Faculty Bibliography

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreaticobiliary cytology including indications for endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) biopsy, techniques for EUS-FNA, terminology and nomenclature to be used for pancreaticobiliary disease, ancillary testing, and post-biopsy management. All documents are based on expertise of the authors, literature review, discussions of the draft document at national and international meetings, and synthesis of online comments of the draft document. This document selectively presents the results of these discussions. This document summarizes recommendations for the clinical and imaging work-up of pancreatic and biliary tract lesions along with indications for cytologic study of these lesions. Prebrushing and FNA requirements are also discussed.

The papanicolaou society of cytopathology (PSC) has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) biopsy, techniques of EUS-FNA, terminology and nomenclature for pancreatobiliary cytology, ancillary testing, and postprocedure management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings over an 18 month period and synthesis of online comments of the draft document on the PSC web site [www.papsociety.org]. This document selectively presents the results of these discussions and focuses on the follow-up and treatment options for patients after procedures performed for obtaining cytology samples for the evaluation of biliary strictures and solid and cystic masses in the pancreas. These recommendations follow the six-tiered terminology and nomenclature scheme proposed by Committee III.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by therapeutic resistance for which the basis is poorly understood. Here, we report that the DNA and p53-binding protein ATDC/TRIM29, which is highly expressed in PDAC, plays a critical role in DNA damage signaling and radioresistance in pancreatic cancer cells. Ataxia-telangiectasia group D-associated gene (ATDC) mediated resistance to ionizing radiation in vitro and in vivo in mouse xenograft assays. ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC. Our results identify a DNA repair pathway leading from MK2 and ATM to ATDC, suggesting its candidacy as a therapeutic target to radiosensitize PDAC and improve the efficacy of DNA-damaging treatment.

The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH.

Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic examinations, adoption of a standardized template for radiology reporting, using universally accepted and agreed on terminology for solid pancreatic neoplasms, is needed. A consensus statement describing a standardized reporting template authored by a multi-institutional group of experts in pancreatic ductal adenocarcinoma that included radiologists, gastroenterologists, and hepatopancreatobiliary surgeons was developed under the joint sponsorship of the Society of Abdominal Radiologists and the American Pancreatic Association. Adoption of this standardized imaging reporting template should improve the decision-making process for the management of patients with pancreatic ductal adenocarcinoma by providing a complete, pertinent, and accurate reporting of disease staging to optimize treatment recommendations that can be offered to the patient. Standardization can also help to facilitate research and clinical trial design by using appropriate and consistent staging by means of resectability status, thus allowing for comparison of results among different institutions.

Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic examinations, adoption of a standardized template for radiology reporting, using universally accepted and agreed on terminology for solid pancreatic neoplasms, is needed. A consensus statement describing a standardized reporting template authored by a multi-institutional group of experts in pancreatic ductal adenocarcinoma that included radiologists, gastroenterologists, and hepatopancreatobiliary surgeons was developed under the joint sponsorship of the Society of Abdominal Radiologists and the American Pancreatic Association. Adoption of this standardized imaging reporting template should improve the decision-making process for the management of patients with pancreatic ductal adenocarcinoma by providing a complete, pertinent, and accurate reporting of disease staging to optimize treatment recommendations that can be offered to the patient. Standardization can also help to facilitate research and clinical trial design by using appropriate and consistent staging by means of resectability status, thus allowing for comparison of results among different institutions. (c) RSNA and the AGA Institute, 2014 Online supplemental material is available for this article.

BACKGROUND: Pancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized. METHODS: Expression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth. RESULTS: Notch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population. CONCLUSION: The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreaticobiliary cytology including indications for endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) biopsy, techniques for EUS-FNA, terminology and nomenclature to be used for pancreaticobiliary disease, ancillary testing and postbiopsy management. All documents are based on expertise of the authors, literature review, discussions of the draft document at national and international meetings and synthesis of online comments of the draft document. This document selectively presents the results of these discussions. This document summarizes recommendations for the clinical and imaging work-up of pancreatic and biliary tract lesions along with indications for cytologic study of these lesions. Prebrushing and FNA requirements are also discussed.

The Papanicolaou Society of Cytopathology (PSC) has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) biopsy, techniques of EUS-FNA, terminology and nomenclature for pancreatobiliary cytology, ancillary testing and post-procedure management. All documents are based on the expertise of the authors, a review of the literature and discussions of the draft document at several national and international meetings over an 18 month period and synthesis of online comments of the draft document on the PSC web site (www.papsociety.org). This document selectively presents the results of these discussions and focuses on the follow-up and treatment options for patients after procedures performed for obtaining cytology samples for the evaluation of biliary strictures and solid and cystic masses in the pancreas. These recommendations follow the six-tiered terminology and nomenclature scheme proposed by committee III.

PURPOSE: Signal transducer and activator of transcription 3 (STAT3) plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 has failed clinically. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate the potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo. EXPERIMENTAL DESIGN: The expression of HAb18G/CD147, pSTAT3, and CD44s was determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 were assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot assay, immunofluorescence staining, immunoprecipitation, and in vivo tumor formation using loss or gain-of-function strategies. RESULTS: Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. Cyclophilin A (CyPA), a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147-dependent mechanisms. HAb18G/CD147 was associated and colocalized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high coexpression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer. CONCLUSIONS: We identified HAb18G/CD147 as a novel upstream activator of STAT3, which interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest that HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies.