Hua-Liang Xiao

High-incidence of PTEN mutations in Chinese patients with primary small cell carcinoma of the esophagus

BackgroundPrimary small cell carcinoma of the esophagus (PSCCE) is a rare and aggressive tumor with poor prognosis. The aim of this study was to investigate the existence of EGFR, KRAS, PIK3CA and PTEN mutations in PSCCE.MethodsClinical–pathological data and paraffin-embedded specimens were collected from 38 patients. Exons 18 to 21 of EGFR, KRAS and PIK3CA status were analyzed by real-time PCR based on ARMS and Scorpion technology in all patients, and the PTEN gene was also screened using real-time PCR and high-resolution melting curve analysis (HRMA).ResultsOnly 1 (2.63%) out of 38 patients had EGFR mutations in L858R missense, and KRAS and PIK3CA were not found in the mutational spot in all patients. However, PTEN mutations presented in 14 (36.84%) out of 38 patients, including exon 5 coding for PTEN missense mutation (n =4, 10.53%), exon 6 (n =7, 18.42%), concurrent exon 5 and exon 6 (n =2, 5.26%), and exon 8 (n =1, 2.63%). Concurrent mutations of these genes were not detected in all samples. No statistically significant associations were found between the clinicopathological features and the mutation status of PTEN.ConclusionsThe incidence of PTEN mutations in Chinese patients with PSCCE was higher than that of previous reports in other histological subtypes of esophageal cancer.

APE1 promotes antioxidant capacity by regulating Nrf-2 function through a redox-dependent mechanism.

APE1 is a multifunctional protein that has recently been implicated in protecting cells from oxidative stress. In the current study, we confirmed that APE1׳s effect on cellular antioxidant capacity is related to its redox activity through the use of an APE1 functional mutant, and we investigated the mechanism through which this multifunctional protein affects the function of the transcription factor Nrf-2 in regulating oxidative stress-induced genes. Using a pair of mutants for both the redox activity and the acetylation-regulated activity of APE1, in vitro assays showed that the redox activity of APE1 is crucial for its nuclear association with Nrf-2 and subsequent activation of Nrf-2׳s transcription of several downstream genes during oxidative challenge. Important oxidative stress genes are affected by APE1 redox activity, including Hmox1, Gstm1, and Txnrd1. In addition, utilizing human non-small-cell lung cancer sample tissue as well as a nude mouse xenograft model, we determined that APE1 expression levels are inversely correlated to oxidative stress in vivo. These findings indicated that interference with these crucial functions of APE1 shows promise in preventing resistance to certain radiotherapies and that further research is necessary to understand APE1׳s complex roles in regulating both the basal redox status and the oxidative stress state of the cellular environment.

High expression of c‑Met and EGFR is associated with poor survival of patients with glottic laryngeal squamous cell carcinoma

The present study was undertaken to explore the association between the expression of hepatocyte growth factor receptor (c-Met) and epidermal growth factor receptor (EGFR) with clinicopathological factors and survival status, to obtain prognostic biomarkers in patients with glottis laryngeal squamous cell carcinoma (GLSCC). The expression status of c-Met and EGFR protein was analyzed in 71 archival laryngeal cancer samples by immunohistochemistry. Statistical methods, including univariate and multivariate Cox regression analysis, were used to determine risk factors of progression. In addition, survival analysis was performed by the Kaplan-Meier method. The present study detected positive expression of c-Met and EGFR in 69.0 and 91.5% of GLSCC samples, respectively. The median disease-free survival (DFS) and overall survival (OS) times of all patients were 42.4 and 81.8 months, respectively, and the 2-year DFS and OS rates were 60.1 and 84.91%, respectively. Univariate Cox regression analysis revealed that patients with high expression of EGFR or c-Met had a predisposition for tumor recurrence. The expression of c-Met expression was significantly associated with that of EGFR (P=0.001). High expression of c-Met or EGFR was associated with shorter DFS and OS times. Findings of the multivariate Cox regression analysis indicated that c-Met-expression may be used as an independent predictor of DFS and OS (P=0.002 and P=0.008, respectively). However, EGFR expression was not an independent predictor for DFS and OS (P=0.352 and P=0.24, respectively). The high expression of c-Met and EGFR was associated with poor survival and are important predictors for prognosis of patients with GLSCC.

LDA-SVM-based EGFR mutation model for NSCLC brain metastases: an observational study.

AbstractEpidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non–small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC.Observation and model set-up.This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China.The study included 31 NSCLC patients with brain metastases.Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy.Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients.EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values.The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this small cohort of patients with NSCLC. Further studies with larger cohorts should be carried out to validate our findings in the clinical setting.

DETECTION OF APOPTOTIC CELLS AND IMMUNOHISTOCHEMICAL STUDY OF bcl-2 AND p53 GENE PROTEIN IN PRIMARY GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA

Objective: To identify the apoptotic cells in gastric MALT lymphoma and its relationship between bcl-2 and p53 gene expression. Methods: TdT-mediated dUTP biotin Nick End labeling (TUNEL) and immuno-histochemistry ABC method were used to display apoptotic cells and the gene protein expression of bcl-2 and p53 independently. Results: Apoptotic indices (AI) in high-grade MALT lymphomas were significantly higher than in mixed-grade group and low-grade group (P<0.05). Bcl-2 was expressed in 83% of low-grade tumors, 61.6% of the median-grade tumors and 43.7% of high-grade tumors. An inverse correlation was observed between the expression of bcl-2 and apoptotic indices. Only 27 cases were p53 positive. The frequency of p53 positivity was significantly increased as the histologic grade advanced (P<0.05). There was also an inverse correlation between the expression of bcl-2 and p53. Conclusion: Apoptosis may be important in tumors development and transmission. p53 and bcl-2 were important regulatory genes of apoptosis and may be associated with transformation from low- grade to high-grade lymphomas.