J Clin Endocrinol Metab 2012; 97:951-6. [PMID: 22238389 DOI: 10.1210/jc.2011-2772] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT The thyroid contains two types of cells, the thyroid follicular cells and the calcitonin-producing cells. The site of origin of the thyroid follicular cells is the median thyroid anlage, an endothelial diverticulum in the midline of the ventral pharynx between the first and the second pharyngeal pouches. The ultimobranchial bodies (UBB), a pair of transient embryonic structures evaginated from the fourth pharyngeal pouch and located symmetrically on the sides of the developing neck, are the source of calcitonin-producing cells. In human embryos, the thyroid bud starts its migration at embryonic day 24 and reaches its final location in front of the trachea at embryonic day 45-50. The UBB fuse with the primitive thyroid when thyroid migration is completed. Lingual thyroids result from the failure of the thyroid precursor cells to migrate from the primordial pharynx to the anterior part of the neck. Therefore, calcitonin-producing cells are not expected to be present in lingual thyroids. OBJECTIVE Our objective was to determine whether calcitonin-producing C cells are present in ectopic lingual thyroids. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE We performed calcitonin immunolabeling and transcript detection on four flash-frozen ectopic lingual thyroids. Additional calcitonin immunolabeling was performed on two other paraffin-embedded ectopic lingual thyroids. RESULTS We report evidence of calcitonin-producing cells in six independent cases of ectopic lingual thyroids. CONCLUSION The UBB are not the only source of calcitonin-producing cells in humans. Interactions between calcitonin-producing and thyroid follicular cells occur earlier than previously accepted.
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Affiliation(s)
- Isabelle Vandernoot
- Research Center of Sainte-Justine Hospital, Department of Pediatrics, University of Montreal, Montréal, Quebec, Canada H3T 1C5
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Yang L, Francois F, Pei Z. Molecular pathways: pathogenesis and clinical implications of microbiome alteration in esophagitis and Barrett esophagus. Clin Cancer Res 2012; 18:2138-44. [PMID: 22344232 DOI: 10.1158/1078-0432.ccr-11-0934] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Esophageal adenocarcinoma is preceded by the development of reflux-related intestinal metaplasia or Barrett esophagus, which is a response to inflammation of the esophageal squamous mucosa, reflux esophagitis. Gastroesophageal reflux impairs the mucosal barrier in the distal esophagus, allowing chronic exposure of the squamous epithelium to the diverse microbial ecosystem or microbiome and inducing chronic inflammation. The esophageal microbiome is altered in both esophagitis and Barrett esophagus, characterized by a significant decrease in gram-positive bacteria and an increase in gram-negative bacteria in esophagitis and Barrett esophagus. Lipopolysaccharides (LPS), a major structure of the outer membrane in gram-negative bacteria, can upregulate gene expression of proinflammatory cytokines via activation of the Toll-like receptor 4 and NF-κB pathway. The potential impact of LPS on reflux esophagitis may be through relaxation of the lower esophageal sphincter via inducible nitric oxide synthase and by delaying gastric emptying via cyclooxygenase-2. Chronic inflammation may play a critical role in the progression from benign to malignant esophageal disease. Therefore, analysis of the pathways leading to chronic inflammation in the esophagus may help to identify biomarkers in patients with Barrett esophagus for neoplastic progression and provide insight into molecular events suitable for therapeutic intervention in prevention of esophageal adenocarcinoma development in patients with reflux esophagitis and Barrett esophagus.
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Affiliation(s)
- Liying Yang
- Department of Medicine and Pathology, New York University School of Medicine, New York, New York 10010, USA
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The histological and immunohistochemical aspects of bile reflux in patients with gastroesophageal reflux disease. Gastroenterol Res Pract 2011; 2011:905872. [PMID: 21822428 PMCID: PMC3142670 DOI: 10.1155/2011/905872] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Accepted: 06/03/2011] [Indexed: 11/17/2022] Open
Abstract
Introduction. The pathogenesis of GERD is strongly related with mixed acid and bile reflux. Benign and malignant esophageal and gastric lesions have been associated with synergetic activity between those parameters. Bile reflux causes reactive gastropathy evaluated with Bile Reflux Index (BRI). The aim was to investigate if the sequence: bile reflux-intestinal metaplasia-GERD-esophagitis, is associated with apoptotic/oncogenetic disturbances. Materials/Methods. Fifteen asymptomatic subjects and 53 GERD patients underwent gastroscopy with biopsies. The specimens examined histologically and immunohistochemically for p53, Ki-67, Bax, and Bcl-2. Results. Elevated BRI score detected in 47% (25/53) of patients with GERD and in 13% (2/15) of controls (P = 0.02). Severe esophageal lesions were significantly more common in BRI (+) patients (14/25) compared to BRI (-) ones (P = 0.0049). Immunohistochemical analysis did not show associations between BRI score and biomarker expression. Conclusions. Bile reflux gastropathy is associated with GERD severity, but not with oncogene expression or apoptotic discrepancies of the upper GI mucosa.
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Murao T, Sakurai K, Mihara S, Marubayashi T, Murakami Y, Sasaki Y. Lifestyle change influences on GERD in Japan: a study of participants in a health examination program. Dig Dis Sci 2011; 56:2857-64. [PMID: 21487772 PMCID: PMC3179841 DOI: 10.1007/s10620-011-1679-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 03/11/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND Though gastroesophageal reflux disease (GERD) has been a prevalent disease in Western countries, the incidence of GERD has only just started to increase in Japan. AIM The aim of this study was to determine which lifestyle factors may be associated with GERD in Japan. METHODS A total of 2,853 participants who took part in a health examination program between July 2004 and March 2005 were enrolled. GERD symptoms were assessed using the Japanese version of the Carlsson-Dent self-administered questionnaire (QUEST). The GERD group consisted of participants with a QUEST score ≥6 and/or endoscopic findings. The GERD group was divided into asymptomatic ERD (erosive reflux disease with no symptoms), symptomatic ERD (erosive reflux disease with symptoms) and NERD (non-erosive reflux disease) groups. Associated factors for these diseases were analyzed by logistic regression analysis. RESULTS GERD was diagnosed in 667 (23.4%) participants. Among the subjects placed in the GERD group, asymptomatic ERD, symptomatic ERD and NERD were diagnosed in 232 (8.1%), 91 (3.2%) and 344 (12.1%) participants, respectively. Factors associated with GERD included a high BMI (body mass index), hiatus hernia, fewer hours of sleep, lack of exercise, and drinking green tea. CONCLUSIONS Relationships between lifestyle, gender and GERD were investigated in the present study. Both lifestyle improvements and consideration of gender differences can be used to help prevent GERD development.
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Affiliation(s)
- Tetsuya Murao
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556 Japan
| | - Kouichi Sakurai
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556 Japan
| | - Syuuichi Mihara
- Japanese Red Cross Kumamoto Health Care Center, 1-1 Nagamineminami, Kumamoto City, Kumamoto 861-8528 Japan
| | - Toru Marubayashi
- Japanese Red Cross Kumamoto Health Care Center, 1-1 Nagamineminami, Kumamoto City, Kumamoto 861-8528 Japan
| | - Yoshitaka Murakami
- Department of Medical Statistics, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu City, Shiga 520-2192 Japan
| | - Yutaka Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556 Japan
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Abstract
AIM To review the records of Cornelia de Lange Syndrome (CDLS) children, affected by Gastro-oesophageal reflux disease (GERD), to detect the presence of Barrett's Esophagus (BE). METHODS A total of 62 CDLS patients were investigated for GERD (1 month-35 years). In all of them a pH-metry, an upper endoscopy with multiple biopsies and a complete radiologic digestive evaluation were carried out. BE was diagnosed in case of replacement of oesophageal mucosa by specialized intestinal-type columnar mucosa. Anti-reflux surgery was considered in case of persistence of BE after medical therapy. Follow-up (mean 3.5 years) consisted in endoscopy every 6 months . RESULTS Gastro-oesophageal reflux disease was found in 50 CDLS patients (80%) and BE in six of them (12% of the GERD group, 9.6% of the entire population, mean age 17 years, range 6-32 years). A short segment BE was observed in three patients, a long one in two patients and an infiltrating adenocarcinoma of the lower oesophagus in one patient. CONCLUSIONS A higher frequency of BE in CDLS patients than in a normal population is found. A delayed diagnosis because of atypical GERD symptoms and an altered intestinal motility as a result of neurological impairment can be recognized as the main cause.
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Affiliation(s)
- Francesco Macchini
- Pediatric Surgery Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
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Das KM, Kong Y, Bajpai M, Kulkarni D, Geng X, Mishra P, Banerjee D, Hirshfield K. Transformation of benign Barrett's epithelium by repeated acid and bile exposure over 65 weeks: a novel in vitro model. Int J Cancer 2010; 128:274-82. [PMID: 20309934 DOI: 10.1002/ijc.25343] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Accepted: 03/04/2010] [Indexed: 12/13/2022]
Abstract
The mechanism by which gastroesophageal reflux promotes metaplasia→dysplasia→carcinoma is unknown. The aim of the study is to determine if repeated exposure to acid and bile confers a tumorigenic phenotype in a telomerase (hTERT)-immortalized benign Barrett's cell line (BAR-T). BAR-T cells were exposed to acid (pH 4) (A) and bile salt (200 μM glycochenodeoxycholic acid) (B) daily for 5 min up to 65+ weeks. The control cells were grown in parallel without any A or B treatment. Cell morphology, proliferation, transformation, and molecular changes in the gene expression for COX-2, TC22, p53 and p53 target genes were analyzed at 8-12 weeks intervals. At 46 weeks BAR-T cells exposed to (A+B) showed distinct phenotypic changes: forming clusters and acini, and at 65 weeks displayed foci in monolayer, and formed distinct colonies in soft agar. Untreated cells did not show any such changes. In A+B-treated BAR-T cells, COX-2 mRNA increased 10- to 20-fold, TC22 mRNA increased by 2- to 3-fold at 22-65 weeks, p53, MDM2, PERP, and p21mRNA increased 2.5-, 6.4-, 4-, and 2.6-fold respectively when compared to untreated cells at 34 weeks. However, at 58 weeks onward, there was a sharp decline of p53 and its target genes to the baseline level. At 65 weeks A+B-treated BAR-T cells formed tumor in nude mice whereas untreated cells did not. We demonstrate a novel in vitro model of transformation of a benign Barrett's cell line following repeated exposure to A+B over the course of 65 weeks.
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Affiliation(s)
- Kiron M Das
- Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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Affiliation(s)
- D F Ransohoff
- Departments of Medicine and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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30
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Abstract
Gastro-oesophageal reflux disease results from impaired function of the LOS and acid clearance of the distal oesophagus. Most patients do not require investigation and respond either to lifestyle changes, antacid/alginates, H2A, PPI or a combination of these treatments. Surgery is only rarely indicated.
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31
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Wang JS, Guo M, Montgomery EA, Thompson RE, Cosby H, Hicks L, Wang S, Herman JG, Canto MI. DNA promoter hypermethylation of p16 and APC predicts neoplastic progression in Barrett's esophagus. Am J Gastroenterol 2009; 104:2153-60. [PMID: 19584833 PMCID: PMC3090447 DOI: 10.1038/ajg.2009.300] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Prediction of progression to cancer in patients with Barrett's esophagus (BE) is difficult using current techniques. We determined whether DNA promoter hypermethylation of genes frequently methylated in esophageal adenocarcinoma (p16 and APC) could be used as predictors of progression in BE. METHODS We first performed a cross-sectional study to evaluate the prevalence of gene hypermethylation in biopsies from patients with normal esophagus (n=17), BE (n=102), and adenocarcinoma (n=42). We then performed a nested case-control study comparing gene hypermethylation in BE patients who progressed from baseline pathology to high-grade dysplasia or cancer (n=7) vs. patients who did not progress (n=50). RESULTS None of the patients with normal esophagus had p16 or APC hypermethylation. Hypermethylation was prevalent in BE without dysplasia or low-grade dysplasia (p16=31% and APC=50%; P<0.01) and high-grade dysplasia or adenocarcinoma (p16=54% and APC=68%; P<0.001) compared with normal esophagus (not detected). Patients who progressed from baseline pathology to high-grade dysplasia or cancer had higher prevalence of hypermethylation in their initial esophagus biopsies compared with those who did not progress for both p16 (100 vs. 33%; P=0.008) and APC (86 vs. 40%; P=0.02). Hypermethylation of both p16 and APC was a strong predictor of subsequent progression to high-grade dysplasia or cancer during a mean follow-up time of 4.1 years (odds ratio (95% confidence interval)=14.97 (1.73,inf), P=0.01). Among patients who were negative for both p16 and APC hypermethylation, none progressed from baseline pathology to high-grade dysplasia or cancer. CONCLUSIONS Hypermethylation of both p16 and APC strongly predicts progression to high-grade dysplasia or cancer in patients with BE. Absence of p16 and APC hypermethylation is associated with a benign course.
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Affiliation(s)
- Jean S. Wang
- Department of Medicine (Gastroenterology), Johns Hopkins University, Baltimore, Maryland, USA
| | - Mingzhou Guo
- Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA, Department of Gastroenterology, Chinese PLA General Hospital, Beijing, P.R. China
| | | | - Richard E. Thompson
- Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA
| | - Hilary Cosby
- Department of Medicine (Gastroenterology), Johns Hopkins University, Baltimore, Maryland, USA
| | - Lisa Hicks
- Department of Medicine (Gastroenterology), Johns Hopkins University, Baltimore, Maryland, USA
| | - Shelun Wang
- Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA, Department of Oncology, 306th Hospital, PLA, Beijing, P.R. China
| | - James G. Herman
- Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Marcia I. Canto
- Department of Medicine (Gastroenterology), Johns Hopkins University, Baltimore, Maryland, USA, Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA
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Festi D, Scaioli E, Baldi F, Vestito A, Pasqui F, Biase ARD, Colecchia A. Body weight, lifestyle, dietary habits and gastroesophageal reflux disease. World J Gastroenterol 2009; 15:1690-701. [PMID: 19360912 PMCID: PMC2668774 DOI: 10.3748/wjg.15.1690] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
While lifestyle modifications are currently used as first-line treatment for subjects with gastroesophageal reflux disease (GERD), the pathogenetic role of lifestyle factors and consequently, the efficacy of lifestyle measures is controversial. Our aim was to systematically review the pathogenetic link between overweight/obesity, dietary habits, physical activity and GERD, and the beneficial effect of specific recommended changes, by means of the available literature from the 1999 to the present. Obesity, in particular, abdominal obesity, plays a key role in determining GERD symptoms and complications through mechanical and metabolic effects. Controlled weight loss (by diet or surgery) is effective in improving GERD symptoms. No definitive data exist regarding the role of diet and, in particular, of specific foods or drinks, in influencing GERD clinical manifestations. Moderate physical activity seems to be beneficial for GERD, while vigorous activity may be dangerous in predisposed individuals. In conclusion, being obese/overweight and GERD-specific symptoms and endoscopic features are related, and weight loss significantly improves GERD clinical-endoscopic manifestations. The role of dietary behavior, mainly in terms of specific dietary components, remains controversial. Mild routine physical activity in association with diet modifications, i.e. a diet rich in fiber and low in fat, is advisable in preventing reflux symptoms.
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Sengpiel C, König IR, Rades D, Noack F, Duchrow M, Schild SE, Ludwig D, Homann N. p53 Mutations in carcinoma of the esophagus and gastroesophageal junction. Cancer Invest 2009; 27:96-104. [PMID: 19160092 DOI: 10.1080/07357900802161047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Recent studies suggested p53 mutations as a prognostic factor. Tumors of the esophagus and gastroesophageal (GE) junction show raising incidence with a general poor prognosis. METHODS p53 Mutational spectra in 103 patients (68 squamous cell carcinoma/SCC and 35 adenocarcinoma/AC) were compared to clinical and pathologic data. RESULTS AND CONCLUSIONS p53 Mutations were found in 26 of 68 SSC (38.2%) and in 12 of 35 AC (34.5%). We only found G > T transversions in smokers with SCC. The survival of patients was not affected by p53 mutational status. In our study, the frequency and mutational spectrum of mutant p53 is similar in both histological types without prognostic relevance.
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Affiliation(s)
- C Sengpiel
- Department of Gastroenterology, University Hospital Schleswig-Holstein, Campus Lubeck, Germany
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34
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Tan BHL, Skipworth RJE, Stephens NA, Wheelhouse NM, Gilmour H, de Beaux AC, Paterson-Brown S, Fearon KCH, Ross JA. Frequency of the mitochondrial DNA 4977bp deletion in oesophageal mucosa during the progression of Barrett's oesophagus. Eur J Cancer 2009; 45:736-40. [PMID: 19211242 DOI: 10.1016/j.ejca.2009.01.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2008] [Revised: 01/06/2009] [Accepted: 01/13/2009] [Indexed: 01/07/2023]
Abstract
PURPOSE The mechanisms of the progression of Barrett's oesophagus (BO) to oesophageal adenocarcinoma (OA) are poorly understood. The frequency of the 4977bp deletion in mitochondrial DNA (mtDNA) was investigated in specimens ranging from normal oesophageal tissue to OA in order to investigate whether this deletion represents a useful biomarker of disease progression. METHODS The presence of the 4977bp deletion was screened by PCR amplification from 70 specimens in total. RESULTS The frequency of specimens with the 4977bp deletion increased in relation to the degree of dysplasia (8.3% in normal squamous epithelium; 15.4% in BO; 40% in low grade dysplasia (LGD); 69.2% in high-grade dysplasia and 90% in para-tumoural tissue). However, the frequency of the deletion reduced sharply in OA specimens (16.7%; p<0.001). CONCLUSION The mtDNA 4977bp deletion may be useful as a biomarker to detect the severity of dysplasia but not the presence of OA.
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Affiliation(s)
- Benjamin H L Tan
- University of Edinburgh, Clinical and Surgical Sciences (Surgery), Royal Infirmary, Edinburgh, UK.
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35
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Vereczkei A, Horvath OP, Varga G, Molnar TF. Gastroesophageal reflux disease and non-small cell lung cancer. Results of a pilot study. Dis Esophagus 2008; 21:457-60. [PMID: 19125801 DOI: 10.1111/j.1442-2050.2007.00796.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The sharp rise in the frequency of adenocarcinoma and relative decrease of squamous cell carcinoma of the respiratory and digestive systems, raises suspicion of a common element in their carcinogenetic cascade, which could result in similar trends in cell-type distribution changes of esophageal and lung cancers. The possible role of chemical irritation caused by gastroesophageal reflux disease (GERD) in non-small cell lung cancer (NSCLC) patients was investigated. There was no significant difference between the adenocarcinoma and the squamous cell carcinoma groups, neither in the composite DeMeester scores nor in any of the separate parameters of the complex score investigated. However, the ratio of detected gastroesophageal reflux cases was considerably higher than in the average population. This factor may be one element of a multifactorial cancer promotion.
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Affiliation(s)
- A Vereczkei
- Department of Surgery, Medical School, University of Pécs, Pécs, Hungary.
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36
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Chassany O, Holtmann G, Malagelada J, Gebauer U, Doerfler H, Devault K. Systematic review: health-related quality of life (HRQOL) questionnaires in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2008; 27:1053-70. [PMID: 18363898 DOI: 10.1111/j.1365-2036.2008.03683.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Although gastro-oesophageal reflux disease (GERD) has a well-established pathophysiology, the impact of GERD symptoms on the patients' quality of life can be profound. Therefore, health-related quality of life (HRQOL) questionnaires have become standard instruments to evaluate the effect of treatment in clinical trials. AIM To evaluate the reliability, validity and responsiveness of available GERD-specific HRQOL. METHODS A systematic literature search using the Medical Subject Headings terms: 'Gastro-oesophageal reflux', 'Heartburn' and 'Oesophagitis' with 'quality of life' and 'questionnaires' was preformed to identify the available HRQOL questionnaires. To analyse the psychometric properties of the respective tools, the actual guidelines for the use of patient-reported outcomes in clinical trials were applied. RESULTS We identified five GERD-specific HRQOL questionnaires but none of them fulfilled all quality criteria; either they did not meet the actual standards for psychometric properties (HBQOL, GERD-HRQL, Jasani et al.Aust Fam Physician 1999; 28: 515), or were impracticable to use in clinical trials. The generic and hybrid instruments lack specificity and sensitivity and were not designed for treatment evaluation in GERD patients. CONCLUSION There is need for a new evaluative tool in the assessment of HRQOL during GERD therapy.
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Affiliation(s)
- O Chassany
- Département de Recherche Clinique et du développement, Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France.
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Seibel EJ, Carroll RE, Dominitz JA, Johnston RS, Melville CD, Lee CM, Seitz SM, Kimmey MB. Tethered capsule endoscopy, a low-cost and high-performance alternative technology for the screening of esophageal cancer and Barrett's esophagus. IEEE Trans Biomed Eng 2008; 55:1032-42. [PMID: 18334395 DOI: 10.1109/tbme.2008.915680] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Esophageal cancer is currently the fastest growing cancer in the United States. To help combat the recent rise in morbidity, our laboratory has developed a low-cost tethered capsule endoscope system (TCE) aimed at improving early detection of esophageal cancer. The TCE contains a resonant fiberoptic laser scanner (1.6 mm O.D.) which fits into 6.4-mm easy-to-swallow capsule at the distal tip. The tethered portion contains a single mode optical fiber multiplexed to three laser diodes at the proximal end. This design offers two main advantages over current endoscope technology. First, because of its small size, the TCE can be swallowed with minimal patient discomfort, thereby obviating sedation. Second, by imaging via directed laser light, the TCE is strategically positioned to employ several burgeoning laser-based diagnostic technologies, such as narrow-band, hyperspectral, and fluorescence imaging. It is believed that the combination of such imaging techniques with novel biomarkers of dysplasia will greatly assist in identifying precancerous conditions such as Barrett's esophagus (BE). As the probe is swallowed, the fiber scanner captures high resolution, wide-field color images of the gastroesophageal junction (500 lines at 0.05-mm resolution) currently at 15-Hz frame rate. Video images are recorded as the capsule is slowly retracted by its tether. Accompanying software generates panoramic images from the video output by mosaicing individual frames to aid in pattern recognition. This initial report describes the rationale for the unique TCE system design, results from preliminary testing in vitro and in vivo, and discussion on the merits of this new platform technology as a basis for developing a low-cost screening program for esophageal cancer.
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Affiliation(s)
- Eric J Seibel
- Department of Mechanical Engineering, University of Washington, Human Photonics Lab, Box 352600, Seattle, WA 98195, USA.
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38
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Pizza F, Rossetti G, Del Genio G, Maffettone V, Brusciano L, Del Genio A, Del Genio A. Influence of esophageal motility on the outcome of laparoscopic total fundoplication. Dis Esophagus 2008; 21:78-85. [PMID: 18197944 DOI: 10.1111/j.1442-2050.2007.00756.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The aim of this study is to evaluate if esophageal dysmotility can influence the outcome of laparoscopic total fundoplication for gatro-esophageal reflux disease (GERD). The advent of laparoscopic fundoplication has greatly reduced the morbidity of antireflux surgery and by now, it should be considered the surgical treatment of choice for GERD. Some authors assert that total versus partial fundoplication should improve the rate of postoperative dysphagia or gas bloat syndrome, particularly in patients with esophageal dysmotility. From September 1992 to December 2005, 420 consecutive patients 171 male and 249 female, mean age 42.8 years (range 12-80) underwent laparoscopic Nissen-Rossetti fundoplication. At manometric evaluation, we divided patients into two groups: group A (163/420; 38.8%) with impaired esophageal peristalsis (peristaltic waves with a pressure < 30 mmHg), and group B (257/420; 61.2%) without impaired peristalsis. We followed up clinically 406 out of 420 (96.7%) patients, 156/163 patients (95.7%) in group A and 250/257 patients (97.3%) in group B. An excellent outcome was observed in 143/156 (91.7%) group A patients and in 234/250 (93.6%) group B patients (P = NS). Both groups showed significant improvement in clinical symptom score with no statistically significant difference between patients with normal and impaired peristalsis. Thus, preoperative defective esophageal peristalsis is not a contraindication to total laparoscopic fundoplication.
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Affiliation(s)
- F Pizza
- I Division of Surgery, Second University of Naples, Naples, Italy.
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39
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Feber A, Xi L, Luketich JD, Pennathur A, Landreneau RJ, Wu M, Swanson SJ, Godfrey TE, Litle VR. MicroRNA expression profiles of esophageal cancer. J Thorac Cardiovasc Surg 2007; 135:255-60; discussion 260. [PMID: 18242245 DOI: 10.1016/j.jtcvs.2007.08.055] [Citation(s) in RCA: 301] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2007] [Revised: 08/12/2007] [Accepted: 08/15/2007] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Expression of microRNAs by array analysis provides unique profiles for classifying tissues and tumors. The purpose of our study was to examine microRNA expression in Barrett esophagus and esophageal cancer to identify potential markers for disease progression. METHODS MicroRNA was isolated from 35 frozen specimens (10 adenocarcinoma, 10 squamous cell carcinoma, 9 normal epithelium, 5 Barrett esophagus, and 1 high-grade dysplasia). MicroRNA expression was analyzed with Ambion bioarrays (Ambion, Austin, Tex) containing 328 human microRNA probes. RESULTS Unsupervised hierarchic clustering resulted in four major branches corresponding with four histologic groups. One branch consisted of 7 normal epithelium samples and 1 squamous cell carcinoma sample. The second branch consisted of 7 squamous cell carcinoma samples and 1 normal epithelium sample. The third branch contained 4 Barrett esophagus samples and 1 squamous cell carcinoma sample. The fourth contained all the adenocarcinoma samples and 1 sample each of Barrett esophagus, normal epithelium, squamous cell carcinoma, and high-grade dysplasia. Supervised classification with principal component analysis determined that the normal epithelium samples were more similar to the squamous cell carcinoma tumors, whereas the Barrett esophagus samples were more similar to adenocarcinoma. Pairwise comparisons between sample types revealed microRNAs that may be markers of tumor progression. Both mir_203 and mir_205 were expressed 2- to 10-fold lower in squamous cell carcinoma and adenocarcinomas than in normal epithelium. The mir_21 expression was 3- to 5-fold higher in both tumors than in normal epithelium. Prediction analysis of microarray classified 3 Barrett esophagus samples as Barrett esophagus, 1 as adenocarcinoma, and 1 as normal epithelium. CONCLUSION Expression profiles of miRNA distinguish esophageal tumor histology and can discriminate normal tissue from tumor. MicroRNA expression may prove useful for identifying patients with Barrett esophagus at high risk for progression to adenocarcinoma.
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Affiliation(s)
- Andrew Feber
- Department of Pathology, Mount Sinai Medical Center, New York, NY 10029, USA
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Dvorak K, Chavarria M, Payne CM, Ramsey L, Crowley-Weber C, Dvorakova B, Dvorak B, Bernstein H, Holubec H, Sampliner RE, Bernstein C, Prasad A, Green SB, Garewal H. Activation of the interleukin-6/STAT3 antiapoptotic pathway in esophageal cells by bile acids and low pH: relevance to barrett's esophagus. Clin Cancer Res 2007; 13:5305-13. [PMID: 17875759 DOI: 10.1158/1078-0432.ccr-07-0483] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES The molecular factors contributing to the development of Barrett's esophagus (BE) are unclear. Our previous studies showed that BE tissues secrete interleukin-6 (IL-6) and express proteins associated with IL-6 signaling, including IL-6 receptor, activated signal transducer and activators of transcription 3 (STAT3), and antiapoptotic proteins Bcl-x(L) and Mcl-1. Here, we test the hypothesis that bile acids and gastric acids, two components of refluxate associated with gastresophageal reflux disease, activate the IL-6/STAT3 pathway. MATERIALS AND METHODS Immunohistochemistry was used to assess levels of phosphorylated STAT3 in esophageal tissue samples from BE patients with different grades of dysplasia. Seg-1 esophageal adenocarcinoma cells were evaluated for STAT3 activation and IL-6 and Bcl-x(L) expression by molecular biology techniques, including Western blot, reverse transcription-PCR, and ELISA after exposure to control media (pH 7.4), media supplemented with a 0.1 mmol/L bile acid cocktail with media at pH 4 or media at pH 4 with bile acid cocktail. RESULTS Immunohistochemical analysis showed that activated, phosphorylated STAT3 is expressed in nuclei of dysplastic BE and cancer tissues. Treatment of Seg-1 cells with media containing bile acid cocktail and acidified to pH 4 resulted in increased activation of STAT3, IL-6 secretion, and increased expression of Bcl-x(L). Inhibition of the STAT3 pathway using STAT3 small interfering RNA or Janus-activated kinase inhibitor resulted in increased apoptosis. CONCLUSIONS The IL-6/STAT3 antiapoptotic pathway is induced by short exposure to bile acid cocktail and low pH. This alteration, if persistent in vivo, may underlie the development of dysplastic BE and tumor progression.
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Affiliation(s)
- Katerina Dvorak
- Department of Cell Biology and Anatomy, College of Medicine, The University of Arizona, Tucson, Arizona 85724, USA.
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Boonstra JJ, Dinjens WN, Tilanus HW, Koppert LB. Molecular biological challenges in he treatment of esophageal adenocarcinoma. Expert Rev Gastroenterol Hepatol 2007; 1:275-86. [PMID: 19072420 DOI: 10.1586/17474124.1.2.275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Despite improvements in detection and treatment, patients diagnosed with esophageal cancer continue to have a poor prognosis, with an increase in 5-year survival rates from 6 to 16% over the past 25 years. In the last decade there has been growing support for neoadjuvant therapy in patients with esophageal cancer. However, in approximately 30-60% of the patients no objective response is achieved after neoadjuvant chemotherapy and/or radiotherapy. These patients do not benefit from neoadjuvant therapy but do suffer from toxic side effects, and appropriate surgical treatment is delayed. Advances in molecular biology and new molecular technologies could possibly contribute to improvement of response to neoadjuvant therapy. This review categorizes the genetic and molecular alterations related to esophageal adenocarcinoma and links these changes to targeting therapy and prediction of tumor response to neoadjuvant chemotherapy and/or radiotherapy.
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Affiliation(s)
- Jurjen J Boonstra
- University Medical Center Rotterdam, Department of Surgery, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
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Abstract
The development of intestinal carcinoma in the setting of inflammatory bowel disease (IBD) has been recognized as an unsavory outcome of chronic inflammation of the bowel. Numerous studies have recently documented the clinical and morphologic features of malignant transformation in this closely-followed group of patients. This article highlights the recent findings of these population-based studies with specific attention to surgical concepts and frames these data in the context of surgical approaches to cancer arising in inflammatory disease. Specifically, the authors address the pathobiology of malignant transformation, the management of colorectal cancer in inflammatory bowel disease, the development of dysplasia in ulcerative colitis, surveillance of patients who have IBD, chemoprevention of cancer, and special features of surgical oncologic management.
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Affiliation(s)
- Juan C Cendan
- Department of Surgery, Division of General and GI Surgery, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA
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Pizza F, Rossetti G, Limongelli P, Del Genio G, Maffettone V, Napolitano V, Brusciano L, Russo G, Tolone S, Di Martino M, Del Genio A. Influence of age on outcome of total laparoscopic fundoplication for gastroesophageal reflux disease. World J Gastroenterol 2007; 13:740-7. [PMID: 17278197 PMCID: PMC4066007 DOI: 10.3748/wjg.v13.i5.740] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To demonstrate that age does not influence the choice of treatment for gastroesophageal reflux disease (GERD). We hypothesized that the outcome of total fundoplication in patients > 65 years is similar to that of patients aged ≤ 65 years.
METHODS: Four hundred and twenty consecutive patients underwent total laparoscopic fundoplication for GERD. Three hundred and fifty-five patients were younger than 65 years (group Y), and 65 patients were 65 years or older (group E). The following elements were considered: presence, duration, and severity of GERD symptoms; presence of a hiatal hernia; manometric evalu-ation, 24 h pH-monitoring data, duration of operation; incidence of complications; and length of hospital stay.
RESULTS: Elderly patients more often had atypical symptoms of GERD and at manometric evaluation had a higher rate of impaired esophageal peristalsis in compari-son with younger patients. A mild intensity of heartburn often leads physicians to underestimate the severity of erosive esophagitis. The duration of the operation was similar between the two groups. The incidence of intraoperative and postoperative complications was low and the difference was not statistically significant between the two groups. An excellent outcome was observed in 92.9% young patients and 91.9% elderly patients.
CONCLUSION: Laparoscopic antireflux surgery is a safe and effective treatment for GERD even in elderly patients, warranting low morbidity and mortality rates and a significant improvement of symptoms comparable to younger patients.
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Affiliation(s)
- F Pizza
- 1st Division of General and Gastrointestinal Surgery, Second University of Naples, Via Villa Albertini, 39 bis, Nola 80037, Naples, Italy.
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Dvorak K, Ramsey L, Payne CM, Sampliner R, Fass R, Bernstein H, Prasad A, Garewal H. Abnormal expression of biomarkers in incompletely ablated Barrett's esophagus. Ann Surg 2007; 244:1031-6. [PMID: 17122630 PMCID: PMC1856620 DOI: 10.1097/01.sla.0000224913.19922.7e] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE The aim of this study was to evaluate expression of cancer risk-associated biomarkers in columnar epithelium at squamocolumnar junctions produced by an ablation procedure and proton pump inhibitors in incompletely ablated Barrett's esophagus (BE) patients that were nondysplastic prior to ablation. SUMMARY BACKGROUND DATA Ablation of BE to squamous epithelium is achievable by combining a re-injury method with acid suppression. We previously reported that, when there is complete ablation, the neo-squamous epithelium is normal histologically and in biomarker expression. However, squamous islands observed after prolonged use of PPIs were associated with abnormalities in p53 expression and Ki-67 labeling. METHODS Twenty-one nondysplastic BE cases with incomplete ablation were evaluated for the expression of Ki-67 (proliferation), cyclooxygenase-2 (COX-2), and p53 by immunohistochemistry. RESULTS Pre-ablation biopsies showed the normal staining patterns in columnar epithelium, ie, normal Ki-67 labeling, rare positive COX-2 staining of interstitial cells, and negative or mild staining for p53 in the majority of patients' biopsies. However, post-ablation biopsies demonstrated abnormal staining patterns in the glandular area at the new squamocolumnar junctions. In 13 of 21 post-ablation cases (62%), increased Ki-67 staining was seen in BE glands. In 8 of 21 patients (38%), increased COX-2 expression was seen in columnar epithelium. Similarly, in 8 of 21 post-ablation junctions (38%), there was increased p53 staining. CONCLUSIONS Our findings of increased expression of cancer-associated biomarkers in incompletely ablated BE patients raise a cautionary note regarding this procedure. We hypothesize that newly formed junctions contain cells undergoing replication, differentiation, etc, and are thus more susceptible to genomic damage.
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Affiliation(s)
- Katerina Dvorak
- Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ, USA
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Zheng Z, Nordenstedt H, Pedersen NL, Lagergren J, Ye W. Lifestyle factors and risk for symptomatic gastroesophageal reflux in monozygotic twins. Gastroenterology 2007; 132:87-95. [PMID: 17241862 PMCID: PMC2230637 DOI: 10.1053/j.gastro.2006.11.019] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2006] [Accepted: 09/28/2006] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Lifestyle and genetic factors dominate the etiology of gastroesophageal reflux disease. We investigated associations between lifestyle factors and gastroesophageal reflux (GER) symptoms, with and without controlling for genetic predisposition. METHODS In 1967 and 1973, questionnaires including lifestyle exposures were mailed to twins in the Swedish Twin Registry, and data on GER symptoms were collected by telephone interview during 1998-2002. Two analytic methods were used: external control analysis (4083 twins with GER symptoms and 21,383 controls) and monozygotic co-twin control analysis (869 monozygotic twin pairs discordant for GER symptoms). RESULTS In the external control analysis, leanness (body mass index [BMI] <20), upper normal weight (BMI 22.5-24.9), overweight (BMI 25-29.9), and obese (BMI > or =30) conferred -19%, 25%, 46%, and 59% increased risk of frequent GER symptoms compared with normal weight (BMI 20-22.4), respectively, among women, whereas no such associations were evident among men. When adjusted for genetic and nongenetic familial factors, these estimates were -28%, 44%, 187%, and 277%, respectively, among men. Frequent smoking rendered a 37% increased risk of frequent GER symptoms among women and 53% among men compared with nonsmokers. Physical activity at work was dose dependently associated with increased risk of frequent GER symptoms, and recreational physical activity decreased this risk. CONCLUSIONS BMI, tobacco smoking, and physical activity at work appear to be risk factors for frequent GER symptoms, whereas recreational physical activity appears to be beneficial. Association between BMI and frequent GER symptoms among men seems to be attenuated by genetic factors.
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Affiliation(s)
- Zongli Zheng
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Helena Nordenstedt
- Unit of Esophageal and Gastric Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Nancy L. Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jesper Lagergren
- Unit of Esophageal and Gastric Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Abstract
Gastroesophageal reflux disease (GERD) is one of the most common disorders in the general population. In recent years, a marked increase in the occurrence of the disease worldwide has been noted. Intense exercise belongs to factors that are known to exacerbate symptoms of GERD. Episodes of reflux seem to be associated with the length and the intensity of the physical activity undertaken. Experimental studies suggest that the gastroesophageal reflux may be increased in athletes due to: decreased gastrointestinal blood flow; alterations of hormone secretion; changes in the motor function of the oesophagus and the ventricle; and the constrained body position during exercise. Disturbances of the balance between two areas of opposite pressure: intra-abdominal and intrathoracic, have also been proven to influence GERD events. GERD is found in sportspeople of various disciplines, but specific types of exercise may have significantly different impacts on the gastroesophageal reflux.Basic prevention of GERD comprise lifestyle and dietary interventions. Adjustments of the exercise load and avoiding meals and drinks about the time of physical effort may ease the symptoms. Unfortunately, in most patients, pharmacological measures are necessary. These include occasional application of antacids and blockers of histamine H2 receptors in mild forms of the disease, and a regular therapy with proton pump inhibitors (PPI) in the majority of other cases. An average dose of PPI varies from 20 to 40 mg/day and should be continued for 4-8 weeks. Unfortunately, symptoms of GERD frequently return and in these situations long-term acid suppression with PPI is usually necessary. As regular physical activity exerts beneficial health effects, the necessity of establishing associations between moderate, recreational exercise and GERD is needed.
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Affiliation(s)
- Pawel Jozkow
- Department of Sports Medicine, Wroclaw University of Physical Education, Wroclaw, Poland.
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47
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Tang LH, Klimstra DS. Barrett's esophagus and adenocarcinoma of the gastroesophageal junction: a pathologic perspective. Surg Oncol Clin N Am 2006; 15:715-32. [PMID: 17030269 DOI: 10.1016/j.soc.2006.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Barrett's esophagus is defined clinically by the presence of endoscopically evident columnar mucosa in the distal esophagus with histopathologic confirmation of the presence of intestinal-type epithelium. The etiology of Barrett's esophagus is understood poorly, but chronic gastroesophageal reflux disease is considered a major contributing factor. Barrett's esophagus is associated with the development of adenocarcinoma of the gastroesophageal junction. It is believed that the development of a Barrett-type mucosa with intestinal goblet-type cells is due to an altered process of differentiation of pluripotent epithelial stem cells in response to the local injury and repair process. The potential identification and isolation of markers for screening purposes and possibly prognostic information are areas of considerable clinical and scientific interest.
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Affiliation(s)
- Laura H Tang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C507, New York, NY 10021, USA.
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Abstract
A study reported in this issue of the American Journal of Gastroenterology has explored the efficacy of high-power argon plasma coagulation (APC) for the eradication of nonneoplastic Barrett's epithelium. Complete eradication was achieved in 77% of 48 patients, with a 10% rate of major complications including hemorrhage, esophageal stricture, and esophageal perforation. Although these observations indicate that high-power APC can eradicate Barrett's epithelium in some patients, it is not clear that this expensive and hazardous therapy conveys any clinical benefit. Even if one makes the substantial leap of faith that APC can decrease the risk of cancer in Barrett's esophagus, that risk is so small for patients without dysplasia that the number needed to treat is unacceptably large. Available data do not support the routine application of endoscopic ablative therapy for patients who have Barrett's esophagus without dysplasia.
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Montgomery E, Mamelak AJ, Gibson M, Maitra A, Sheikh S, Amr SS, Yang S, Brock M, Forastiere A, Zhang S, Murphy KM, Berg KD. Overexpression of Claudin Proteins in Esophageal Adenocarcinoma and Its Precursor Lesions. Appl Immunohistochem Mol Morphol 2006; 14:24-30. [PMID: 16540726 DOI: 10.1097/01.pai.0000151933.04800.1c] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Claudins are components of tight junctions important in intercellular barriers and cell polarity. The authors identified upregulation of Claudins 3, 4, and 7 in gastric adenocarcinoma using Affymetrix U-133 oligonucleotide microarrays and immunohistochemistry (IHC). While normal gastric mucosa lacked Claudin 3, 4, and 7 expression, intestinal metaplasia and dysplasia showed these proteins. The authors hypothesized that Claudins would be similarly overexpressed in Barrett's esophagus (BE)/adenocarcinoma. Claudins 3, 4, and 7 gene expression was analyzed by Affymetrix U-133 microarrays in three esophageal adenocarcinomas, one case of BE, and three normal esophagi. IHC validation was performed using tissue microarrays constructed from esophageal resection specimens containing squamous (44 cases), gastric (40 cases), and non-dysplastic BE (16 cases), low-grade and high-grade dysplasia (16 and 26 cases), adenocarcinoma (58 cases), and nodal metastases (27 cases). IHC staining was scored semiquantitatively (0+ to 4+). By microarray analysis, Claudin 3 showed a marked increase in mRNA expression compared with normal esophagus (approximately 100-fold). Claudins 4 and 7 were modestly increased (2.2- and 1.3-fold). By IHC, Claudin 3 expression was 1+ in most (>95%) normal squamous or gastric tissues and 2+ to 4+ in more than 80% of high-grade dysplasia, adenocarcinoma, and metastases specimens. Claudin 4 protein expression was 2+ or less in most squamous and gastric mucosa (>90%) but 3+ or 4+ in BE, low- and high-grade dysplasia, adenocarcinoma, and metastases specimens (>90%). Claudin 7 expression was minimal in squamous and gastric mucosa but strong (3+ to 4+) in BE and low-grade dysplasia. In high-grade dysplasia, adenocarcinoma, and metastases, Claudin 7 was less intense, with 60% to 70% staining 3+ or 4+ and 30% to 40% staining weakly (1+ or 2+). The findings suggest that alterations in Claudin proteins are an early event in tumorigenesis and may provide targets for diagnosis and directed therapy for esophageal adenocarcinoma and its precursors.
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50
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Erbil Y, Türkoglu U, Barbaros U, Balik E, Olgac V, Kaya H, Cimşit B. Oxidative damage in an experimentally induced gastric and gastroduodenal reflux model. Surg Innov 2006; 12:219-25. [PMID: 16224642 DOI: 10.1177/155335060501200306] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The exact pathophysiologic mechanisms of esophageal cell damage and carcinogenesis by gastroesophageal reflux are not clearly understood. The aim of this study was to evaluate the damage to the esophageal epithelium that occurs after acid reflex and mixed acid and bile reflux by assessing histopathology, reactive oxygen species, and DNA damage. Eighty 10-week-old male Sprague-Dawley rats were divided into two groups, an acid reflux group and a mixed (acid/bile) reflux group. Acid reflux was achieved by esophagogastroplasty in which mixed reflux was encouraged via esophagoduodenal anastomosis. Each group contained a control subgroup that underwent sham laparotomy alone. The rats were killed 3, 6, 9, and 12 months after surgery. Malondialdehyde, protein carbonyl content, and DNA damage were determined in lymphocytes. Histopathologic analysis was performed according to the histologic activity index. Inflammation, ulcer, and regeneration in both reflux groups were significantly increased in the esophagus at 3, 6, 9, and 12 months compared with the control group. Mucosal damage was greater in the mixed reflux group compared with the gastric reflux group. Malondialdehyde and carbonyl content in the serum, and DNA damage in lymphocytes, were significantly increased in both reflux groups. At 9 and 12 months, oxidative damage was increased in the mixed reflux group compared with the acid reflux group. Oxygen-derived free radicals seem to be one of the important mediators in the evaluation and generation of reflux esophagitis. The impact of oxygen free radicals, as demonstrated in this study, can be evaluated by assessing the damage that they incur to lipid membranes, serum proteins, and circulating lymphocyte DNA. Serum malondialdehyde and carbonyl content as well as lymphocyte DNA damage were significantly increased in the setting of acid and mixed acid/bile reflux in these rodent models. Further, these serum and lymphocytic changes were associated with esophageal ulceration, inflammation, and regeneration. Evaluation of such markers as serum malondialdehyde and carbonyl content as well as evaluation of lymphocyte DNA might prove to be useful investigations in patients with precancerous and cancerous conditions in addition to conventional methods of diagnosis. Further studies, both animal and human are warranted.
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Affiliation(s)
- Yesim Erbil
- Department of General Surgery, Istanbul Medical Faculty, Istanbul, Turkey.
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