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1.  Parameters predicting lymph node metastasis in patients with superficial esophageal squamous cell carcinoma 
Endoscopic resection is a less invasive treatment than esophagectomy for superficial esophageal squamous cell carcinoma, but patients with lymph node metastasis need additional treatment after endoscopic resection. The purpose of this study was to establish a set of indicators to identify superficial esophageal squamous cell carcinoma patients at a high risk of metastasis. 271 superficial esophageal squamous cell carcinoma esophagectomy cases were reviewed retrospectively. The relationships between clinicopathological parameters and immunohistochemical findings (p53, Cyclin D1, EGFR and VEGF) on tissue microarrays, on the one hand, and lymph node metastasis were assessed by univariate and multivariate logistic regression analyses. Patients with intraluminal masses and ulcerated masses had a high risk of lymph node metastasis. Patients with superficial esophageal squamous cell carcinoma 1) thinner than 1200µm; 2) confined to the mucosa; 3) with submucosal invasion <250µm; 4) with submucosal invasion ≥250µm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or 5) with submucosal invasion ≥250µm but with weak VEGF expression and well differentiated histology had almost no risk of lymph node metastasis. We recommend endoscopic resection for all erosive, papillary and plaque-like superficial esophageal squamous cell carcinomas where endoscopic resection is clinically feasible, and esophagectomy for all other erosive, papillary and plaque-like cases and all intraluminal masses and ulcerated tumors. No additional treatment is needed for endoscopic resection cases with superficial esophageal squamous cell carcinoma 1) thinner than 1200µm; 2) confined to the mucosa; 3) with submucosal invasion <250µm; 4) with submucosal invasion ≥250µm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or 5) with submucosal invasion ≥250µm but with weak VEGF expression and well differentiated histology. These clinical and pathological criteria should enable more accurate selection of patients for these procedures.
doi:10.1038/modpathol.2012.89
PMCID: PMC3505024  PMID: 22627741
superficial cancer; esophageal cancer; squamous cell carcinoma; endoscopic resection; lymph node metastasis
2.  Outcomes from a prospective trial of endoscopic radiofrequency ablation of early squamous cell neoplasia of the esophagus 
Gastrointestinal endoscopy  2011;74(6):1181-1190.
Background
Radiofrequency ablation (RFA) is safe and effective for eradicating neoplasia in Barrett’s esophagus.
Objective
Evaluate RFA for eradicating early esophageal squamous cell neoplasia (ESCN) defined as moderate- and high-grade squamous intraepithelial neoplasia (MGIN, HGIN) and early flat-type esophageal squamous cell carcinoma (ESCC).
Design
Prospective cohort study.
Setting
Tertiary referral center.
Patients
Esophageal unstained lesions (USLs) were identified using Lugol’s chromoendoscopy. Inclusion: at least 1 flat (type 0-IIb) USL ≥3cm, USL-bearing esophagus ≤12 cm, and a consensus diagnosis of MGIN, HGIN, or ESCC by two expert GI pathologists. Exclusion: prior endoscopic resection or ablation, stricture, or any non-flat mucosa.
Interventions
Circumferential RFA creating a continuous treatment area (TA) including all USLs. At 3-month intervals thereafter, chromoendoscopy with biopsies, followed by focal RFA of USLs, if present.
Main outcome measures
Complete response (CR) at 12 months, defined as absence of MGIN, HGIN or ESCC in TA; CR after one RFA session; neoplastic progression from baseline; and adverse events.
Results
29 patients (14 male, mean age 60.3 years) with MGIN (18), HGIN (10), or ESCC (1) participated. Mean USL length was 6.2 cm (TA 8.2 cm). At 3-months, after one RFA session, 86% of patients (25/29) were CR. At 12-months, 97% (28/29) of patients were CR. There was no neoplastic progression. There were 4 strictures, all dilated to resolution.
Limitations
Single center study with limited number of patients.
Conclusions
In patients with early ESCN (MGIN, HGIN, flat-type ESCC), RFA was associated with a high rate of histological complete response (97% of patients), no neoplastic progression, and an acceptable adverse event profile.
doi:10.1016/j.gie.2011.05.024
PMCID: PMC3505032  PMID: 21839994
3.  Aryl hydrocarbon receptor expression is associated with a family history of upper gastrointestinal cancer in a high risk population exposed to aromatic hydrocarbons 
Background
Polycyclic aromatic hydrocarbon (PAH) exposure is a risk factor for esophageal squamous cell carcinoma (ESCC), and PAHs are ligands of the aryl hydrocarbon receptor (AhR). This study measured the expression of AhR and related genes in frozen esophageal cell samples from patients exposed to different levels of indoor air pollution, who did or did not have high-grade squamous dysplasia (HGD), and who did or did not have a family history (FH) of upper gastrointestinal cancer (UGI Ca).
Methods
147 samples were evaluated, including 23 (16%) from patients with HGD and 48 (33%) from patients without DYS who heated their homes with coal, without a chimney (a “high” indoor air pollution group), and 27 (18%) from patients with HGD and 49 (33%) from patients without DYS who did not heat their homes at all (a “low” indoor air pollution group). Nearly half (64 (44%)) had a FH of UGI Ca. RNA was extracted and Quantitative-PCR analysis was performed.
Results
AhR gene expression was detectable in 85 (58%) of the samples, and was more than 9-fold higher in those with a FH of UGI Ca (median expression (IQR) -1964 (-18000, -610) versus -18000 (-18000, -1036) Wilcoxon P = 0.02). Heating status, dysplasia category, age, gender, and smoking were not associated with AhR expression (linear regression, all P-values ≥0.1).
Conclusion
AhR expression was higher in patients with a FH of UGI Ca. Such individuals may be more susceptible to the deleterious effects of PAH exposure, including PAH-induced cancer.
doi:10.1158/1055-9965.EPI-08-1098
PMCID: PMC2796959  PMID: 19690180
Gastrointestinal tract cancer; Esophagus; Aryl hydrocarbon receptor; family history of cancer; gene expression; polycyclic aromatic hydrocarbons
5.  Serum 25(OH)-Vitamin D concentration and risk of esophageal squamous dysplasia 
Background
Squamous dysplasia is the precursor lesion for esophageal squamous cell carcinoma (ESCC), and nutritional factors play an important role in the etiology of this cancer. Previous studies using a variety of measures of vitamin D exposure have reached different conclusions about the association between vitamin D and risk of developing esophageal cancer.
Methods
We measured serum 25-hydroxyvitamin D (25(OH)D) concentrations in a cross-sectional analysis of 720 subjects from Linxian, China, a population at high risk for developing ESCC. All subjects underwent endoscopy and biopsy and were categorized by presence or absence of histologic squamous dysplasia. We used crude and multivariate adjusted generalized linear models to estimate the relative risk (RR) and 95% confidence intervals (CI) for the association between squamous dysplasia and sex-specific quartiles of serum 25(OH)D concentration.
Results
Two hundred and thirty (32%) of 720 subjects had squamous dysplasia. Subjects with dysplasia had significantly higher median serum 25(OH)D concentrations then subjects without dysplasia, 36.5 and 31.5 nmol/L respectively (Wilcoxon two-sample test p = 0.0004). In multivariate adjusted models, subjects in the highest compared to the lowest quartile were at significantly increased risk of squamous dysplasia, RR (95% CI) = 1.86 (1.35–2.62). Increased risks were similar when examined in men and women separately: Men RR (95% CI) = 1.74 (1.08–2.93); Women RR (95% CI) = 1.96 (1.28–3.18).
Conclusions
Higher serum 25(OH)D concentration was associated with significantly increased risk of squamous dysplasia. No obvious source of measured or unmeasured confounding explains this finding.
doi:10.1158/1055-9965.EPI-07-0461
PMCID: PMC2812415  PMID: 17855710
Esophageal cancer; Squamous dysplasia; Vitamin D; Serum 25(OH)D; China
6.  Serum pepsinogens and risk of esophageal squamous dysplasia 
Pepsinogens are a class of endopeptidases that are secreted by the gastric epithelium and released into the circulation. Low serum pepsinogen I (PGI) and low serum pepsinogen I / pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy, and have recently been shown to be associated with increased risk of esophageal squamous cell carcinoma (ESCC). We conducted the current study to test whether these markers are also associated with esophageal squamous dysplasia (ESD), the precursor lesion of ESCC.
We measured serum PGI and PGII, using enzyme-linked immunosorbent (ELISA) assays, in 125 case subjects (patients with moderate or severe ESD) and 250 sex-matched control subjects (no ESD) selected from an endoscopic screening study in Linxian, China. We used conditional logistic regression models adjusted for age, smoking, and place of residence to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).
Serum PGI showed no statistically significant association with ESD, whether analyzed as a dichotomous, ordinal (quartiles), or continuous variable. Lower serum PGI/II ratio, however, showed a dose-response association with increased risk of ESD, with an adjusted OR (95% CI) of 2.12 (1.08 − 4.18), comparing the lowest versus the highest quartile. The association between lower serum PGI/II ratio and log OR of ESD was nearly linear, and the p-value for the continuous association was 0.03.
Lower serum PGI/II ratio was linearly associated with higher risk of ESD. This result is consistent with recent findings that gastric atrophy may increase the risk of ESCC.
doi:10.1002/ijc.23918
PMCID: PMC2605159  PMID: 18844222
Esophageal cancer; Squamous dysplasia; Pepsinogen; China
7.  PROMOTER METHYLATION IN CYTOLOGY SPECIMENS AS AN EARLY DETECTION MARKER FOR ESOPHAGEAL SQUAMOUS DYSPLASIA AND EARLY ESOPHAGEAL SQUAMOUS CELL CARCINOMA 
The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northern China. This cancer has a very poor prognosis, mostly because it is usually diagnosed at a late stage. Detection an earlier stage can dramatically improve prognosis. Microscopic evaluation of esophageal balloon cytology (EBC) specimens has been the most common method for early detection of ESCC, but this technique is limited by low sensitivity and specificity. The use of molecular markers may improve these screening characteristics. This study evaluates whether measurement of gene methylation in EBC specimens may have utility for the detection of esophageal squamous dysplasia and early ESCC. We evaluated the presence of methylation in eight genes shown to be methylated in ESCC in previous studies in EBC specimens from 147 patients with endoscopic biopsy diagnoses ranging from normal mucosa through severe squamous dysplasia. Methylation status was determined using quantitative methylation-specific PCR techniques. The sensitivity and specificity of methylation of each individual gene and combinations of these genes to detect biopsy-proven high-grade (moderate or severe) squamous dysplasia was determined. For individual genes, the sensitivities ranged from 9–34% and the specificities ranged from 77–99%. Using a panel of four genes (AHRR, p16INK4a, MT1G, and CLDN3) resulted in sensitivity and specificity of 50% and 68%, respectively. This study suggests that evaluation of gene methylation in EBC samples may have utility for early detection of esophageal squamous dysplasia and early ESCC, however, identification of more sensitive methylation markers will be required for development of a clinically useful screening test.
doi:10.1158/1940-6207.CAPR-08-0061
PMCID: PMC2615136  PMID: 19137073
gene methylation; early detection; cytology; esophageal squamous cell cancer
8.  Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma 
BMC Cancer  2013;13:578.
Background
Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC.
Methods
We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age- and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia.
Results
Telomere lengths were comparable among the low- and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD.
Conclusions
Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples.
doi:10.1186/1471-2407-13-578
PMCID: PMC3882883  PMID: 24308314
Esophageal squamous cell carcinoma; Esophageal squamous dysplasia; Early detection; Screening; Balloon cytology; Telomeres

Results 1-8 (8)