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 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.

Pancreatic adenocarcinoma has a five-year survival rate of less than 6%. This low survival rate is attributed to the lack of accurate detection methods, which limits diagnosis to late-stage disease. Here, an in vivo pilot study assesses the feasibility of optical spectroscopy to improve clinical detection of pancreatic adenocarcinoma. During surgery on 6 patients, we collected spectrally-resolved reflectance and fluorescence in vivo. Site-matched in vivo and ex vivo data agreed qualitatively and quantitatively. Quantified differences between adenocarcinoma and normal tissues in vivo were consistent with previous results from a large ex vivo data set. Thus, optical spectroscopy is a promising method for the improved diagnosis of pancreatic cancer in vivo.

BACKGROUND: The Society of University Surgeons (SUS) has an ongoing competitive funding program to support research training for residents. We sought to determine the career track of award recipients. METHODS: We included in the study SUS resident awardees who completed awards from 1989-2007. Characteristics of awardees and their academic productivity were extracted from curriculum vitae provided by awardees (n = 24), or from online sources (n = 7). RESULTS: Awardees spent an average of 2.7 y (range, 1-4 y) of dedicated research time during residency. Awardees averaged 9.8 publications (range, 1-32), with 5.4 as first author (range, 1-17), with their mentor within 3 y of award completion, with an average maximum impact factor of 5.7. A total of 25 residents (81%) pursued fellowships. At an average follow-up of 11.4 y (range, 4-22 y) from the end of the award and 7.2 y (range, 0-18 y) from end of clinical training, awardees had a Hirsch index of 14.5 (range, 2-48). At the time of the study, 26 awardees (84%) were in academic surgery. Of the 23 awardees who had completed surgical training >/= 3 y earlier, 11 (48%) received independent research funding, seven of whom (30%) received R01 or equivalent funding. CONCLUSIONS: The SUS resident research awardees had a productive research experience. Although our retrospective study cannot determine causation, the SUS award mechanism delivers on its promise of supporting junior surgeon-scientists who pursue academic careers and establish independent research programs. Further studies are needed to determine how rates of subsequent independent research funding can be improved.

The spread of cancer throughout the body is driven by circulating tumour cells (CTCs). These cells detach from the primary tumour and move from the bloodstream to a new site of subsequent tumour growth. They also carry information about the primary tumour and have the potential to be valuable biomarkers for disease diagnosis and progression, and for the molecular characterization of certain biological properties of the tumour. However, the limited sensitivity and specificity of current methods for measuring and studying these cells in patient blood samples prevents the realization of their full clinical potential. The use of microfluidic devices is a promising method for isolating CTCs. However, the devices are reliant on three-dimensional structures, which limits further characterization and expansion of cells on the chip. Here we demonstrate an effective approach to isolating CTCs from blood samples of pancreatic, breast and lung cancer patients, by using functionalized graphene oxide nanosheets on a patterned gold surface. CTCs were captured with high sensitivity at a low concentration of target cells (73 +/- 32.4% at 3-5 cells per ml blood).

INTRODUCTION: The pancreas can serve as the destination for metastatic spread of malignancies from multiple organ sites. Breast cancer metastases to the pancreas are part of this spectrum and surgeons evaluate such patients as part of their practice. Uniform clinical guidelines for these cases do not exist and care is primarily driven by the personal experience of the treating surgeon. DISCUSSION: We present two patients with breast cancer metastases to their pancreas and review their workup and clinical management in light of our experience and the existing published literature. We propose that metastatic disease to the pancreas has to remain in the differential diagnosis for any patient with a new pancreatic mass and prior cancer history. Surgical resection is a viable treatment option for patients with isolated metastatic disease to the pancreas if the underlying biology of the metastatic tumor is favorable.

Specific protein glycoforms may be uniquely informative about the pathological state of a cyst and may serve as accurate biomarkers. Here we tested that hypothesis using antibody-lectin sandwich arrays in broad screens of protein glycoforms and in targeted studies of candidate markers. We profiled 16 different glycoforms of proteins captured by 72 different antibodies in cyst fluid from mucinous and nonmucinous cysts (n = 22), and we then tested a three-marker panel in 22 addition samples and 22 blinded samples. Glycan alterations were not widespread among the proteins and were mainly confined to MUC5AC and endorepellin. Specific glycoforms of these proteins, defined by reactivity with wheat germ agglutinin and a blood group H antibody, were significantly elevated in mucinous cysts, whereas the core protein levels were not significantly elevated. A three-marker panel based on these glycoforms distinguished mucinous from nonmucinous cysts with 93% accuracy (89% sensitivity, 100% specificity) in a prevalidation sample set (n = 44) and with 91% accuracy (87% sensitivity, 100% specificity) in independent, blinded samples (n = 22). Targeted lectin measurements and mass spectrometry analyses indicated that the higher wheat germ agglutinin and blood group H reactivity was due to oligosaccharides terminating in GlcNAc or N-acetyl-lactosamine with occasional alpha1,2-linked fucose. The results show that MUC5AC and endorepellin glycoforms may be highly specific and sensitive biomarkers for the differentiation of mucinous from nonmucinous pancreatic cysts.

PURPOSE OF REVIEW: This review intends to describe recent studies on pancreatic tumor-associated stroma and potential opportunities and limitations to its targeting. RECENT FINDINGS: One of the defining features of pancreatic cancer is extensive desmoplasia, or an inflammatory, fibrotic reaction. Carcinoma cells live in this complex microenvironment which is comprised of extracellular matrix (ECM), diffusible growth factors, cytokines and a variety of nonepithelial cell types including endothelial cells, immune cells, fibroblasts, myofibroblasts and stellate cells. In addition to the heterogeneity noted in the nonneoplastic cells within the tumor microenvironment, it has also been recognized that neoplastic cancer cells themselves are heterogeneous, and include a subpopulation of stem-cell like cells within tumors termed cancer stem cells. Due to the failure of current therapeutics to improve outcomes in patients with pancreatic cancer, new therapeutic avenues targeting different components of the tumor microenvironment are being investigated. In this review article, we will focus on recent studies regarding the function of the tumor stroma in pancreatic cancer and therapeutic treatments that are being advanced to target the stroma as a critical part of tumor management. SUMMARY: Recent studies have shed new light on the contribution of the pancreatic cancer fibroinflammatory stroma to pancreatic cancer biology. Additional studies are needed to better define its full contribution to tumor behavior and how to best understand the optimal ways to develop therapies that counteract its pro-neoplastic properties.