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BACKGROUND: Progression of Barrett esophagus (BE) to esophageal adenocarcinoma occurs among a minority of BE patients. To date, BE behavior cannot be predicted on the basis of histologic features. AIMS: We compared BE samples that did not develop dysplasia or carcinoma upon follow-up of ≥ 7 years (BE nonprogressed [BEN]) with BE samples that developed carcinoma upon follow-up of 3 to 4 years (BE progressed [BEP]). METHODS: The NanoString nCounter miRNA assay was used to profile 24 biopsy samples of BE, including 13 BENs and 11 BEPs. Fifteen samples were randomly selected for miRNA prediction model training; nine were randomly selected for miRNA validation. RESULTS: Unpaired t tests with Welch’s correction were performed on 800 measured miRNAs to identify the most differentially expressed miRNAs for cases of BEN and BEP. The top 12 miRNAs (P < .003) were selected for principal component analyses: miR-1278, miR-1301, miR-1304–5p, miR-517b-3p, miR-584–5p, miR-599, miR-103a-3p, miR-1197, miR-1256, miR-509–3–5p, miR-544b, miR-802. The 12-miRNA signature was first self-validated on the training dataset, resulting in 7 out of the 7 BEP samples being classified as BEP (100% sensitivity) and 7 out of the 8 BEN samples being classified as BEN (87.5% specificity). Upon validation, 4 out of the 4 BEP samples were classified as BEP (100% sensitivity) and 4 out of the 5 BEN samples were classified as BEN (80% specificity). Twenty-four samples were evaluated, and 22 cases were correctly classified. Overall accuracy was 91.67%. CONCLUSION: Using miRNA profiling, we have identified a 12-miRNA signature able to reliably differentiate cases of BEN from BEP.

BACKGROUND: CDX-2 is a nuclear homeobox transcription factor not normally expressed in esophageal and gastric epithelia, reported to highlight intestinal metaplasia (IM) in the esophagus. Pathological absence of goblet cells at initial screening via hematoxylin and eosin (HE) and alcian blue (AB) staining results in patient exclusion from surveillance programs. AIMS: This study aimed to determine whether non-goblet cell IM, as defined by CDX-2 positivity, can be considered to be a precursor to Barrett’s esophagus (BE). METHODS: This study received IRB approval (17,284). Patients with gastroesophageal reflux disease (n = 181) who underwent upper-gastrointestinal endoscopy with biopsies of the distal esophagus to rule out BE using HE/AB staining and CDX-2 immunostaining were followed for 3 years. Initial and follow-up staining results were evaluated for age/sex. RESULTS: Differences between development of goblet cell IM in CDX-2-negative and CDX-2-positive groups were evaluated. A Kaplan–Meier curve showed that, out of the 134 patients initially positive for CDX-2, 25 (18.7%) had developed goblet cell IM after 2 years and 106 (79.1%) after 3 years. Conversely, of the 47 patients initially negative for CDX-2, 8 (17.9%) developed goblet cell IM after 24 months and only 11 (23.8%) after 40 to 45 months (P = .049; age-adjusted Cox proportional hazard regression model). CONCLUSION: In cases that are initially AB negative and CDX-2 positive, CDX-2 was demonstrated to have a potential prognostic utility for early detection of progression to BE. CDX-2 expression is significantly predictive for risk of goblet cell IM development 40 to 45 months after initial biopsy.

BackgroundAcinar cell carcinoma of the pancreas is a rare malignancy representing less than 1% of all pancreatic malignancies.MethodsWe report on a case series of 21 patients with acinar cell carcinoma of the pancreas treated at a high-volume quaternary center. A systematic review of the medical literature was performed that described typical therapeutic management approaches for acinar cell carcinoma of the pancreas and reported on disease control and survival rates. Data for the case series were obtained from a prospective database.ResultsIn our systematic review of 6 articles, study patients had a median age of 61 years, 66% were male, 52% had stage I/II disease, and 55% of lesions were located in the pancreatic head. The rates of median survival were approximately 47 months after resection with adjuvant therapy, 38 months for nonmetastatic, locally unresectable disease, and 17 months for metastatic disease treated with chemotherapy. Combination fluoropyrimidine-based chemotherapy regimens had better rates of disease control than other therapies. Our case series included 21 study patients, 14 of whom required resection and 7 who had metastatic disease. The rates of median survival were 40.2 + 31.9 months in those who underwent surgery and were treated with adjuvant therapy and 13.8 + 11.3 months for patients with metastatic disease.ConclusionsMultidisciplinary treatment for acinar cell carcinoma of the pancreas should be considered due to the rarity of the disease and its lack of high-level therapeutic data. Progress in the molecular analysis of this tumor may improve outcomes through the use of personalized therapy based on underlying tumor mutations.

BACKGROUND: Identifying the molecular switch responsible for the neoplastic progression of Barrett’s esophagus (BE) and initiation of adenocarcinoma is clinically essential and it will have a profound impact on patient diagnosis, prognosis, and treatment. The cellular apoptosis susceptibility gene CAS/CSE1L is overexpressed in various cancers, including a rare report on esophageal adenocarcinoma; however, its expression in BE neoplasia has not been addressed. METHODS: We investigated the expression of the CAS/CSE1L protein immunohistochemically in 56 esophageal resection specimens for adenocarcinoma arising in BE. For each specimen, a full representative section of the invasive adenocarcinoma (ADC) was selected to include, when possible, BE, low grade dysplasia (LGD) and high grade dysplasia (HGD). Samples were stained for CAS/CSE1L expression using a rabbit polyclonal antibody recognizing the N-terminus of human CAS/CSE1L. Protein expression levels were measured using the Allred semiquantitative scoring system. The data was evaluated using chi-squared statistical analysis. Gene expression Omnibus was queried for CAS/CSE1L and BE neoplasia. RESULTS: We found minimal to absent CAS/CSE1L in all BE tissue samples; however, CAS/CSE1L was upregulated in 60% of LGD and overexpressed in HGD and ADC. The results were statistically significant (P< 0.05). The localization of CAS/CSE1L protein was nuclear in BE; it became nuclear and cytoplasmic in LGD and HGD, and predominantly cytoplasmic in ADC. A similar progressive increase was observed for CAS/CSE1L gene expression. CONCLUSION: These findings show changes in CAS/CSE1L during BE progression. CAS/CSE1L may represent a potential marker for dysplasia/carcinoma.

Solid-pseudopapillary neoplasm of the pancreas (SPN) is a rare neoplasm that is typically indolent in nature. Surgical resection is the preferred method of treatment and often associated with a good prognosis. Local invasion and metastasis have been reported in a small subset of patients. Currently, there are limited data on the molecular mutation profile of invasive and metastatic SPN. In this report, we present the case of a 38-year-old female with a locally-invasive and unresectable SPN that, despite exhaustive chemoradiotherapy, progressed to liver metastasis. Pyrosequencing of the primary pancreatic tumor antecedent to metastasis showed an uncommon EGFR mutation at L861Q in the kinase domain of exon 21. This finding, if confirmed in additional cases of metastatic SPN, would support preoperative testing for EGFR mutation analysis to detect aggressive SPNs.

Background Barrett esophagus (BE) continues to be a major risk factor for developing esophageal adenocarcinoma. Methods We review the risk factors, diagnosis, and management of BE, with an emphasis on the most current endoscopic diagnostic modalities for BE. Results Novel diagnostic modalities have emerged to address the inadequacies of standard, untargeted biopsies, such as dye-based and virtual chromoendoscopy, endoscopic mucosal resection, molecular biomarkers, optical coherence tomography, confocal laser endomicroscopy, volumetric laser endomicroscopy, and endocytoscopy. Treatment of BE depends on the presence of intramucosal cancer or dysplasia, particularly high-grade dysplasia with or without visible mucosal lesions. Conclusions Recent advances in endoscopic diagnostic tools demonstrate promising results and help to mitigate the shortcomings of the Seattle protocol. Future research as well as refining these tools may help aid them in replacing standard untargeted biopsies.

Background: Esophageal adenocarcinoma (EAC) is an aggressive malignancy with an increasing incidence in the US. Progression of Barrett's Esophagus (BE) to EAC occurs via a stepwise process, and consequently periodic esophageal biopsies are utilized in order to monitor patients with BE. While a small percent of BE patients will progress to dysplasia and cancer, the majority of them will continue to have long-standing BE without progression. In the absence of dysplasia, the behavior of BE cannot be predicted based on evaluation of histologic features alone. Studies have demonstrated the utility of microRNAs in differentiating between the specific evolutionary events in the progression of BE to dysplasia and cancer. To date, there has yet to be a comparison between cases of BE that have not progressed to dysplasia or carcinoma, or cases of BE-Non-progression (BEN), and cases of BE that have progressed to dysplasia and/or carcinoma, or cases of BE- Progression (BEP). Through miRNA profiling, we have determined an assay of candidate miRNAs that reliably differentiate cases of BEN from BEP. Methods: Fifty cases of BE were profiled with two different miRNA profiling techniques: the HTG EdgeSeq miRNA WT Assay and the nanoString Assay. There were 15 cases of BEN (follow up >7 years) as well as of 11 cases of BEP (progression to dysplasia and/or EAC within 3 years). These cases were used for miRNA discovery and miRNA prediction model training. Another independent patient data set of 24 BE cases (13 cases of BEN and 11 cases of BEP; namely Normalized Nano), was profiled with nanoString miRNA Assay. This set was used as an independent validating cohort. Results: Six significant miRNAs were identified and confirmed using two different statistical methods (Limma test and Wilcoxen rank sum test). Family-wise error rate for type I error (FWER) was set to less than 0.05 in order to minimize the probability of discovering false positives. The final miRNA model demonstrated a high prediction performance at the optimal cutoff with a specificity of 80% and 50%; as well as sensitivity 100% and 75% for the two sets in order to capture a high proportion of the BEPs. We then independently validated this miRNA signature with the Normalized Nano set, which demonstrated a sensitivity of 70% and a specificity of 67.5% in this independent validation. While the prediction performance was weaker, we consistently validated its prediction power and clinical utility on an independent patient cohort with a completely different miRNA profiling technique. Conclusion: The reliability of these candidate miRNAs support further investigation in a larger population of patients, and may have potentially prognostic utility in the evaluation of BE patients with the goal of early detection of BE progression. Citation Format: James Saller, Kun Jiang, Kevin Neill, Zachary Mayer, Jae Lee, Luis Pena, F. Scott Corbett, Jose Pimiento, Mokenge Malafa, Anthony Magliocco, Domenico Coppola. An miRNA signature selects patients at risk for Barrett's Esophagus progression to dysplasia and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5410.

In recent years, molecular advances have improved our understanding of the biologic basis of genesis, growth, and progression of human NETs. Emerging therapies (VEGF and mTOR inhibitors) have shown clinical efficacy in unselected patient populations with advanced pancreatic NETS. These results suggest that further molecular characterization of human NETs may rationalize patient tailoring approaches for future clinical trials of targeted therapeutics. That will maximize clinical impact on NET patient management and further improve our understanding of the various resistance pathways. Therefore, future advances in continued discovery, validation, and qualification of promising molecular biomarkers will develop more personalized diagnostic and therapeutic options to make precision medicine a reality for patients with neuroendocrine tumors.

Human cellular apoptosis susceptibility (chromosomal segregation 1-like, CSE1L) gene plays a role in nuclear-to-cytoplasm transport and chromosome segregation during mitosis, cellular proliferation, and apoptosis. CSE1L is involved in colon carcinogenesis. CSE1L gene expression was assessed with three data sets using Affymetrix U133 + gene chips on normal human colonic mucosa (NR), adenomas (ADs), and colorectal carcinoma (CRC). CSE1L protein expression in CRC, AD, and NR from the same patients was measured by immunohistochemistry using a tissue microarray. We evaluated CSE1L expression in CRC cells (HCT116, SW480, and HT29) and its biological functions. CSE1L mRNA was significantly increased in all AD and CRC compared with NR (P