Yueming Zhang

Radiofrequency ablation for early esophageal squamous cell neoplasia.

Esophageal cancer is the sixth most common cause of cancer death in the world [1]. Over 80% of esophageal cancers occur in developing countries [1], and in these areas, 90% of these cancers are esophageal squamous cell carcinoma (ESCC) [2]. The precursor lesion of ESCC is squamous intraepithelial neoplasia (squamous dysplasia), defined histologically as nuclear atypia (enlargement, pleomorphism and hyperchromasia), loss of normal cellular polarity, and abnormal tissue maturation [3,4]. WHO subclassifies squamous intraepithelial neoplasia into low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN), depending on the extent of the nuclear atypia and the involvement of the epithelium [4]. In China, where ESCC and its precursors are very common in some areas, a three-tier system is used, including LGIN (mild dysplasia, involving the lower third of the epithelium), medium-grade intraepithelial neoplasia (MGIN, moderate dysplasia, involving the lower two-thirds of the epithelium), and HGIN (severe dysplasia, involving the full thickness of the epithelium) [3]. Follow-up studies in China have shown that the rate of progression to ESCC differs significantly between LGIN (5.3% over 3.5 years), MGIN (26.7%), and HGIN (65.2%), and because of their significant risk of progression, MGIN and HGIN are targets for screening and therapy [5,6]. Current treatment of esophageal squamous cell neoplasia (ESCN, including squamous intraepithelial neoplasia and invasive squamous cell carcinoma) involves surgery for lesions invading into the deep submucosa or beyond and endoscopic treatment for lesions restricted to the epithelial layer (intraepithelial neoplasia; m1) or the lamina propria (m2). Lesions invading into the muscularis mucosae (m3) or superficial submucosa (sm1) are considered the “grey zone” between endoscopic and surgical treatment. One option for endoscopic treatment of early ESCN involves endoscopic resection (ER) of unstained lesions (USLs) after Lugol’s chromoscopy, as USLs are predictive for the presence of neoplasia. ER allows for histological staging of infiltration depth, tumor differentiation, lymph-vascular invasion, while completely removing the visible lesion. USLs larger than 15 mm require either piecemeal resection with the standard cap-based ER techniques or endoscopic submucosal dissection (ESD) for complete resection. Widespread ER/ESD, however, is technically demanding, with procedure times of many hours, and is associated with severe esophageal stenosis for lesions that encompass >75% of the circumference and a significant risk for esophageal perforation and bleeding. Complete endoscopic resection is also not necessarily the best approach for all patients with early ESCN. Large flat type lesions (i.e. type 0-IIb), which carry a very low risk for deeper invasion, can be effectively treated by an endoscopic ablation technique that is much easier to apply and is associated with a very low rate of complications, such as esophageal stenosis. A safe, effective and technically easy to administer ablation method is especially attractive for geographic areas where ESCN is endemic and most endoscopists have a lower level of expertise in ER/ESD. In China, there are many high-risk areas for ESCN, such as the Taihang mountain range in North-central China and areas in Sichuan, Shandong, Jiangsu and Fujian Provinces and the Xinjiang Uygur Autonomous Region [7]. These high-risk areas in China are estimated to include a total of over 100 million people, and invasive ESCN occurs here at rates approaching or surpassing 100/100,000 people per year [2], an incidence approximately 30-fold of that of Barrett’s related esophageal adenocarcinoma in the Western world [8]. The Chinese government is supporting widespread endoscopic screening using Lugol’s chromoscopy in these high-risk areas and in 2010 it is estimated that 57,000 subjects will undergo such a screening endoscopy. From this screening process, it is estimated that 5% of patients will have MGIN, HGIN, or early cancer limited to the epithelium and will be eligible for endoscopic therapy.

Parameters predicting lymph node metastasis in patients with superficial esophageal squamous cell carcinoma

1Department of Pathology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 2Department of Pathology, Chengde Medical College, Chengde, China; 3Department of Endoscopy, Cancer Institute (Hospital), Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 4Department of Pathology, Beijing Chaoyang Hospital, Beijing, China and 5Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

Discovery of a Novel Immune Gene Signature with Profound Prognostic Value in Colorectal Cancer: A Model of Cooperativity Disorientation Created in the Process from Development to Cancer.

Immune response-related genes play a major role in colorectal carcinogenesis by mediating inflammation or immune-surveillance evasion. Although remarkable progress has been made to investigate the underlying mechanism, the understanding of the complicated carcinogenesis process was enormously hindered by large-scale tumor heterogeneity. Development and carcinogenesis share striking similarities in their cellular behavior and underlying molecular mechanisms. The association between embryonic development and carcinogenesis makes embryonic development a viable reference model for studying cancer thereby circumventing the potentially misleading complexity of tumor heterogeneity. Here we proposed that the immune genes, responsible for intra-immune cooperativity disorientation (defined in this study as disruption of developmental expression correlation patterns during carcinogenesis), probably contain untapped prognostic resource of colorectal cancer. In this study, we determined the mRNA expression profile of 137 human biopsy samples, including samples from different stages of human colonic development, colorectal precancerous progression and colorectal cancer samples, among which 60 were also used to generate miRNA expression profile. We originally established Spearman correlation transition model to quantify the cooperativity disorientation associated with the transition from normal to precancerous to cancer tissue, in conjunction with miRNA-mRNA regulatory network and machine learning algorithm to identify genes with prognostic value. Finally, a 12-gene signature was extracted, whose prognostic value was evaluated using Kaplan–Meier survival analysis in five independent datasets. Using the log-rank test, the 12-gene signature was closely related to overall survival in four datasets (GSE17536, n = 177, p = 0.0054; GSE17537, n = 55, p = 0.0039; GSE39582, n = 562, p = 0.13; GSE39084, n = 70, p = 0.11), and significantly associated with disease-free survival in four datasets (GSE17536, n = 177, p = 0.0018; GSE17537, n = 55, p = 0.016; GSE39582, n = 557, p = 4.4e-05; GSE14333, n = 226, p = 0.032). Cox regression analysis confirmed that the 12-gene signature was an independent factor in predicting colorectal cancer patient’s overall survival (hazard ratio: 1.759; 95% confidence interval: 1.126–2.746; p = 0.013], as well as disease-free survival (hazard ratio: 2.116; 95% confidence interval: 1.324–3.380; p = 0.002).

Genes involved in the transition from normal epithelium to intraepithelial neoplasia are associated with colorectal cancer patient survival.

Whether the heterogeneity in tumor cell morphology and behavior is the consequence of a progressive accumulation of genetic alterations or an intrinsic property of cancer-initiating cells established at initiation remains controversial. The hypothesis of biological predetermination in human cancer was proposed many years ago and states that the biological potency of cancer cells is predestinated in the precancerous stage. The present study aimed to investigate whether the aberrant molecular events occurring in initial cancer stages could eventually influence colorectal cancer (CRC) progression. We analyzed the mRNA and miRNA expression profiles of colorectal normal mucosa, low-grade intraepithelial neoplasia (LIN), high-grade intraepithelial neoplasia (HIN), and adenocarcinoma tissues. Compared with the transitions from LIN to HIN to invasive carcinoma, the transition from normal epithelium to LIN appeared to be associated with greater changes in the number and expression levels of mRNAs and miRNAs, with a differential expression of 2322 mRNAs and 71 miRNAs detected. Utilizing these early molecular changes, a miRNA-hub network analysis showed that 166 genes were identified as targets regulated by 30 miRNAs. Among these genes, a 55-gene signature regulated by 5 miRNAs was shown to be associated with overall survival or disease-free survival in three independent sample sets. Thus, the molecular changes in the transcriptome associated with the transition from normal to intraepithelial neoplasm may influence CRC progression.