Publications by authors named "Parakrama T Chandrasoma"

20 Publications

  • Page 1 of 1

Proposed approach to the challenging management of progressive gastroesophageal reflux disease.

World J Gastrointest Endosc 2018 Sep;10(9):175-183

Keck School of Medicine, University of Southern California, Los Angeles, CA 91108, United States.

The progression of gastroesophageal reflux disease (GERD) in patients who are taking proton pump inhibitors (PPIs) has been reported by several investigators, leading to concerns that PPI therapy does not address all aspects of the disease. Patients who are at risk of progression need to be identified early in the course of their disease in order to receive preventive treatment. A review of the literature on GERD progression to Barrett's esophagus and the associated physiological and pathological changes was performed and risk factors for progression were identified. In addition, a potential approach to the prevention of progression is discussed. Current evidence shows that GERD can progress; however, patients at risk of progression may not be identified early enough for it to be prevented. Biopsies of the squamocolumnar junction that show microscopic intestinalization of metaplastic cardiac mucosa in endoscopically normal patients are predictive of future visible Barrett's esophagus, and an indicator of GERD progression. Such changes can be identified only through biopsy, which is not currently recommended for endoscopically normal patients. GERD treatment should aim to prevent progression. We propose that endoscopically normal patients who partially respond or do not respond to PPI therapy undergo routine biopsies at the squamocolumnar junction to identify histological changes that may predict future progression. This will allow earlier intervention, aimed at preventing Barrett's esophagus.
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http://dx.doi.org/10.4253/wjge.v10.i9.175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162253PMC
September 2018

Strongyloidiasis hyperinfection in a patient with a history of systemic lupus erythematosus.

Am J Trop Med Hyg 2014 Oct 4;91(4):806-9. Epub 2014 Aug 4.

Department of Pathology, Department of Surgery, and Department of Gastroenterology, Los Angeles County-University of Southern California Medical Center, Los Angeles, California.

Strongyloidiasis is a parasitic disease caused by Strongyloides stercoralis, a nematode predominately endemic to tropical and subtropical regions, such as Southeast Asia. Autoinfection enables the organism to infect the host for extended periods. Symptoms, when present, are non-specific and may initially lead to misdiagnosis, particularly if the patient has additional co-morbid conditions. Immunosuppressive states place patients at risk for the Strongyloides hyperinfection syndrome (SHS), whereby the organism rapidly proliferates and disseminates within the host. Left untreated, SHS is commonly fatal. Unfortunately, the non-specific presentation of strongyloidiasis and the hyperinfection syndrome may lead to delays in diagnosis and treatment. We describe an unusual case of SHS in a 30-year-old man with a long-standing history of systemic lupus erythematosus who underwent a partial colectomy. The diagnosis was rendered on identification of numerous organisms during histologic examination of the colectomy specimen.
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http://dx.doi.org/10.4269/ajtmh.14-0228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183409PMC
October 2014

Histologic definition of gastro-esophageal reflux disease.

Curr Opin Gastroenterol 2013 Jul;29(4):460-7

Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

Purpose Of Review: To review recent data supporting the development of new histology-based definitions of gastro-esophageal reflux disease (GERD).

Recent Findings: Three precisely definable columnar epithelial types--cardiac, oxyntocardiac and intestinal--may be interposed between esophageal squamous epithelium and gastric oxyntic (acid secreting) mucosa. This enables definition of a new histologic concept: the squamo-oxyntic gap. The squamo-oxyntic gap is zero or very small in autopsies performed on patients without evidence of GERD. The gap progressively increases in length with the severity of GERD, indicating that the squamo-oxyntic gap is a marker for chronic GERD. The distal part of the gap lines gastric-type rugal folds and, therefore, is distal to the present endoscopic definition of the gastro-esophageal junction. I contend that this distal gap segment (which has esophageal submucosal glands) is actually the dilated distal esophagus; this is the pathologic correlate of destruction of the abdominal segment of the lower esophageal sphincter. The dilated distal esophagus is mistaken for 'gastric cardia' by present endoscopic definitions.

Summary: I believe that these data support the adoption of novel histologic definitions of GERD as follows: the presence of any squamo-oxyntic gap defines GERD; the length of the gap is a measure of severity of chronic GERD; and the presence of intestinal metaplasia in the gap defines Barrett esophagus and cancer risk.
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http://dx.doi.org/10.1097/MOG.0b013e32836228faDOI Listing
July 2013

The GCTM-5 epitope associated with the mucin-like glycoprotein FCGBP marks progenitor cells in tissues of endodermal origin.

Stem Cells 2012 Sep;30(9):1999-2009

Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.

Monoclonal antibodies against cell surface markers are powerful tools in the study of tissue regeneration, repair, and neoplasia, but there is a paucity of specific reagents to identify stem and progenitor cells in tissues of endodermal origin. The epitope defined by the GCTM-5 monoclonal antibody is a putative marker of hepatic progenitors. We sought to analyze further the distribution of the GCTM-5 antigen in normal tissues and disease states and to characterize the antigen biochemically. The GCTM-5 epitope was specifically expressed on tissues derived from the definitive endoderm, in particular the fetal gut, liver, and pancreas. Antibody reactivity was detected in subpopulations of normal adult biliary and pancreatic duct cells, and GCTM-5-positive cells isolated from the nonparenchymal fraction of adult liver expressed markers of progenitor cells. The GCTM-5-positive cell populations in liver and pancreas expanded greatly in numbers in disease states such as biliary atresia, cirrhosis, and pancreatitis. Neoplasms arising in these tissues also expressed the GCTM-5 antigen, with pancreatic adenocarcinoma in particular showing strong and consistent reactivity. The GCTM-5 epitope was also strongly displayed on cells undergoing intestinal metaplasia in Barrett's esophagus, a precursor to esophageal carcinoma. Biochemical, mass spectrometry, and immunochemical studies revealed that the GCTM-5 epitope is associated with the mucin-like glycoprotein FCGBP. The GCTM-5 epitope on the mucin-like glycoprotein FCGBP is a cell surface marker for the study of normal differentiation lineages, regeneration, and disease progression in tissues of endodermal origin.
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http://dx.doi.org/10.1002/stem.1167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777443PMC
September 2012

Intraluminal pH and goblet cell density in Barrett's esophagus.

J Gastrointest Surg 2012 Mar 18;16(3):469-74. Epub 2011 Nov 18.

Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Introduction: Goblet cells in Barrett's esophagus (BE) vary in their density within the Barrett's segment. Exposure of Barrett's epithelium to bile acids is a major stimulant for goblet cell formation. The dissociation of bile acids into forms that penetrate Barrett's epithelium is known to be pH dependent. We hypothesized that variations in the esophageal luminal pH environment explains the variability in goblet cell density. The aim of this study was to correlate esophageal luminal pH with goblet cell density in patients with BE.

Methods: A customized six-sensor pH catheter was positioned with the most distal sensor in the stomach and the remaining sensors located 1 cm below and 1, 3, 5, and 8 cm above the upper border of the lower esophageal sphincter in five normal subjects and six patients with long-segment BE. The luminal pH was measured by each sensor for 24-h and expressed as median pH. Patients with BE had four quadrant biopsies at levels corresponding to the location of the pH sensors. Goblet cell density was graded from 0 to 3 based on the number per high-power field.

Results: In normal subjects, the median pH values recorded in the sensors within the lower esophageal sphincter (LES) and esophageal body were all above 5. In patients with BE, the median pH recorded by the sensor within the LES was 2.8 and increased progressively to 4.7 in the sensor at 8 cm above the LES. Goblet cell density was significantly lower in the distal Barrett's segment exposed to a median pH of 2.2 and increased in the proximal Barrett's segment exposed to a median pH of 4.4 (p = 0.003).

Conclusion: Patients with BE have a goblet cell gradient that correlates directly with an esophageal luminal pH gradient. This suggests that goblet cell differentiation is pH dependent and likely due to the effect of pH on bile acid dissociation.
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http://dx.doi.org/10.1007/s11605-011-1776-3DOI Listing
March 2012

Histopathology of the endoscopic esophagogastric junction in patients with gastroesophageal reflux disease.

Wien Klin Wochenschr 2008 ;120(11-12):350-9

University Clinic of Surgery, Medical University Vienna, Austria.

Background: Discrepancy exists between the endoscopic (rugal folds) and the histopathologic (oxyntic mucosa) definition of proximal stomach. We compared endoscopy and histopathology of the esophagogastric junction in patients with gastroesophageal reflux disease.

Methods: A total of 102 consecutive patients (60 women) with gastroesophageal reflux disease prospectively underwent endoscopy including multilevel biopsy sampling at the level of the rise of rugal folds (level 0), and also 0.5 cm and 1.0 cm distal and 0.5 cm and > or = 1 cm proximal to this point. Columnar lined esophagus (CLE) was cataloged according to the histopathologic Paull-Chandrasoma classification and esophagitis according to the endoscopic Los Angeles classification. Hiatal hernia was diagnosed if the endoscopic rugal folds commenced > or = 2 cm above the diaphragm; competency of the esophagogastric valve was graded according to the Hill classification.

Results: All patients had histopathologic CLE with maximal presence at level 0 (97%) and a decrease towards proximal and distal biopsy levels (level -0.5 cm, 81%; level -1.0, 28%; level + 0.5 cm, 40%; level + 1.0 cm, 18%). Histopathologic CLE (distance between CLE-positive biopsy levels) was longer than endoscopic CLE (P < 0.001). All 19 patients with intestinal metaplasia (18.6%) were identified from 4-quadrant biopsies obtained at the squamocolumnar junction and at 0.5 cm distal from it. Persons with intestinal metaplasia were significantly older, had increased frequency of endoscopic hiatal hernia, higher Hill grade and presence of endoscopic CLE (P < 0.05); no significant difference was observed regarding sex, endoscopic esophagitis or length of endoscopic and histopathologic CLE (P > 0.05). None of the patients had dysplasia or carcinoma.

Conclusions: In patients with gastroesophageal reflux disease the esophagogastric junction cannot be identified by endoscopy but requires histopathology of multilevel biopsies. The squamocolumnar junction harbors the highest yield of intestinal metaplasia.
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http://dx.doi.org/10.1007/s00508-008-0997-2DOI Listing
November 2008

Towards the molecular characterization of disease: comparison of molecular and histological analysis of esophageal epithelia.

J Gastrointest Surg 2007 Sep;11(9):1095-104

Department of Surgery, University of Southern California, Los Angeles, CA, USA.

Reliable quantification of gene expression offers the possibility of more accurate and prognostically relevant characterization of tissues than potentially subjective interpretations of histopathologists. We measured the expression of 18 selected genes and compared them to histological features in a spectrum of esophageal disease to evaluate the feasibility of molecular characterization of normal and pathologic esophageal epithelia. Esophageal tissue biopsies from 82 patients with foregut symptoms were laser capture microdissected, and the expression levels of 18 selected genes were measured by quantitative real-time polymerase chain reaction. Linear discriminant analysis, which uses combinations of genes to distinguish between histological groups, was performed to compare gene expression and the following five histological groups: (1) normal squamous epithelium (n = 35), (2) reflux esophagitis (n = 13), (3) non-dysplastic Barrett's (n = 33), (4) dysplastic Barrett's (n = 16), (5) adenocarcinoma (n = 31). A panel of seven genes had 90-94% predictive power to distinguish non-dysplastic and dysplastic Barrett's esophagus. Clustering analysis revealed structure in gene expression values even in the absence of histology. Expression levels in 17 genes differed significantly across histological groups. Classification based on gene expression agreed with histopathological assessment in the following percentage of cases: normal squamous epithelium = 53%, reflux esophagitis = 31%, non-dysplastic Barrett's = 76%, dysplastic Barrett's = 40%, and adenocarcinoma = 59%. Interestingly, predictive power improved markedly when inflammatory and dysplastic tissues were removed (77-94%). Gene expression classification agrees well with histopathological examination. When differences occur, it is unclear whether this effect is due to intraobserver variability in pathological diagnosis or to a genuine difference between gene expression and histopathology.
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http://dx.doi.org/10.1007/s11605-007-0208-xDOI Listing
September 2007

Body mass index is associated with Barrett esophagus and cardiac mucosal metaplasia.

Dig Dis Sci 2006 Sep 22;51(9):1589-94. Epub 2006 Aug 22.

Department of Surgical Pathology, University of Southern California, Keck School of Medicine and LAC+USC Medical Center, Room 16-905, 1200 N. State Street, Los Angeles, California 90033, USA.

A positive association between body mass index (BMI) and risk of esophageal adenocarcinoma has been reported. Barrett esophagus (BE) is a precursor lesion for esophageal adenocarcinoma. Cardiac mucosa (CM) and BE are both reflux-induced metaplastic columnar epithelia in the esophagus. We investigated the association between BMI and BE/CM in a case-control study. A total of 174 BE patients, 333 CM patients, and 274 controls were included in this study. Multivariate logistic regression methods were used to estimate odds ratios (OR) for BE or CM associated with BMI. Linear regression analysis was employed to examine the relationship between length of columnar lined esophagus (CLE) and BMI. A dose-dependent relationship was found between BMI and BE (P=.0004). The multivariate-adjusted OR for BE was 3.3 (95% confidence interval [CI], 1.6-6.7) when obese individuals (BMI >or=30 kg/m(2)) were compared to lean individuals (BMI < 22 kg/m(2)). Similarly, a dose-dependent relationship was found between BMI and CM (P=.03). The multivariate-adjusted OR for CM comparing obese to lean persons was 1.8 (95% CI, 1.04-3.10). The length of CLE was positively related to BMI (P=.04). In conclusion, BMI is associated with BE and CM and appears to act early in the sequence of events leading from gastroesophageal reflux disease to metaplasia (CM and BE) to dysplasia and finally to adenocarcinoma.
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http://dx.doi.org/10.1007/s10620-006-9118-0DOI Listing
September 2006

Clinical biology and surgical therapy of intramucosal adenocarcinoma of the esophagus.

J Am Coll Surg 2006 Aug 22;203(2):152-61. Epub 2006 Jun 22.

Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

Background: Mucosal ablation and endoscopic mucosal resection have been proposed as alternatives to surgical resection as therapy for intramucosal adenocarcinoma (IMC) of the esophagus. Acceptance of these alternative therapies requires an understanding of the clinical biology of IMC and the results of surgical resection modified for treatment of early disease.

Study Design: Retrospective review of 78 patients (65 men, 13 women; median age 66 years) with IMC who were treated with progressively less-extensive surgical resections (ie, en bloc, transhiatal, and vagal-sparing esophagectomy) from 1987 to 2005.

Results: The tumor was located in a visible segment of Barrett's esophagus in 65 (83%) and in cardia intestinal metaplasia in 13 (17%). A visible lesion was present in 53 (68%) and in all but 4 the lesion was cancer. In those patients with visible Barrett's, the tumor was within 3 cm of the gastroesophageal junction in 66% and within 1 cm in 37%. Esophagectomy was en bloc in 23, transhiatal in 31, vagal-sparing in 20, and transthoracic in 4. Operative mortality was 2.6%. Vagal-sparing esophagectomy had less morbidity, a shorter hospital stay, and no mortality. Of the patients who had en bloc resection, a median of 41 nodes were removed. One patient had one lymph node metastasis on hematoxylin and eosin staining and two others, normal on hematoxylin and eosin staining, had micrometastases on immunohistochemistry. Actuarial survival at 5 years was 88% and was similar for all types of resections. Two patients died from systemic metastases and seven from noncancer causes.

Conclusions: IMC occurred in cardia intestinal metaplasia and in Barrett's esophagus. Two-thirds of patients with IMC had a visible lesion. Most tumors occurred near the gastroesophageal junction. Node metastases were uncommon, questioning the need for lymphadenectomy. A vagal-sparing technique had less morbidity than other forms of resection and no mortality. Survival after all types of resection was similar. Outcomes of endoscopic techniques should be compared with this benchmark.
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http://dx.doi.org/10.1016/j.jamcollsurg.2006.05.006DOI Listing
August 2006

Antireflux surgery normalizes cyclooxygenase-2 expression in squamous epithelium of the distal esophagus.

Am J Gastroenterol 2006 Jul;101(7):1458-66

Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

Background: In some patients GERD presents with heartburn and regurgitation symptoms but a relative paucity of endoscopic and clinical findings, while in others symptoms may be minor or absent yet there is significant mucosal damage on endoscopy including the presence of Barrett's esophagus. The initial injury of gastroesophageal reflux is to the squamous esophageal mucosa, but while substantial research has been devoted to determining which genes are involved in the progression of Barrett's to dysplasia and cancer, little is known about the gene expression alterations in the squamous mucosa of patients with reflux. We hypothesized that the expression of cyclooxygenase-2 (Cox-2) might be increased in the squamous esophageal mucosal of patients with reflux, and might be a molecular indicator of reflux injury. Further, we hypothesized that Cox-2 expression in the squamous mucosa would be reduced following the elimination of reflux with an antireflux operation.

Methods: Biopsies of the distal esophageal squamous mucosa were taken 3 cm above the squamocolumnar junction (SCJ) in 28 GERD patients before and after Nissen fundoplication. Following microdissection and RNA isolation, quantitative real-time PCR was used to measure Cox-2 gene expression in paraffin-embedded (N = 16) and fresh frozen (N = 12) tissue. Biopsies from patients (paraffin N = 15, frozen N = 14) with normal acid exposure and no evidence of mucosal injury were analyzed as controls.

Results: Median Cox-2 expression in the squamous epithelium from paraffin embedded biopsies in patients with reflux disease was significantly increased compared to controls (p = 0.04). The presence of esophagitis or Barrett's esophagus did not significantly alter the expression of Cox-2 compared to patients with nonerosive reflux disease (NERD). After antireflux surgery median Cox-2 expression values were significantly reduced (p = 0.0003) and were normalized to levels similar to controls without reflux (p = 0.74). Similar results were observed in the prospectively obtained fresh frozen tissue.

Conclusions: Cox-2 gene expression is increased in the distal esophageal squamous mucosa of most patients with GERD, and the elevation was similar whether there was mucosal injury in the form of esophagitis or Barrett's or no visible mucosal injury. This suggests that increased Cox-2 expression may serve as a molecular marker of reflux disease. The increased Cox-2 expression in patients with reflux was usually normalized following antireflux surgery. These findings demonstrate for the first time that gene expression can be altered by surgical correction of reflux. Thus, in addition to symptom control and improvement in the quality of life, perhaps future studies assessing the efficacy of antireflux therapy should also focus on the impact of the therapy on gene expression in the esophageal squamous mucosa.
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http://dx.doi.org/10.1111/j.1572-0241.2006.00601.xDOI Listing
July 2006

Molecular determinants in targeted therapy for esophageal adenocarcinoma.

Arch Surg 2006 May;141(5):476-81; discussion 481-2

Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, USA.

Hypothesis: Cyclooxygenase 2 (COX-2), vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) are useful biological determinants in targeted therapy for esophageal adenocarcinoma.

Design: Prospective analysis.

Setting: University tertiary referral center.

Patients: Sixteen patients with squamous mucosa and normal results of a pH study without mucosal injury (control group), 15 with Barrett esophagus (metaplasia group), and 44 with adenocarcinoma (carcinoma group).

Interventions: Biopsy specimens were obtained 3 cm above the gastroesophageal junction. Dysplastic tissue was additionally isolated from 9 of the patients in the carcinoma group. After laser-capture microdissection, quantitative real-time polymerase chain reaction was used to measure gene expression across the spectrum of the metaplasia-dysplasia-carcinoma sequence.

Main Outcome Measures: Expression of COX-2, VEGF, and EGFR in each patient group.

Results: Expression of both COX-2 and VEGF was significantly up-regulated in patients with metaplasia, dysplasia, and cancer compared with controls (P<.01). Expression levels of both were significantly higher in cancer than in the metaplasia group (P<.05) and increased sequentially from metaplasia to dysplasia to cancer. Expression of VEGF was significantly higher in the dysplastic tissue than in nondysplastic Barrett epithelium (P<.05). No change in expression levels of EGFR was seen in the histologic progression to esophageal adenocarcinoma.

Conclusion: Gene expression data suggest that pharmacologic inhibition of COX-2 and VEGF may be useful adjuncts in targeted therapy for esophageal adenocarcinoma.
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http://dx.doi.org/10.1001/archsurg.141.5.476DOI Listing
May 2006

Increasing cyclooxygenase-2 (cox-2) gene expression in the progression of Barrett's esophagus to adenocarcinoma correlates with that of Bcl-2.

Int J Cancer 2006 Aug;119(4):765-70

Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.

Previous studies from our laboratory and others have suggested that increased expression of cox-2 is important in the genesis of esophageal adenocarcinoma. In vitro studies suggest that cox-2 regulates expression of the anti-apoptotic protein bcl-2, thus possibly accounting for reduced apoptosis in carcinogenesis. The aim of this study was to investigate the relationship of these 2 genes in the development of Barrett's-associated adenocarcinoma. Histologic sections from endoscopic biopsies or esophagectomy specimens were classified as non-dysplastic Barrett's (n = 30), intraepithelial neoplasia (n = 12) and adenocarcinoma (n = 48). The desired tissue was isolated by laser capture microdissection and expression levels of cox-2 and bcl-2 were measured by quantitative real-time PCR (Taqman). Gene expression levels were compared to samples of the distal esophageal squamous epithelium (n = 55) and reflux-esophagitis (n = 25), without Barrett's or cancer. Expression of both bcl-2 and cox-2 were increased in non-dysplastic Barrett's (p = 0.0077, p = 0.0037), intraepithelial neoplasia (p = 0.0053, p = 0.0220) and adenocarcinoma (p < 0.0001, p < 0.0001) compared to squamous epithelium or reflux-esophagitis. Furthermore, there is a significant correlation between these two genes, especially in carcinoma (p < 0.0001).
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http://dx.doi.org/10.1002/ijc.21922DOI Listing
August 2006

Survivin, a potential biomarker in the development of Barrett's adenocarcinoma.

Surgery 2005 Oct;138(4):701-6; discussion 706-7

Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, USA.

Background: Survivin, a member of the inhibitor-of-apoptosis family, is reported to be overexpressed in esophageal cancer but no data are available about its status in the metaplastic/dysplastic sequence. The aim of this study was to measure survivin gene expression in normal squamous/columnar epithelium and in the various stages of development of Barrett's adenocarcinoma.

Methods: Endoscopic biopsy or operative specimen samples from 5 tissue types were analyzed: (1) squamous epithelium from 3 cm above the gastroesophageal junction in patients with a negative pH study and no histologic injury (n = 17, pH- control); (2) antral tissue from patients with no evidence of Barrett's, dysplasia, or cancer (n = 29, antral control); (3) specialized intestinal metaplasia from patients with Barrett's esophagus (n = 16; Barrett's group); (4) low- or high-grade dysplasia (n = 12, dysplasia group), and (5) adenocarcinoma (n = 45 cancer group). After laser-capture microdissection cellular RNA was extracted from each tissue and reverse transcribed to complementary DNA. Expression levels of survivin were measured by reverse-transcription polymerase chain reaction.

Results: Survivin gene expression was greater in columnar (antral) compared with squamous (pH-) control tissues (P = .03). Expression in quiescent Barrett's epithelium was similar to both control tissues. Expression levels in dysplastic epithelium were greater than in squamous control (P = .01) and Barrett's tissues (P = .04), but not higher than columnar control tissues, whereas expression in adenocarcinoma was greater than all tissues except dysplasia (P < .001).

Conclusions: Survivin expression may be a biomarker in the development of Barrett's adenocarcinoma that is able to distinguish between quiescent Barrett's, dysplastic Barrett's, and Barrett's adenocarcinoma.
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http://dx.doi.org/10.1016/j.surg.2005.06.051DOI Listing
October 2005

Quantitative, tissue-specific analysis of cyclooxygenase gene expression in the pathogenesis of Barrett's adenocarcinoma.

J Gastrointest Surg 2004 Dec;8(8):1007-16; discussion 1016-7

From the Department of Biochemistry and Molecular Biology, USC/Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

Cyclooxygenase (Cox-2) is implicated in the pathogenesis of many cancers including esophageal adenocarcinoma (EAC), whereas the role of the isoform Cox-1 in carcinogenesis is not well understood. To further elucidate the role of these factors in the development of EAC, we measured the gene expressions (mRNA levels) of Cox-2 and Cox-1 by real-time quantitative polymerase chain reaction (QRT-PCR) in tissues from normal esophagus with and without erosive gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), dysplasia, adenocarcinoma, and in healthy gastric antrum. All tissues were purified by laser capture microdissection from endoscopic or surgical resection specimens. Median Cox-2 gene expression did not differ significantly among the esophageal control groups but was elevated 5-fold in BE, 8-fold in dysplasia and 16-fold in EAC compared to normal esophageal controls with no erosive GERD. Erosive GERD tissue had slightly higher median Cox-2 expression but Cox-2 expression in normal antrum was much higher than that in a normal esophagus, close to that of dysplasia. In contrast to that of Cox-2, Cox-1 expression was significantly decreased in all neoplastic tissues compared to normal controls. Cox-1 and Cox-2 expression varied over a wide range in the neoplastic tissues but over a relatively narrow range in the esophageal normal tissues. The occurrence of substantial alterations in Cox-1 and Cox-2 expression at the BE stage indicates that these are early events in the development of EAC. These results confirm the important role of Cox-2 amplification in the pathogenesis of esophageal adenocarcinoma, but the unexpected down-regulation of Cox-1 raises questions about its role in carcinogenesis.
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http://dx.doi.org/10.1016/j.gassur.2004.09.025DOI Listing
December 2004

Histologic classification of patients based on mapping biopsies of the gastroesophageal junction.

Am J Surg Pathol 2003 Jul;27(7):929-36

Department of Surgical Pathology, Keck School of Medicine at the University of Southern California, Los Angeles, CA 90033, USA.

This study consists of 959 consecutive patients in whom endoscopic biopsies were taken according to a protocol that permitted mapping and measurement of epithelial types in the gastroesophageal region. The epithelial types were classified as normal (oxyntic and squamous) and questionably abnormal (oxyntocardiac, cardiac, intestinal) by strict histologic criteria. Patients were classified into four groups based on the length of histologically defined abnormal glandular epithelium in the measured biopsies. A total of 811 (84.6%) patients had 0 to 0.9 cm of questionably abnormal columnar epithelium between normal oxyntic mucosa and squamous epithelium. Of these, 161 (19.9%) patients had no abnormal epithelium, 158 (19.4%) patients had oxyntocardiac mucosa, 372 (45.9%) patients had cardiac mucosa, and 120 (14.8%) patients had intestinal metaplasia. A total of 148 (15.4%) patients had >or=1 cm of abnormal columnar epithelium. All but one patient in this group had cardiac or intestinal epithelia. The prevalence of intestinal epithelium increased progressively with increasing length of abnormal columnar epithelium, being present in 70.4% in the 1- to 2-cm group, 89.5% in the 3- to 4-cm group, and 100% with in the >or=5 cm group. We propose a histologic grading system of biopsies based on these findings.
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http://dx.doi.org/10.1097/00000478-200307000-00008DOI Listing
July 2003

Barrett's esophagus can and does regress after antireflux surgery: a study of prevalence and predictive features.

J Am Coll Surg 2003 May;196(5):706-12; discussion 712-3

Department of Surgery, Division of Thoracic and Foregut Surgery, University of Southern California, Los Angeles, CA 90033, USA.

Background: To investigate the factors leading to histologic regression of metaplastic and dysplastic Barrett's esophagus (BE).

Study Design: The study sample consisted of 91 consecutive patients with symptomatic Barrett's esophagus. Pre- and posttreatment endoscopic biopsies from 77 Barrett's patients treated surgically and 14 treated with proton pump inhibitors (PPI) were reviewed. An expert pathologist confirmed the presence of intestinal metaplasia (IM) with or without dysplasia. Posttreatment histology was classified as having regressed if two consecutive biopsies taken more than 6 months apart plus all subsequent biopsies showed loss of IM or loss of dysplasia. Clinical factors associated with regression were studied by multivariate analysis, as was the time course of its occurrence.

Results: Histopathologic regression occurred in 28 of 77 patients (36.4%) after antireflux surgery and in 1 of 14 patients (7.1%) treated with PPIs alone (p < 0.03). After surgery, regression from low-grade dysplastic to nondysplastic BE occurred in 17 of 25 patients (68%) and from IM to no IM in 11 of 52 (21.2%). Both types of regression were significantly more common in short (< 3 cm) than long (> 3 cm) segment Barrett's esophagus; 19 of 33 (58%) and 9 of 44 (20%) patients, respectively (p = 0.0016). Eight patients progressed, five from IM alone to low-grade dysplasia and three from low- to high-grade dysplasia. All those who progressed had long segment BE. On multivariate analysis, presence of short segment Barrett's and type of treatment were significantly associated with regression; age, gender, surgical procedure, and preoperative lower esophageal sphincter and pH characteristics were not. The median time of biopsy-proved regression was 18.5 months after surgery, with 95% occurring within 5 years.

Conclusions: This study refutes the widely held assumption that once established, Barrett's esophagus does not change. More than one-third of patients with visible segments of Barrett's esophagus undergo histologic regression after antireflux surgery. Regression is dependent on the length of the columnar-lined esophagus and time of followup after antireflux surgery.
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http://dx.doi.org/10.1016/S1072-7515(03)00147-9DOI Listing
May 2003

Cytokeratin and DAS-1 immunostaining reveal similarities among cardiac mucosa, CIM, and Barrett's esophagus.

Am J Gastroenterol 2002 Oct;97(10):2514-23

Department of Cardiothoracic Surgery, The University of Southern California, Keck School of Medicine, Los Angeles, USA.

Objective: The normal histology at the gastroesophageal junction, and in particular the nature of cardiac mucosa, remains in dispute. Likewise, the relationship of intestinal metaplasia at the gastroesophageal junction (CIM) to Barrett's and intestinal metaplasia of the stomach (GIM) is unclear. The aim of this study was to assess the immunostaining characteristics of cardiac mucosa and CIM and compare their staining pattern with that of other foregut mucosal types. We hypothesized that the immunostaining patterns of these foregut tissues would provide insight into the nature and etiology of cardiac mucosa and CIM.

Methods: Paraffin-embedded biopsy specimens from 50 patients with normal antral or fundic mucosa, cardiac mucosa, squamous mucosa, CIM, GIM, or Barrett's were obtained and immunostained with a panel of monoclonal antibodies including those for cytokeratins 7 and 20 (CK7/CK20) and DAS-1.

Results: Biopsies from normal gastric antral and fundic mucosa and squamous esophageal mucosa all showed a non-Barrett's type CK7/CK20 immunostaining pattern, whereas in 85% of patients, cardiac mucosa had a Barrett's type CK7/CK20 pattern (p < 0.001). A Barrett's type CK7/ CK20 staining pattern was seen in 100% of Barrett's, 78% of CIM, and 0% of GIM patients. Likewise, DAS-1 staining was similar in patients with CIM and Barrett's and significantly different in patients with GIM.

Conclusions: Cytokeratin immunostaining of cardiac mucosa demonstrates significant differences from recognized normal gastric and esophageal mucosa but a similarity to Barrett's. This suggests that cardiac mucosa, like Barrett's, may be acquired. Likewise, immunostaining similarities between CIM and Barrett's biopsies point to the possibility of a reflux etiology for CIM in some patients.
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http://dx.doi.org/10.1111/j.1572-0241.2002.06033.xDOI Listing
October 2002

Detection of Barrett's epithelium by acoustic microscopy.

Ultrasound Med Biol 2002 Feb;28(2):203-7

Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Barrett's esophagus is associated with increased risk of adenocarcinoma of the gastroesophageal junctional region. The presence of goblet cells (intestinal metaplasia) in columnar cell-lined esophageal mucosa defines Barrett's change. The diagnosis of Barrett's esophagus is based on the presence of intestinal metaplasia in a biopsy from an endoscopically visualized abnormal columnar epithelium. In this pilot study, acoustic microscopy was used to identify the mucosal structure of 10 distal esophageal biopsies. Sections cut at 5 microm of archival paraffin blocks on glass slides were used for this study. Acoustic microscopy permitted the identification of low- and high-power images of epithelial architecture and cellular detail, including Barrett's epithelium. This modality of visualization has the potential to detect lesions such as Barrett's metaplasia, low- and high-grade dysplasia and early carcinoma. If it can be applied to in vivo endoscopy, acoustic microscopy has the potential to increase the accuracy of the diagnosis of Barrett's esophagus, dysplasia and malignancy by providing a method of accurately directing biopsies at endoscopy.
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http://dx.doi.org/10.1016/s0301-5629(01)00492-6DOI Listing
February 2002