Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance.

Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear.

Cbl and Cbl-b Ubiquitin Ligases are Essential for Intestinal Epithelial Stem Cell Maintenance.

Among the signaling pathways that control the stem cell self-renewal and maintenance vs. acquisition of differentiated cell fates, those mediated by receptor tyrosine kinase (RTK) activation are well established as key players. CBL family ubiquitin ligases are negative regulators of RTKs but their physiological roles in regulating stem cell behaviors are unclear.

Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer.

Introduction: The inhibition of Hedgehog (Hh) signaling in pancreatic ductal adenocarcinoma (PDAC) reduces desmoplasia and promotes increased vascularity. In contrast to these findings, the Hh ligand Sonic Hedgehog (SHH) is a potent proangiogenic factor in non-tumor models. The aim of this study was to determine the molecular mechanisms by which SHH affects the tumor stroma and angiogenesis.

Primary and Metastatic Pancreatic Cancer Cells Exhibit Differential Migratory Potentials.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by early metastatic spread in more than 50% of patients. In this study, we sought to understand the migratory properties of (non)metastatic PDAC cells and determine whether the migration of cancer stem cell (CSC) populations accounts for the aggressive nature of this disease.

Methods: The migratory abilities of primary and metastatic PDAC cell lines were investigated using a microfluidic device and time-lapse photography.

Management of Locally Advanced Pancreatic Cancer: Results of an International Survey of Current Practice.

Objective: The aim of this study was to investigate surgeon preferences for the management of patients with locally advanced pancreatic cancer (LAPC).

Background: Select patients with LAPC may become candidates for curative resection following neoadjuvant therapy, and recent reports of survival are encouraging. Yet the optimal management approach remains unclear.

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD), seen primarily in Gammaproteobacteria.

Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival.

Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice.

Cytologic characteristics of circulating epithelioid cells in pancreatic disease.

Background: Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin.

Methods: Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment.

Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice.

Background & Aims: Little is known about the origin of pancreatic intraductal papillary mucinous neoplasms (IPMN). Pancreatic duct glands (PDGs) are gland-like outpouches budding off the main pancreatic ducts that function as a progenitor niche for the ductal epithelium; they express gastric mucins and have characteristics of side-branch IPMNs. We investigated whether PDGs are a precursor compartment for IPMNs and the role of Trefoil factor family 2 (TFF2)-a protein expressed by PDGs and the gastric mucosa that are involved in epithelial repair and tumor suppression.

A Size-Selective Intracellular Delivery Platform.

Identifying and separating a subpopulation of cells from a heterogeneous mixture are essential elements of biological research. Current approaches require detailed knowledge of unique cell surface properties of the target cell population. A method is described that exploits size differences of cells to facilitate selective intracellular delivery using a high throughput microfluidic device.

Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment.

Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC.

Circulating Epithelial Cells in Patients with Pancreatic Lesions: Clinical and Pathologic Findings.

Background: Circulating epithelial cell (CEC) isolation has provided diagnostic and prognostic information for a variety of cancers, previously supporting their identity as circulating tumor cells in the literature. However, we report CEC findings in patients with benign, premalignant, and malignant pancreatic lesions using a size-selective filtration device.

Study Design: Peripheral blood samples were drawn from patients found to have pancreatic lesions on preoperative imaging at a surgical clinic.

Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer.

New combinations of cytotoxic chemotherapy have been proven to increase response rates and survival times compared with single-agent gemcitabine for patients with metastatic pancreatic cancer. These responses have been dramatic for a subset of patients, therefore raising questions about the management of limited metastatic disease with surgery or other ablative methods. Similarly, for patients having a complete radiographic response to chemotherapy in the metastatic compartment, whether to consider local therapy in the form of radiation or surgery for the primary tumor is now an appropriate question.

Pancreatic duct glands (PDGs) are a progenitor compartment responsible for pancreatic ductal epithelial repair.

Pancreatic duct glands (PDGs) have molecular features known to mark stem cell niches, but their function remains to be determined. To investigate the role of PDGs as a progenitor niche, PDGs were analyzed in both humans and mice. Cells were characterized by immunohistochemistry and microarray analysis.

Early detection of sporadic pancreatic cancer: summative review.

Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society.

Circulating tumor cells found in patients with localized and advanced pancreatic cancer.

Objectives: Isolation of circulating tumor cells (CTCs) holds the promise of diagnosing and molecular profiling cancers from a blood sample. Here, we test a simple new low-cost filtration device for CTC isolation in patients with pancreatic ductal adenocarcinoma (PDAC).

Methods: Peripheral blood samples drawn from healthy donors and PDAC patients were filtered using ScreenCell devices, designed to capture CTCs for cytologic and molecular analysis.

Survival in ampullary cancer: potential role of different KRAS mutations.

Objective: The prognosis of ampullary adenocarcinoma (AA) usually is favorable; however, a subset of AA have poor biology and outcomes similar to pancreatic cancer. Patients in this subset will have early recurrence and death usually within 2 years. To date, there are no genetic markers to identify these patients.

The influence of anesthesia on heart rate complexity during elective and urgent surgery in 128 patients.

Background: As an emerging "new vital sign," heart rate complexity (by sample entropy [SampEn]) has been shown to be a useful trauma triage tool by predicting occult physiologic compromise and need for life-saving interventions. Sample entropy may be confounded by anesthesia possibly limiting its value intraoperatively. We investigated the effects of anesthesia on SampEn during elective and urgent surgical procedures.

The effect of antecolic versus retrocolic reconstruction on delayed gastric emptying after classic non-pylorus-preserving pancreaticoduodenectomy.

Background: Delayed gastric emptying (DGE) after pancreaticoduodenectomy increases length of hospital stay and costs, and may be influenced by surgical techniques.

Methods: We retrospectively compared 400 patients with antecolic gastrojejunostomy with 400 patients with retrocolic gastrojejunostomy for the occurrence of DGE.

Results: The prevalence of DGE was 15% in the antecolic group and 21% in the retrocolic group (P = .

Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize major discussion points from the 2014 NCCN Pancreatic Adenocarcinoma Panel meeting. The panel discussion focused mainly on the management of borderline resectable and locally advanced disease.

High performing whipple patients: factors associated with short length of stay after open pancreaticoduodenectomy.

Introduction: Despite the decreasing mortality of pancreaticoduodenectomy (PD), it continues to be associated with prolonged length of postoperative hospital stay (LOS). This study aimed to determine factors that could predict short LOS after PD. Additionally, as preliminary data of minimally invasive PD emerges, we sought to determine the average LOS after open PD at a high-volume center to set a standard to which minimally invasive PD can be compared.

Not all mixed-type intraductal papillary mucinous neoplasms behave like main-duct lesions: implications of minimal involvement of the main pancreatic duct.

Background: The malignant potential of intraductal mucinous neoplasm of the pancreas (IPMN) is associated closely with main pancreatic duct (MPD) involvement. Because mixed-type IPMN is thought to have the same malignant potential as that of main-duct (MD)-IPMN, resection is recommended; however, the biological nature of mixed-type IPMN with only minimal involvement of MPD (min-mix-IPMN) may be different.

Methods: A prospective database of 404 resected IPMNs was re-reviewed to subclassify mixed-type IPMNs.

Accurate prediction of nodal status in preoperative patients with pancreatic ductal adenocarcinoma using next-gen nanoparticle.

Objective: The objective of this study is to assess lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI) in identifying malignant nodal involvement in patients with pancreatic ductal adenocarcinoma.

Methods: Magnetic resonance imaging was performed in 13 patients with known or high index of suspicion of pancreatic cancer and who were scheduled for surgical resection. Protocols included T2*-weighted imaging before and after administration of Ferumoxytol (Feraheme) for the evaluation of lymph node involvement.

Branch duct intraductal papillary mucinous neoplasms: does cyst size change the tip of the scale? A critical analysis of the revised international consensus guidelines in a large single-institutional series.

Objective: The aim of this study was to critically analyze the safety of the revised guidelines, with focus on cyst size and worrisome features in the management of BD-IPMN.

Background: The Sendai guidelines for management of branch duct (BD) intraductal papillary mucinous neoplasm (IPMN) espouse safety of observation of asymptomatic cysts smaller than 3 cm without nodules (Sendai negative). Revised international consensus guidelines published in 2012 suggest a still more conservative approach, even for lesions of 3 cm or larger.