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Pancreatic Neoplasms: HELP
Articles by Edward B. Stelow
Based on 14 articles published since 2010
(Why 14 articles?)
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Between 2010 and 2020, Ed Stelow wrote the following 14 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline Standardized terminology and nomenclature for pancreatobiliary cytology: the Papanicolaou Society of Cytopathology guidelines. 2014

Pitman, Martha B / Centeno, Barbara A / Ali, Syed Z / Genevay, Muriel / Stelow, Ed / Mino-Kenudson, Mari / Fernandez-del Castillo, Carlos / Max Schmidt, C / Brugge, William / Layfield, Lester / Anonymous9540785. ·Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Diagn Cytopathol · Pubmed #24554455.

ABSTRACT: The Papanicolaou Society of Cytopathology 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 of pancreatobiliary disease, ancillary testing, and postbiopsy treatment and 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 Papanicolaou Society of Cytopathology web site (www.papsociety.org). This document selectively presents the results of these discussions and focuses on a proposed standardized terminology scheme for pancreatobiliary specimens that correlate cytological diagnosis with biological behavior and increasingly conservative patient management of surveillance only. The proposed terminology scheme recommends a six-tiered system: Nondiagnostic, Negative, Atypical, Neoplastic (benign or other), Suspicious and Positive. Unique to this scheme is the "Neoplastic" category separated into "benign" (serous cystadenoma), or "Other" (premalignant mucinous cysts, neuroendocrine tumors, and solid-pseudopapillary neoplasms). The positive or malignant category is reserved for high-grade, aggressive malignancies including ductal adenocarcinoma, acinar cell carcinoma, poorly differentiated neuroendocrine carcinomas, pancreatoblastoma, lymphoma, and metastases. Interpretation categories do not have to be used. Some pathology laboratory information systems require an interpretation category, which places the cytological diagnosis into a general category. This proposed scheme provides terminology that standardizes the category of the various diseases of the pancreas, some of which are difficult to diagnose specifically by cytology. In addition, this terminology scheme attempts to provide maximum flexibility for patient management, which has become increasingly conservative for some neoplasms.

2 Article Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth. 2019

Nagdas, Sarbajeet / Kashatus, Jennifer A / Nascimento, Aldo / Hussain, Syed S / Trainor, Riley E / Pollock, Sarah R / Adair, Sara J / Michaels, Alex D / Sesaki, Hiromi / Stelow, Edward B / Bauer, Todd W / Kashatus, David F. ·Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA. · Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA. · Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA. · Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA. Electronic address: kashatus@virginia.edu. ·Cell Rep · Pubmed #31412251.

ABSTRACT: Mitochondria undergo fission and fusion to maintain homeostasis, and tumors exhibit the dysregulation of mitochondrial dynamics. We recently demonstrated that ectopic HRas

3 Article CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response. 2018

Szlachta, Karol / Kuscu, Cem / Tufan, Turan / Adair, Sara J / Shang, Stephen / Michaels, Alex D / Mullen, Matthew G / Fischer, Natasha Lopes / Yang, Jiekun / Liu, Limin / Trivedi, Prasad / Stelow, Edward B / Stukenberg, P Todd / Parsons, J Thomas / Bauer, Todd W / Adli, Mazhar. ·Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, 1340 JPA, Pinn Hall, Charlottesville, VA, 22908, USA. · Department of Surgery, University of Virginia School of Medicine, 1215 Lee St, Charlottesville, VA, 22908, USA. · Department of Pathology, University of Virginia School of Medicine, Charlottesville, 1215 Lee St, Charlottesville, VA, 22908, USA. · Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, 1340 JPA, Pinn Hall, Charlottesville, VA, 22908, USA. · Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, 1340 JPA, Pinn Hall, Charlottesville, VA, 22908, USA. adli@virginia.edu. ·Nat Commun · Pubmed #30323222.

ABSTRACT: Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment. We develop drug response evaluation by in vivo CRISPR screening (DREBIC) method and validated its efficacy using large-scale experimental data from independent experiments. Comparative analyses demonstrate that DREBIC predicts drug response in cancer cells from a wide range of tissues with high accuracy and identifies therapeutic vulnerabilities of cancer-causing mutations to MEK inhibitors in various cancer types.

4 Article Adjuvant Trametinib Delays the Outgrowth of Occult Pancreatic Cancer in a Mouse Model of Patient-Derived Liver Metastasis. 2016

Newhook, Timothy E / Lindberg, James M / Adair, Sara J / Kim, Alison J / Stelow, Edward B / Rahma, Osama E / Parsons, J Thomas / Bauer, Todd W. ·Department of Surgery, University of Virginia, Charlottesville, VA, USA. · Department of Pathology, University of Virginia, Charlottesville, VA, USA. · Department of Medicine, Division of Medical Oncology, University of Virginia, Charlottesville, VA, USA. · Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA. · Department of Surgery, University of Virginia, Charlottesville, VA, USA. twb7f@virginia.edu. ·Ann Surg Oncol · Pubmed #26847682.

ABSTRACT: PURPOSE: Most patients with pancreatic ductal adenocarcinoma (PDAC) die within 5 years following resection plus adjuvant gemcitabine (Gem) from outgrowth of occult metastases. We hypothesized that inhibition of the KRAS pathway with the MEK inhibitor trametinib would inhibit the outgrowth of occult liver metastases in a preclinical model. METHODS: Liver metastases harvested from two patients with PDAC (Tumors 608, 366) were implanted orthotopically in mice. Tumor cell lines were derived and transduced with lentiviruses encoding luciferase and injected into spleens of mice generating microscopic liver metastases. Growth kinetics of liver metastases were measured with bioluminescent imaging and time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) were determined. RESULTS: Trametinib (0.3 mg/kg BID) significantly prolonged OS versus control (Tumor 608: 114 vs. 43 days, p < 0.001; Tumor 366: not reached vs. 167 days, p = 0.0488). In vivo target validation demonstrated trametinib significantly reduced phosphorylated-ERK and expression of the ERK-responsive gene DUSP6. In a randomized, preclinical trial, mice were randomized to: (1) control, (2) adjuvant Gem (100 mg/kg IP, Q3 days) × 7 days followed by surveillance, or (3) adjuvant Gem followed by trametinib. Sequential Gem-trametinib significantly decreased metastatic cell outgrowth and increased TTP and PFS. CONCLUSIONS: Treatment of mice bearing micrometastases with trametinib significantly delayed tumor outgrowth by effectively inhibiting KRAS-MEK-ERK signaling. In a randomized, preclinical, murine trial adjuvant sequential Gem followed by trametinib inhibited occult metastatic cell outgrowth in the liver and increased PFS versus adjuvant Gem alone. An adjuvant trial of sequential Gem-trametinib is being planned in patients with resected PDAC.

5 Article Clinicopathologic characteristics of 29 invasive carcinomas arising in 178 pancreatic mucinous cystic neoplasms with ovarian-type stroma: implications for management and prognosis. 2015

Jang, Kee-Taek / Park, Sang Mo / Basturk, Olca / Bagci, Pelin / Bandyopadhyay, Sudeshna / Stelow, Edward B / Walters, Dustin M / Choi, Dong Wook / Choi, Seoung Ho / Heo, Jin Seok / Sarmiento, Juan M / Reid, Michelle D / Adsay, Volkan. ·Departments of *Pathology #Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Departments of ‡Pathology **Surgery, Emory University School of Medicine, Atlanta, GA †Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY §Department of Pathology, Wayne State University School of Medicine, Detroit, MI Departments of ∥Pathology ¶Surgery, University of Virginia School of Medicine, Charlottesville, VA. ·Am J Surg Pathol · Pubmed #25517958.

ABSTRACT: Information on the clinicopathologic characteristics of invasive carcinomas arising from mucinous cystic neoplasms (MCNs) is limited, because in many early studies they were lumped and analyzed together with noninvasive MCNs. Even more importantly, many of the largest prior studies did not require ovarian-type stroma (OTS) for diagnosis. We analyzed 178 MCNs, all strictly defined by the presence of OTS, 98% of which occurred in perimenopausal women (mean age, 47 y) and arose in the distal pancreas. Twenty-nine (16%) patients had associated invasive carcinoma, and all were female with a mean age of 53. Invasion was far more common in tumors with grossly visible intracystic papillary nodule formation ≥1.0 cm (79.3% vs. 8.7%, P=0.000) as well as in larger tumors (mean cyst size: 9.4 vs. 5.4 cm, P=0.006); only 4/29 (14%) invasive carcinomas occurred in tumors that were <5 cm; however, none were <3 cm. Increased serum CA19-9 level (>37 U/L) was also more common in the invasive tumors (64% vs. 23%, P=0.011). Most invasive carcinomas (79%) were of tubular type, and the remainder (5 cases) were mostly undifferentiated carcinoma (2, with osteoclast-like giant cells), except for 1 with papillary features. Interestingly, there were no colloid carcinomas; 2 patients had nodal metastasis at the time of diagnosis, and both died of disease at 10 and 35 months, respectively. While noninvasive MCNs had an excellent prognosis (100% at 5 y), tumors with invasion often had an aggressive clinical course with 3- and 5-year survival rates of 44% and 26%, respectively (P=0.000). The pT2 (>2 cm) invasive tumors had a worse prognosis than pT1 (≤2 cm) tumors (P=0.000), albeit 3 patients with T1a (<0.5 cm) disease also died of disease. In conclusion, invasive carcinomas are seen in 16% of MCNs and are mostly of tubular (pancreatobiliary) type; colloid carcinoma is not seen in MCNs. Serum CA19-9 is often higher in invasive carcinomas, and invasion is typically seen in OTS-depleted areas with lower progesterone receptor expression. Invasion is not seen in small tumors (<3 cm) and those lacking intracystic papillary (mural) nodules of ≥1 cm, thus making the current branch-duct intraductal papillary mucinous neoplasm management protocols also applicable to MCNs.

6 Article Co-treatment with panitumumab and trastuzumab augments response to the MEK inhibitor trametinib in a patient-derived xenograft model of pancreatic cancer. 2014

Lindberg, James M / Newhook, Timothy E / Adair, Sara J / Walters, Dustin M / Kim, Alison J / Stelow, Edward B / Parsons, J Thomas / Bauer, Todd W. ·Department of Surgery, University of Virginia Health System, Charlottesville, VA, 22908 USA. · Department of Pathology, University of Virginia Health System, Charlottesville, VA, 22908 USA. · Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA, 22908 USA. · Department of Surgery, University of Virginia Health System, Charlottesville, VA, 22908 USA. Electronic address: twb7f@virginia.edu. ·Neoplasia · Pubmed #25117978.

ABSTRACT: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and epidermal growth factor receptor (EGFR) family signaling are drivers of tumorigenesis in pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated that combinatorial treatment of PDAC xenografts with the mitogen-activated protein kinase-extracellular-signal-regulated kinase (ERK) kinase1/2 (MEK1/2) inhibitor trametinib and the dual EGFR/human epidermal growth factor receptor 2 (HER2) inhibitor lapatinib provided more effective inhibition than either treatment alone. In this study, we have used the therapeutic antibodies, panitumumab (specific for EGFR) and trastuzumab (specific for HER2), to probe the role of EGFR and HER2 signaling in the proliferation of patient-derived xenograft (PDX) tumors. We show that dual anti-EGFR and anti-HER2 therapy significantly augmented the growth inhibitory effects of the MEK1/2 inhibitor trametinib in three different PDX tumors. While significant growth inhibition was observed in both KRAS mutant xenograft groups receiving trametinib and dual antibody therapy (tumors 366 and 608), tumor regression was observed in the KRAS wild-type xenografts (tumor 738) treated in the same manner. Dual antibody therapy in conjunction with trametinib was equally or more effective at inhibiting tumor growth and with lower apparent toxicity than trametinib plus lapatinib. Together, these studies provide further support for a role for EGFR and HER2 in pancreatic cancer proliferation and underscore the importance of therapeutic intervention in both the KRAS-rapidly accelerated fibrosarcoma kinase (RAF)-MEK-ERK and EGFR-HER2 pathways to achieve maximal therapeutic efficacy in patients.

7 Article EUS-guided 22-gauge fine-needle aspiration versus core biopsy needle in the evaluation of solid pancreatic neoplasms. 2014

Strand, Daniel S / Jeffus, Susanne K / Sauer, Bryan G / Wang, Andrew Y / Stelow, Edward B / Shami, Vanessa M. ·Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia. ·Diagn Cytopathol · Pubmed #24550162.

ABSTRACT: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is widely used for diagnosis of pancreatic lesions. The Echotip Procore Needle (Wilson-Cook Medical) is a new 22G fine biopsy needle (FNB) for obtaining core biopsy material at time of EUS. This study aimed to compare the technical and diagnostic performance of conventional FNA and FNB. Thirty-two patients met the design criteria for this prospective paired cohort study. All lesions sampled were solid (non-cystic) pancreatic masses by EUS appearance. Patients were randomized to receive FNA or FNB by first attempt. A cytopathologist performed on-site evaluations. Samples were assessed for accuracy of diagnosis, cellularity, contamination, and sufficiency for ancillary studies. Technical and diagnostic performances were compared. Compared to FNA, there was a statistically significant decreased ability of FNB to achieve a diagnosis (FNA 93.8%, FNB 28.1%, P < 0.001). FNB was diagnostically superior to FNA in 1 of 32 cases. Technical failures were observed in five cases due to resistance to advancement of the FNB needle. Regarding operator perceived ease-of-use, FNA outperformed FNB (P < 0.001). Eight cases had insufficient FNB material to survive tissue processing. There was no significant difference in mean specimen cellularity between devices. FNA samples showed an increased amount of contaminant (P = 0.036) but were more sufficient for ancillary studies (P = 0.502). Although deemed comparable to FNA when providing material for cytology, the pledged advantage of FNB acting like a core biopsy needle was not apparent in our series. Additional studies are needed before routine adoption of 22G FNB can be recommended.

8 Article Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens. 2013

Walters, Dustin M / Stokes, Jayme B / Adair, Sara J / Stelow, Edward B / Borgman, Cheryl A / Lowrey, Bryce T / Xin, Wenjun / Blais, Edik M / Lee, Jae K / Papin, Jason A / Parsons, J Thomas / Bauer, Todd W. ·Department of Surgery, University of Virginia, Charlottesville, Virginia, United States of America. ·PLoS One · Pubmed #24204737.

ABSTRACT: BACKGROUND: Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC. METHODS: Human PDACs were resected and orthotopically implanted and propagated in immunocompromised mice. Patient survival was correlated with xenograft growth and metastatic rate in mice. Human and mouse tumor pathology were compared. Tumors were analyzed for genetic mutations, gene expression, receptor tyrosine kinase activation, and cytokine expression. RESULTS: Fifteen human PDACs were propagated orthotopically in mice. Xenograft-bearing mice developed peritoneal and liver metastases. Time to tumor growth and metastatic efficiency in mice each correlated with patient survival. Tumor architecture, nuclear grade and stromal content were similar in patient and xenografted tumors. Propagated tumors closely exhibited the genetic and molecular features known to characterize pancreatic cancer (e.g. high rate of KRAS, P53, SMAD4 mutation and EGFR activation). The correlation coefficient of gene expression between patient tumors and xenografts propagated through multiple generations was 93 to 99%. Analysis of gene expression demonstrated distinct differences between xenografts from fresh patient tumors versus commercially available PDAC cell lines. CONCLUSIONS: The orthotopic xenograft model derived from fresh human PDACs closely recapitulates the clinical, pathologic, genetic and molecular aspects of human disease. This model has resulted in the identification of rational therapeutic strategies to be tested in clinical trials and will permit additional therapeutic approaches and identification of biomarkers of response to therapy.

9 Article Cercariform cells: another cytologic feature distinguishing solid pseudopapillary neoplasms from pancreatic endocrine neoplasms and acinar cell carcinomas in endoscopic ultrasound-guided fine-needle aspirates. 2013

Samad, Arbaz / Shah, Akeesha A / Stelow, Edward B / Alsharif, Mariam / Cameron, Stuart E H / Pambuccian, Stefan E. ·Department of Laboratory Medicine and Pathology, University of Minnesota, University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota, USA. ·Cancer Cytopathol · Pubmed #23765692.

ABSTRACT: BACKGROUND: Solid pseudopapillary neoplasm (SPPN) is a rare tumor of unknown origin that occurs predominantly in the body or tail of the pancreas in young women. The authors recently identified cercariform (Greek: tailed) cells, similar to those described in urothelial carcinomas, as a consistent cytologic feature in ultrasound-guided fine-needle aspiration (EUS-FNA) samples from SPPNs. The objective of the current multi-institutional study was to define the value of these cells in the differential diagnosis of SPPN with other neoplasms characterized cytologically by the presence of monotonous, uniform cells in pancreatic aspirates: pancreatic neuroendocrine tumors (Pan-NETs) and acinar cell carcinomas (ACCs). METHODS: The files of 4 academic hospitals were searched for SPPNs, Pan-NETs, and ACCs that were diagnosed by EUS-FNA. The slides were reviewed, and several cytologic features were recorded semiquantitatively to identify discriminating features between SPPNs, Pan-NETs, and ACCs. RESULTS: From the analysis of 18 SPPNs, 4 ACCs, and 20 Pan-NETs, the following cytologic features were identified as common to all 3 neoplasms: single cells and rosettes/acinar cell groups, round-to-plasmacytoid cells, pale-to-granular cytoplasm, fine vacuoles, and binucleated cells. Papillary structures, cercariform cells, large cytoplasmic vacuoles, reniform nuclei, hyaline globules/magenta-colored material, and degenerative features (cholesterol crystals, calcifications, foam cells, or giant cells) were significantly more common in SPPNs. Prominent nuclear grooves were encountered in only 4 of 18 SPPNs. CONCLUSIONS: The current results indicated that the presence of cercariform cells is another useful clue for the cytologic diagnosis of SPPN in challenging cases.

10 Article Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib. 2013

Walters, Dustin M / Lindberg, James M / Adair, Sara J / Newhook, Timothy E / Cowan, Catharine R / Stokes, Jayme B / Borgman, Cheryl A / Stelow, Edward B / Lowrey, Bryce T / Chopivsky, Maria E / Gilmer, Tona M / Parsons, John T / Bauer, Todd W. ·Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA. ·Neoplasia · Pubmed #23441129.

ABSTRACT: Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients.

11 Article Fine-needle aspiration features of paraduodenal pancreatitis (groove pancreatitis): a report of three cases. 2012

Chute, Deborah J / Stelow, Edward B. ·Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. chuted@ccf.org ·Diagn Cytopathol · Pubmed #21548125.

ABSTRACT: Chronic pancreatitis is notorious for mimicking both the clinical and radiologic presentation of pancreatic carcinoma. Paraduodenal pancreatitis is believed to result from focal chronic pancreatitis which affects the minor papilla of the duodenum. Currently, there is limited information available regarding the cytologic features of paraduodenal pancreatitis. In this study, we report the cytologic features of three patients with paraduodenal pancreatitis who had EUS-guided FNAs of the pancreas. The cytologic features were highly variable between cases, likely due to sampling of the various components of paraduodenal pancreatitis. The most common findings were spindled stromal cells, foamy cells, and granular debris. Although most often interpreted as negative for malignancy, the sampling of an area with abundant spindle cells or Brunner gland hyperplasia can mimic neoplasia. Careful attention to the clinical history and radiologic description can help to prevent over-diagnosis on FNA.

12 Article Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. 2011

Stokes, Jayme B / Adair, Sara J / Slack-Davis, Jill K / Walters, Dustin M / Tilghman, Robert W / Hershey, E Dan / Lowrey, Bryce / Thomas, Keena S / Bouton, Amy H / Hwang, Rosa F / Stelow, Edward B / Parsons, J Thomas / Bauer, Todd W. ·Department of Surgery, University of Virginia, Charlottesville, Virginia, USA. ·Mol Cancer Ther · Pubmed #21903606.

ABSTRACT: Current therapies for pancreatic ductal adenocarcinoma (PDA) target individual tumor cells. Focal adhesion kinase (FAK) is activated in PDA, and levels are inversely associated with survival. We investigated the effects of PF-562,271 (a small-molecule inhibitor of FAK/PYK2) on (i) in vitro migration, invasion, and proliferation; (ii) tumor proliferation, invasion, and metastasis in a murine model; and (iii) stromal cell composition in the PDA microenvironment. Migration assays were conducted to assess tumor and stromal cell migration in response to cellular factors, collagen, and the effects of PF-562,271. An orthotopic murine model was used to assess the effects of PF-562,271 on tumor growth, invasion, and metastasis. Proliferation assays measured PF-562,271 effects on in vitro growth. Immunohistochemistry was used to examine the effects of FAK inhibition on the cellular composition of the tumor microenvironment. FAK and PYK2 were activated and expressed in patient-derived PDA tumors, stromal components, and human PDA cell lines. PF-562,271 blocked phosphorylation of FAK (phospho-FAK or Y397) in a dose-dependent manner. PF-562,271 inhibited migration of tumor cells, cancer-associated fibroblasts, and macrophages. Treatment of mice with PF-562,271 resulted in reduced tumor growth, invasion, and metastases. PF-562,271 had no effect on tumor necrosis, angiogenesis, or apoptosis, but it did decrease tumor cell proliferation and resulted in fewer tumor-associated macrophages and fibroblasts than control or gemcitabine. These data support a role for FAK in PDA and suggest that inhibitors of FAK may contribute to efficacious treatment of patients with PDA.

13 Article Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer. 2011

Stokes, Jayme B / Nolan, Norris J / Stelow, Edward B / Walters, Dustin M / Weiss, Geoffrey R / de Lange, Eduard E / Rich, Tyvin A / Adams, Reid B / Bauer, Todd W. ·Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA. js3xv@virginia.edu ·Ann Surg Oncol · Pubmed #21213060.

ABSTRACT: BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma (PDA) represent a high-risk group of patients due to tumor or patient-related characteristics. The optimal management of these patients has not been fully defined. MATERIALS AND METHODS: All patients undergoing evaluation for PDA between 2005 and 2008 were identified. Clinical, radiographic, and pathological data were retrospectively reviewed. Patients were staged as borderline resectable using the M.D. Anderson Cancer Center (MDACC) classification. RESULTS: A total of 170 patients with PDA were identified, 40 with borderline resectable disease. Of these, 34 borderline resectable patients (85%) completed neoadjuvant therapy and were restaged; pancreatic resection was completed in 16 patients (46%). Also, 8 patients completed 50 Gy of radiation in 28 fractions in 6 weeks, whereas 8 patients received 50 Gy in 20 fractions in 4 weeks plus chronomodulated capecitabine. An R0 resection was achieved in 12 of the 16 patients (75%). Also, 5 patients (63%) treated in 20 fractions had >90% pathologic response versus 1 (13%) treated in 28 fractions (P < .05). Borderline resectable patients completing surgery had similar survival to patients with resectable disease who underwent surgery. Patients receiving accelerated fractionation radiation had improved survival compared with patients treated with standard fractionation protocol. CONCLUSIONS: A neoadjuvant approach to borderline resectable PDA identifies patients who are most likely to benefit from pancreatic resection. Preoperative capecitabine-based chemoradiation is an effective, well-tolerated treatment for these patients. Neoadjuvant therapy for borderline resectable PDA warrants further investigation using treatment schedules that can safely intensify irradiation dose.

14 Article Pancreatic acinar cell carcinomas with prominent ductal differentiation: Mixed acinar ductal carcinoma and mixed acinar endocrine ductal carcinoma. 2010

Stelow, Edward B / Shaco-Levy, Ruthy / Bao, Fei / Garcia, Joaquin / Klimstra, David S. ·Deparment of Pathology, University of Virginia, Charlottesville, USA. ·Am J Surg Pathol · Pubmed #20182344.

ABSTRACT: BACKGROUND: Pancreatic acinar cell carcinomas (ACCs) are clinically and pathologically distinct from pancreatic ductal adenocarcinomas (PDAs). Whereas endocrine differentiation has been well shown in ACCs, significant ductal components are rare. This paper reviews the clinicopathologic features of a series of ACCs with prominent ductal differentiation. DESIGN: Cases of pancreatic ACCs with significant ductal differentiation were identified in the surgical pathology databases of 2 academic centers. Patient clinical information, gross and histologic features, and histochemical and immunohistochemical (IHC) results were recorded. Cases were tested for KRAS2 mutations. RESULTS: Eleven cases were identified (10 men and 1 woman; age range 52 to 79 y). Four patients presented with jaundice. At last follow-up, 7 patients died of disease and 2 others had recurrences. Tumors measured between 2 and 5.5 cm and were ill-defined, nodular, and multilobulated. Ten were located in the head of the pancreas. All but 2 exhibited extrapancreatic invasion. All cases showed significant evidence of both acinar and ductal differentiation, estimated to be at least 25% of the neoplastic cells, and 3 cases in addition had endocrine differentiation in more than 25% of cells. Five cases were predominately acinar with intracellular and sometimes extracellular mucin ("mucinous acinar cell carcinoma" pattern). Six cases seemed more mixed with areas recapitulating typical PDAs whereas the other portions of the tumors seemed akin to typical acinar cell carcinomas ("combined acinar and ductal" pattern). IHC positive staining results were as: trypsin (92%), chymotrypsin (92%), monoclonal carcinoembryonic antigen (100%), CK19 (100%), B72.3 (73%), CA19.9 (73%), CD56 (18%), synaptophysin (36%), and chromogranin (36%). One case showed p53 over-expression aznd none showed DPC4/Smad4 loss. Two cases had KRAS2 mutations. CONCLUSION: Despite the early embryologic divergence of acinar and ductal cell lineages, rare pancreatic tumors have both acinar and ductal differentiation, usually predominantly the former. The clinical course is highly aggressive.