Predicting malignant transformation of esophageal squamous cell lesions by combined biomarkers in an endoscopic screening program.

AIM: To determine the association of p53, carcinoembryonic antigen (CEA) and CA19-9 protein expression with esophageal carcinogenesis. METHODS: An iodine staining endoscopic screening program of esophageal lesions was carried out in the high-incidence area of Feicheng County, China. Seventy-seven patients with basal cell hyperplasia (BCH), 247 with low-grade dysplasia (LGD), 51 with high-grade dysplasia (HGD), 134 with invasive cancer, and 80 normal controls diagnosed by mucous membrane biopsy pathology were enrolled. Immunohistochemical detection of p53, CEA and CA19-9 proteins was performed. In the ROC curve analysis, the expression of a single biomarker and the expression of a combination of biomarkers were used to predict the risk of these four esophageal lesions. RESULTS: The positive rates of p53 protein expression in invasive cancer, HGD, LGD, BCH and the normal control groups were 53.0%, 52.9%, 35.6%, 27.3% and 20.0%, respectively; the positive rates of CA19-9 protein expression were 44.0%, 33.3%, 16.5%, 9.2% and 6.2%, respectively; the positive rates of CEA protein expression were 74.6%, 60.8%, 23.3%, 23.7% and 16.2%, respectively. The positive rates of the combined expression of the three biomarkers were 84.3%, 76.5%, 47.6%, 42.9% and 27.5%, respectively. In the receiver operating characteristic curves of the combination of the three biomarkers, the specificity was 88.8% for the normal controls, and the sensitivity was 58.2% for invasive cancer, 25.5% for HGD, 11.2% for LGD, and 6.5% for BCH. CONCLUSION: p53, CEA and CA19-9 protein expression was correlated with esophageal carcinogenesis, and testing for the combination of these biomarkers is useful for identifying high-risk patients with precancerous lesions.

Effects of endoscopic mucosal resection in patients with low-grade intraepithelial dysplasia of esophageal squamous cells.

BACKGROUND: This study evaluated the effects of endoscopic mucosal resection (EMR) on patients with low-grade intraepithelial dysplasia (LGD) of the esophageal squamous cells. METHODS: A randomized study recruited 128 LGD patients. These patients were randomly divided into treatment and control groups after the preoperative examination. The treatment group was composed of 63 LGD cases who received EMR. The control group included 65 LGD cases that were not treated with EMR. Clinical interviews and endoscopy were conducted after 30 months as postoperative follow-up. RESULTS: Concerning the percentages of esophageal lesions that changed from serious conditions into slight conditions (namely from high-grade intraepithelial dysplasia (HGD) to LGD, basal cell hyperplasia, esophagitis and normal mucosa) there was a significantly linear trend relationship between the treatment group and control group. In downstaging of dysplasia grade, the total percentage for the 52 cases (82.5%) in the treatment group was significantly higher than that for the 32 cases (49.2%) in the control group (Pearson χ(2) = 15.734, p < 0.001). Also, in patients that remained at the LGD grade or had upstaging of their dysplasia grade, the proportions of the change were significantly different between the two groups. CONCLUSION: The percentage rate of regression of LGD was increased in the EMR treatment group as compared to that of the control group. EMR may prevent or delay the progression of LGD to HGD.

Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County.

BACKGROUND: The purpose of this study was to evaluate the association of multi-genotype polymorphisms with the stepwise progression of esophageal squamous cell cancer (ESCC) and the possibility of predicting those at higher risk. METHODS: A total of 1,004 subjects were recruited from Feicheng County, China, between Jan. 2004 and Dec. 2007 and examined by endoscopy for esophageal lesions. These subjects included 270 patients with basal cell hyperplasia (BCH), 262 patients with esophageal squamous cell dysplasia (ESCD), 226 patients with ESCC, and 246 controls with Lugol-voiding area but diagnosed as having normal esophageal squamous epithelial cells by histopathology. The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants. RESULTS: The alleles ALDH2 and MTHFR C677T were critical for determining individual susceptibility to esophageal cancer. Compared to the ALDH 1*1 genotype, the ALDH 2*2 genotype was significantly associated with increased risks of BCH, ESCD, and ESCC. However, the TT genotype of MTHFR C677T only increased the risk of ESCC. Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold. The generalized odds ratio (ORG) of the two combined genotypes was 1.83 (95%CI: 1.55-2.16), indicating a strong genetic association with the risk of carcinogenic progression in the esophagus. CONCLUSIONS: The study demonstrated that the genotypes ALDH2*2 and MTHFR 677TT conferred elevated risk for developing esophageal carcinoma and that the two susceptibility genotypes combined to synergistically increase the risk.

The effect of oxidized low-density lipoprotein combined with adriamycin on the proliferation of Eca-109 cell line.

BACKGROUND: The purpose of this study was to identify the affect on the proliferation Eca-109 cells treated with oxidized low-density lipoprotein (ox-LDL) combined with adriamycin (ADM). METHODS: Eca-109 cell were cultured in the presence of oxLDL/ADM, and cell proliferation tested by MTT and cell apoptosis was monitored by the proportion of apoptosis and cell cycle by flow cytomester. We simultaneously evaluated the level of associated- apoptosis Bcl-2, Bax, and Caspase-3 gene mRNA and protein. RESULTS: OxLDL were cytotoxic and activate apoptosis. OxLDL combined with ADM significant enhanced the proportion rate of apoptosis on a time and dose dependency. The expressions of the inhibiting apoptosis Bcl-2 gene mRNA and protein were down regulated, whereas, the expressions of the promoting apoptosis Bax, and Caspase-3 genes mRNA and protein were up regulation. CONCLUSION: These results suggested that oxLDL have cytotoxicity and activate apoptosis on the Eca-109 cells. OxLDL combined with ADM have a synergistic effect on the apoptosis induced Eca-109 cells. Furthermore, oxLDL may contribute to the improvement of clinical chemotherapy of cancer need to make further investigation.

Relationship between the expression of hTERT and EYA4 mRNA in peripheral blood mononuclear cells with the progressive stages of carcinogenesis of the esophagus.

OBJECTIVE: To establish a relationship between esophageal squamous cell diseases and the expression of human telomerase reverse transcriptase (hTERT) and Eyes absent 4 (EYA4) mRNA in peripheral blood mononuclear cells. METHODS: Subjects were 50 patients with esophageal squamous cell carcinoma (ESCC), 50 with dysplasia (ESCD), 50 with basal cell hyperplasia (BCH) and 50 controls. All subjects were residents of Feicheng County, Shandong Province, China , diagnosed by histopathology. Expression of hTERT and EYA4 mRNA in peripheral blood was determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The hTERT and EYA4 mRNA positive expression increased according to disease severity. At the cut-off value of > or = 0.2, the positive expression rates of EYA4 were 14% for controls, 20.0% for BCH, 26% for ESCD and 52% for ESCC, respectively. At the cut-off value of > or = 0.8, the positive expression rates of hTERT in the four groups were 24%, 30.0%, 52% and 80%, respectively. Using a positive value of 0.47 for EYA4, the testing sensitivities in the ESCD and ESCC groups were 4% and 16%, respectively, and the testing specificity increased to 100%. Using a positive value of 1.0 for hTERT, the testing sensitivities in the ESCD and ESCC groups were 48% and 60%, respectively, and the testing specificity increased to 72%. The testing sensitivities in the predicting ESCD and ESCC in the discriminant model including EYA4 and hTERT and the five traditional risk factors (sex, age, smoking, alcohol drinking, and family history of esophageal cancer) were 70% and 80%, and testing specificities were 76% and 88% respectively. However, the testing sensitivities and specificities in the predicting ESCD and ESCC in the model only including the above five traditional risk factors were lower than that in the former case. CONCLUSION: EYA4 and hTERT mRNA expression increased with the severity of esophageal pathological changes and may be useful for identifying high-risk endoscopy candidates or for monitoring changes in premalignant esophageal lesions.