Sharmila Anandasabapathy

MicroRNA-196a is a potential marker of progression during Barrett's metaplasia-dysplasia-invasive adenocarcinoma sequence in esophagus.

Barretts esophagus (BE)/Barretts metaplasia (BM) is a recognized precursor of esophageal adenocarcinoma (EA) with an intermediary stage of dysplasia. The low yield and high cost of endoscopic screening of patients with BE underscores the need for novel biomarkers, such as microRNA (miRNA), which have emerged as important players in neoplastic progression for risk assessment of developing dysplasia/adenocarcinoma. Recently, we reported highly elevated levels of miRNA-196a (miR-196a) in EA and demonstrated its growth-promoting and anti-apoptotic functions. Here, we evaluated miR-196a as a marker of BE progression to low-grade dysplasia, high-grade dysplasia, and EA using microdissected paraffin-embedded tissues from 11 patients. Higher levels of miR-196a were observed in EA, BE, and dysplastic lesions compared with normal squamous mucosa, and in high-grade dysplasia compared with BE and low-grade dysplasia. Using frozen tumor tissues from 10 additional patients who had advanced EA, we evaluated the correlation of miR-196a with its in silico-predicted targets, keratin 5 (KRT5), small proline-rich protein 2C (SPRR2C), and S100 calcium-binding protein A9 (S100A9), which are down-regulated during BE progression. MiR-196a levels inversely correlated with the predicted target mRNA levels in EA. We confirmed that miR-196a specifically targets KRT5, SPRR2C, and S100A9 3 UTRs using miR-196a-mimic and luciferase reporter-based assays. In conclusion, this study identified miR-196a as a potential marker of progression of BE and KRT5, SPRR2C, and S100A9 as its targets.

Retrospective study of clinicopathologic features and prognosis of high-grade neuroendocrine carcinoma of the esophagus.

Clinicopathologic features of esophageal neuroendocrine carcinoma (NEC), apart from those of small-cell carcinoma, have not been characterized. We evaluated the clinicopathologic features and prognosis including overall survival of NEC of the esophagus. We identified 40 patients with esophageal NEC from our institutional database. All cancers had been clinically staged using endoscopic ultrasonography, computed tomography, and positron emission tomography. Neuroendocrine differentiation was confirmed by immunohistochemical staining. The NEC component was classified into small-cell and large-cell subtypes, and non-neuroendocrine components were evaluated. Patients with locoregional disease were treated with chemoradiation with or without surgery or with surgery only. Patients with distant metastasis were treated with systemic therapy. The extent of residual tumors was evaluated in esophagectomy specimens after preoperative chemoradiation. Twenty-seven patients had large-cell NEC, and 13 had small-cell neuroendocrine carcinoma. An adenocarcinoma component was present in 15 patients and squamous carcinoma component in 1 patient. Synaptophysin was positive in all cases, and chromogranin was positive in 31 cases. Seventeen patients had distant metastasis, and 21 had locoregional disease. Seventeen patients with locoregional disease received preoperative chemoradiation. Disease progressed in 7 patients, and 10 had residual tumor in resection specimens. Overall survival was better with locoregional disease than with distant metastasis (P=0.006). Overall survival was better in patients with non-neuroendocrine component than in patients with pure NEC (P=0.031). There was no difference in prognosis between patients with large-cell NEC and those with small-cell neuroendocrine carcinoma. Esophageal NEC is an aggressive tumor, and patients with mix NEC have better outcome.

Clinical and endoscopic factors predict higher pathologic grades of Barrett dysplasia

Barrett esophagus is highly prevalent in the Western world; however, only a minority of affected individuals progress to esophageal adenocarcinoma. Whereas many studies have examined risk factors for development of Barrett metaplasia, few data are available on risk factors for progression to neoplasia. Identifying simple, reliable, clinical, and endoscopic predictors of high‐grade dysplasia and adenocarcinoma would be helpful for risk stratification in screening and surveillance programs.

Frequent loss of heterozygosity of chromosome 1q in esophageal adenocarcinoma: loss of chromosome 1q21.3 is associated with shorter overall survival.

Previous microarray expression profiling studies have shown that genes located on chromosome region 1q21‐23 were down‐regulated in the progression of Barrett esophagus to esophageal adenocarcinoma and that, among patients with the latter condition, these genes were differentially expressed between responders and nonresponders of preoperative chemoradiation therapy. It was unclear whether this difference was due to loss of heterozygosity (LOH) or to other genetic alterations at this locus.

Adenocarcinoma of the lower esophagus with Barrett's esophagus or without Barrett's esophagus: Differences in patients' survival after preoperative chemoradiation

It remains unclear whether the overall survival (OS) of patients with localized esophageal adenocarcinoma (LEA) with Barretts esophagus (BE) (Barretts-positive) and those with LEA without BE (Barretts-negative) following preoperative chemoradiation is different. Based on the published differences in the molecular biology of the two entities, we hypothesized that the two groups will have a different clinical biology (and OS). In this retrospective analysis, all patients with LEA had surgery following preoperative chemoradiation. Apart from age, gender, baseline clinical stage, location, class of cytotoxics, post-therapy stage, and OS, LEAs were divided up into Barretts-positive and Barretts-negative groups based on histologic documentation of BE. The Kaplan-Meier and Cox regression analytic methods were used. We analyzed 362 patients with LEA (137 Barretts-positive and 225 Barretts-negative). A higher proportion of Barretts-positive patients had (EUS)T2 cancers (27%) than those with Barretts-negative cancer (17%). More Barretts-negative LEAs involved gastroesophageal junction than Barretts-positive ones (P = 0.001). The OS was significantly shorter for Barretts-positive patients than that for Barretts-negative patients (32 months vs. 51 months; P = 0.04). In a multivariate analysis for OS, Barretts-positive LEA (P = 0.006), old age (P = 0.016), baseline positive nodes (P = 0.005), more than 2 positive (yp)N (P = 0.0001), higher (yp)T (P = 0.003), and the use of a taxane (0.04) were the independent prognosticators. Our data demonstrate that the clinical biology (reflected in OS) is less favorable for patients with Barretts-positive LEA than for patients with Barretts-negative LEA. Our intriguing findings need confirmation followed by in-depth molecular study to explain these differences.