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"Peters, Jeffrey H"
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Macrophage subtype predicts lymph node metastasis in oesophageal adenocarcinoma and promotes cancer cell invasion in vitro
Background:
Currently, there is a lack of ideal biomarkers for predicting nodal status in preoperative stage of oesophageal adenocarcinoma (EAC) to aid optimising therapeutic options. We studied the potential of applying subtype macrophages to predict lymph node metastasis and prognosis in EAC.
Material and Methods:
Fifty-three EAC resection specimens were immunostained with CD68, CD40 (M1), and CD163 (M2). Lymphatic vessel density (LVD) was estimated with the staining of D2-40. Subsequently, we tested if M2d macrophage could promote EAC cell migration and invasion.
Results:
In EAC without neoadjuvant treatment, an increase in M2-like macrophage was associated with poor patient survival, independent of the locations of macrophages in tumour. The M2/M1 ratio that represented the balance between M2- and M1-like macrophages was significantly higher in nodal-positive EACs than that in nodal-negative EACs, and inversely correlated with patient overall survival. The M2/M1 ratio was not related to LVD. EAC cell polarised THP1 cell into M2d-like macrophage, which promoted EAC cell migration and invasion. Neoadjuvant therapy appeared to diminish the correlation between the M2/M1 ratio and survival.
Conclusions:
The ratio of M2/M1 macrophage may serve as a sensitive marker to predict lymph node metastasis and poor prognosis in EAC without neoadjuvant therapy. M2d macrophage may have important roles in EAC metastasis.
Journal Article
HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma
The
HER2
oncogene was recently reported to be amplified and overexpressed in esophageal adenocarcinoma. However, the relationship of
HER2
amplification in esophageal adenocarcinoma with prognosis has not been well defined. The scoring systems for clinically evaluating HER2 in esophageal adenocarcinoma are not established. The aims of the study were to establish a HER2 scoring system and comprehensively investigate
HER2
amplification and overexpression in esophageal adenocarcinoma and its precursor lesion. Using a tissue microarray, containing 116 cases of esophageal adenocarcinoma, 34 cases of Barrett's esophagus, 18 cases of low-grade dysplasia and 15 cases of high-grade dysplasia,
HER2
amplification and overexpression were analyzed by HercepTest and chromogenic
in situ
hybridization methods. The amplification frequency in an independent series of 116 esophageal adenocarcinoma samples was also analyzed using Affymetrix SNP 6.0 microarrays. In our studies, we have found that
HER2
amplification does not associate with poor prognosis in total 232 esophageal adenocarcinoma patients by chromogenic
in situ
hybridization and high-density microarrays. We further confirm the similar frequency of
HER2
amplification by chromogenic
in situ
hybridization (18%; 21 out of 116) and SNP 6.0 microarrays (16%, 19 out of 116) in esophageal adenocarcinoma. HER2 protein overexpression was observed in 12% (14 out of 116) of esophageal adenocarcinoma and 7% (1 out of 15) of high-grade dysplasia. No
HER2
amplification or overexpression was identified in Barrett's esophagus or low-grade dysplasia. All HER2 protein overexpression cases showed
HER2
gene amplification. Gene amplification was found to be more frequent by chromogenic
in situ
hybridization than protein overexpression in esophageal adenocarcinoma (18
vs
12%). A modified two-step model for esophageal adenocarcinoma HER2 testing is recommended for clinical esophageal adenocarcinoma HER2 trial.
Journal Article
Bile Salts at Low pH Cause Dilation of Intercellular Spaces in In Vitro Stratified Primary Esophageal Cells, Possibly by Modulating Wnt Signaling
Background
The presence of dilated intercellular spaces in the stratified squamous lining of the esophagus is the pathognomonic feature of reflux esophagitis secondary to gastroesophageal reflux disease (GERD). In addition to stomach acid, bile salts are major constituents of gastroesophageal refluxate. The aim of our study was to determine the effect of bile salts cocktail at different pHs on epithelial junctions in an in vitro transwell model of stratified esophageal squamous epithelium.
Discussion
Human telomerase reverse transcriptase (hTERT) immortalized primary esophageal EPC1 cells were grown on polyester transwell surfaces in calcium-enriched media. The cells exhibited gradual stratification into an 11-layered squamous epithelium over 7 days, together with epithelial barrier function as indicated by increased transepithelial electrical resistance (TEER). This stratified epithelium demonstrated well-formed tight junctions, adherens junctions, and desmosomes as visualized by immunofluorescence and electron microscopy. When exposed to short pulses of bile salts at pH 5, but not either condition alone, there was loss of stratification and decrease in TEER, concomitant with disruption of adherens junctions, tight junctions, and desmosomes, leading to the appearance of dilated intercellular spaces. At the cellular level, bile salts at pH 5 activated the Wnt pathway (indicated by increased β-catenin Ser552 phosphorylation).
Conclusion
In conclusion, in our in vitro transwell model bile salts at pH 5, but not bile salts or media at pH 5 alone, modulate Wnt signaling, disrupt different junctional complexes, and cause increased permeability of stratified squamous esophageal epithelium. These changes approximate the appearance of dilated intercellular space similar to that found in GERD patients.
Journal Article
Office-Based Unsedated Small-Caliber Endoscopy Is Equivalent to Conventional Sedated Endoscopy in Screening and Surveillance for Barrett's Esophagus: A Randomized and Blinded Comparison
A major limitation to screening and surveillance of Barrett's esophagus is the complexity, expense, and risk associated with sedation for upper endoscopy. This study examines the feasibility, accuracy, and patient acceptability of office-based unsedated endoscopy as an alternative.
Of 274 eligible adults scheduled for endoscopic screening for gastroesophageal reflux symptoms or surveillance of Barrett's esophagus at a tertiary care center, 121 underwent unsedated small-caliber endoscopy and conventional endoscopy in a randomized crossover study. The two procedures were compared with regard to histological detection of Barrett's esophagus and dysplasia and biopsy size. Patients answered questionnaires assessing the tolerability of the procedures.
The prevalence of Barrett's esophagus was 26% using conventional endoscopy and 30% using unsedated endoscopy (P= 0.503). The level of agreement between the two approaches was \"moderate\" (kappa= 0.591). Each modality detected four cases of low-grade dysplasia with concordance on one case. The tissue samples collected with unsedated endoscopy were smaller than with conventional endoscopy (P < 0.001). The majority of subjects rated their experience with both procedures as being well tolerated with minimal or no difficulty. When asked which procedure they would prefer in the future, 71% (81/114) chose unsedated small-caliber endoscopy.
Office-based unsedated small-caliber endoscopy is technically feasible, well tolerated, and accurate in screening for Barrett's esophagus, despite yielding a smaller biopsy specimen. This approach bears the potential to eliminate the infrastructure and cost required for intravenous sedation in this application.
Journal Article
The Pathogenesis of Barrett’s Esophagus: Secondary Bile Acids Upregulate Intestinal Differentiation Factor CDX2 Expression in Esophageal Cells
Clinical evidence strongly suggests that bile acids are important in the development of Barrett's esophagus, although the mechanism remains unknown. Caudal-related homeobox 2 (CDX2) is a transcription factor recently implicated in early differentiation and maintenance of normal intestinal epithelium and is suggested to play a key role in the pathogenesis of intestinal metaplasia in Barrett's esophagus.
The aim of this study was to investigate the effect of primary and secondary bile acids on CDX2 mRNA expression in human esophageal cells.
Human esophageal cells: (1) squamous, immortalized by SV40 (Het-1A); (2) adenocarcinoma (SEG-1); and (3) squamous cell carcinoma (HKESC-1 & HKESC-2), were exposed in cell culture for 1-24 h to 100-1,000 microM deoxycholic, chenodeoxycholic, and glycocholic acids. Total RNA was extracted before and after bile acid treatment and reverse transcribed to cDNA. CDX2 mRNA expression was determined by both quantitative real-time and reverse transcription PCR (RT-PCR).
CDX2 mRNA expression was absent before bile acid exposure in all cell lines. CDX2 expression increased in a dose- and time-dependent fashion with deoxycholic and chenodeoxycholic, but not glycocholic, acid in all four cell lines. The maximal induction of CDX2 expression was seen in SEG-1 adenocarcinoma cells. Expression in Het-1A cells also increased significantly as did expression in HKESC-1,2 cells, although to a lesser extent than in adenocarcinoma.
These findings show that secondary bile acid stimulation upregulates CDX2 gene expression in both normal and cancer cell lines. They further support the role of bile acids in the pathogenesis of Barrett's esophagus and link the clinical evidence of a high prevalence of luminal bile acids in Barrett's to expression of the gene thought to be responsible for the phenotypic expression of intestinal metaplasia.
Journal Article
Esophageal Sphincter Device for Gastroesophageal Reflux Disease
In this trial, a magnetic device to augment the lower esophageal sphincter was implanted in 100 patients with gastroesophageal reflux disease. At 1 year, esophageal acid exposure had decreased and symptoms had improved. Six patients had serious adverse events.
The fundamental pathologic abnormality in gastroesophageal reflux disease is an incompetent lower esophageal sphincter.
1
–
3
First-line therapy for gastroesophageal reflux disease is acid suppression, usually with proton-pump inhibitors. Although effective, proton-pump inhibitors provide incomplete control of reflux symptoms in up to 40% of patients.
4
–
6
A partial response can occur because these drugs do not address an incompetent sphincter or prevent reflux; consequently, some patients have only partial relief from symptoms and seek alternative treatment if their quality of life is compromised. At present, the only established option for these patients is antireflux surgery, typically Nissen fundoplication. However, the acceptance . . .
Journal Article
Cyclin E involved in early stage carcinogenesis of esophageal adenocarcinoma by SNP DNA microarray and immunohistochemical studies
Background
Cyclin E is a cell cycle regulator which is critical for driving G1/S transition. Abnormal levels of cyclin E have been found in many cancers. However, the level changes of cyclin E in esophageal adenocarcinoma and its precancerous lesion have not been well studied. Here, we focus on the gene amplification and expression of cyclin E in these lesions, and aim to ascertain the relationship with clinicopathological characteristics.
Methods
Genomic DNA was analyzed from 116 esophageal adenocarcinoma and 26 precancerous lesion patients using Affymetrix SNP 6.0 arrays. The protein overexpression of cyclin E was also detected using immunohistochemistry from tissue microarrays containing esophageal adenocarcinoma and precancerous lesions. Patient survival and other clinical data were collected and analyzed. The intensity and percentage of the cyclin E expressing cells in tissue microarrays were scored by two pathologists. Fisher exact tests and Kaplan-Meier methods were used to analyze data.
Results
By genomic analysis, cyclin E was amplified in 19.0% of the EAC samples. By immunohistochemistry, high expression of cyclin E was observed in 2.3% of squamous mucosa tissues, 3.7% in columnar cell metaplasia, 5.8% in Barrett’s esophagus, 19.0% in low grade dysplasia, 35.7% in high grade dysplasia, and 16.7% in esophageal adenocarcinoma. The differences in cyclin E high expression between neoplastic groups and non-dysplasia groups are statistically significant (
p
< 0.05). The prognosis for patients with high cyclin E expression appeared slightly better than for those with low cyclin E expression although this was not statistically significant (p = 0.13).
Conclusions
The expression of cyclin E significantly increases from non-dysplasia esophageal lesion to low and high grade dysplasia, suggesting that cyclin E plays an important role in the early stage of carcinogenesis. Importantly, cyclin E is also amplified and highly expressed in a subset of esophageal adenocarcinoma patients, but this increase is not associated with worse prognosis.
Journal Article