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Pancreatic Neoplasms: HELP
Articles by Wendy L. Frankel
Based on 13 articles published since 2010
(Why 13 articles?)
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Between 2010 and 2020, Wendy Frankel wrote the following 13 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101. 2016

Katz, Matthew H G / Shi, Qian / Ahmad, Syed A / Herman, Joseph M / Marsh, Robert de W / Collisson, Eric / Schwartz, Lawrence / Frankel, Wendy / Martin, Robert / Conway, William / Truty, Mark / Kindler, Hedy / Lowy, Andrew M / Bekaii-Saab, Tanios / Philip, Philip / Talamonti, Mark / Cardin, Dana / LoConte, Noelle / Shen, Perry / Hoffman, John P / Venook, Alan P. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston. · Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, Minnesota. · Department of Surgery, University of Cincinnati, Cincinnati, Ohio. · Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland. · Department of Medical Oncology, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, University of California-San Francisco, San Francisco. · Department of Radiology, Columbia University, New York, New York. · Department of Pathology, Ohio State University, Columbus. · Department of Surgery, University of Louisville, Louisville, Kentucky. · Department of Surgery, Ochsner Medical Center, New Orleans, Louisiana. · Department of Surgery, Mayo Clinic, Rochester, Minnesota. · Department of Medical Oncology, University of Chicago, Chicago, Illinois. · Department of Surgery, University of California, San Diego. · Department of Medical Oncology, Ohio State University, Columbus. · Department of Medical Oncology, Karmanos Cancer Center, Detroit, Michigan. · Department of Surgery, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, Vanderbilt University, Nashville, Tennessee. · Department of Medical Oncology, University of Wisconsin-Madison, Madison, Wisconsin. · Department of Surgery, Wake Forest University, Winston Salem, North Carolina. · Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania. ·JAMA Surg · Pubmed #27275632.

ABSTRACT: IMPORTANCE: Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE: To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. INTERVENTIONS: Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES: Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS: The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. CONCLUSIONS AND RELEVANCE: The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01821612.

2 Article Alliance for clinical trials in oncology (ALLIANCE) trial A021501: preoperative extended chemotherapy vs. chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas. 2017

Katz, Matthew H G / Ou, Fang-Shu / Herman, Joseph M / Ahmad, Syed A / Wolpin, Brian / Marsh, Robert / Behr, Spencer / Shi, Qian / Chuong, Michael / Schwartz, Lawrence H / Frankel, Wendy / Collisson, Eric / Koay, Eugene J / Hubbard, JoLeen M / Leenstra, James L / Meyerhardt, Jeffrey / O'Reilly, Eileen / Anonymous2150914. ·The University of Texas MD Anderson Cancer Center, University of Texas, 1400 Pressler Street FCT 17.6058, Unit #1484, Houston, TX, 77030-4009, USA. mhgkatz@mdanderson.org. · Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA. · The University of Texas MD Anderson Cancer Center, University of Texas, 1400 Pressler Street FCT 17.6058, Unit #1484, Houston, TX, 77030-4009, USA. · University of Cincinnati, Cincinnati, OH, USA. · Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. · NorthShore Evanston Hospital, Evanston, IL, USA. · The University of California at San Francisco, San Francisco, CA, USA. · University of Maryland/Greenebaum Cancer Center, Baltimore, MD, USA. · New York-Presbyterian Hospital/Columbia University Medical Center, New York, NY, USA. · The Ohio State University, Columbus, OH, USA. · Mayo Clinic, Rochester, MN, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. ·BMC Cancer · Pubmed #28750659.

ABSTRACT: BACKGROUND: Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined. METHODS: In Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m DISCUSSION: This study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02839343 , registered July 14, 2016.

3 Article Primary Pancreatic Secretinoma: Further Evidence Supporting Secretin as a Diarrheogenic Hormone. 2017

Chey, William Y / Frankel, Wendy L / Roy, Sashwati / Datta, Soma / Sen, Chandan K / Dillhoff, Mary / Muscarella, Peter / Soergel, Konrad H / Tompkins, Ronald K / Chang, Ta-Min / Bradley, Edward L / Ellison, Edwin Christopher. ·*Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH †Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH ‡Department of Surgery, Center for Regenerative Medicine and Cell Based Therapies, Comprehensive Wound Center, Laser Capture Molecular Core, The Ohio State University Wexner Medical Center, Columbus, OH §Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, WI ¶Department of Surgery, University of California at Los Angeles, School of Medicine, Los Angeles, CA ||Department of Surgery, Florida State University, Tallahassee, FL **William and Sheila Konar Center for Digestive and Liver Diseases, Division of Gastroenterology and Hepatology, University of Rochester Medical Center, Rochester, NY. ·Ann Surg · Pubmed #27501174.

ABSTRACT: OBJECTIVES: To document the existence of primary pancreatic secretinoma in patients with watery diarrhea syndrome (WDS) and achlorhydria and establish secretin as a diarrheogenic hormone. BACKGROUND: Vasoactive intestinal peptide (VIP) has been widely accepted as the main mediator of WDS. However, in 1968, Zollinger et al reported 2 female patients with pancreatic neuroendocrine tumors, WDS, and achlorhydria. During surgery on the first, a 24-year-old patient, they noticed distended duodenum filled with fluid and a dilated gallbladder containing dilute bile with high bicarbonate concentration. After excision of the tumor, WDS ceased and gastric acid secretion returned. The second, a 47-year-old, patient's metastatic tumor extract given intravenously in dogs, produced significantly increased pancreatic and biliary fluid rich in bicarbonate. They suggested a secretin-like hormone of islet cell origin explains WDS and achlorhydria. These observations, however, predated radioimmunoassay, immunohistochemical staining, and other molecular studies. METHODS: The first patient's tumor tissue was investigated for secretin and VIP. Using both immunohistochemistry and laser microdissection and pressure catapulting technique for RNA isolation and subsequent reverse transcription polymerase chain reaction, the expression levels of secretin, and VIP were measured. RESULTS: Immunoreactive secretin and its mRNA were predominantly found in the tumor tissue whereas VIP and its mRNA were scarce. CONCLUSIONS: The findings strongly support that the WDS and achlorhydria in this patient may have been caused by secretin as originally proposed in 1968 and that secretin may act as a diarrheogenic hormone.

4 Article The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. 2015

Basturk, Olca / Yang, Zhaohai / Tang, Laura H / Hruban, Ralph H / Adsay, Volkan / McCall, Chad M / Krasinskas, Alyssa M / Jang, Kee-Taek / Frankel, Wendy L / Balci, Serdar / Sigel, Carlie / Klimstra, David S. ·*Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY †Department of Pathology, Penn State Hershey MC, Hershey, PA ‡Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD §Department of Pathology, Emory University, Atlanta, GA ¶Department of Pathology, Ohio State University, Columbus, OH ∥Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea. ·Am J Surg Pathol · Pubmed #25723112.

ABSTRACT: The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67>20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of "hot spots." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.

5 Article Deletions of RDINK4/ARF enhancer in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors. 2014

Poi, Ming J / Drosdeck, Joe / Frankel, Wendy L / Muscarella, Peter / Li, Junan. ·From the *Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, †College of Pharmacy, ‡Comprehensive Cancer Center, Departments of §Surgery and ∥Pathology, College of Medicine, and ¶Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH. ·Pancreas · Pubmed #25003221.

ABSTRACT: OBJECTIVE: The presence of an enhancer element, RD (RD), in the prominent INK4-ARF locus provides a novel en bloc mechanism to simultaneously regulate the transcription of p15, p14ARF, and p16 genes. However, knowledge about RD alterations and its potential contributions to cancer progression remains limited. In this study, we aimed to evaluate the incidence of RD alterations in pancreatic tumors. METHODS: DNAs from 14 gastrinomas and 6 nonfunctioning pancreatic neuroendocrine tumors were subjected to quantitative real-time polymerase chain reaction-based assays to determine deletions in p15, p14ARF, and p16 (both exons 1 and 2). RESULTS: RD was frequently deleted in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors with an incidence of 30% (6/20 samples). In comparison, the incidences of deletions of p15 (exon 1), p14ARF (exon 1β), and p16 (exon 1α) are 10% (2/20 samples), 10% (2/20 samples), and 45% (9/20 samples), respectively. Whereas some RD deletion events arose from deletions of the entire INK4-ARF locus, RD deletions in some specimens seemed to be independent of genetic alterations in any of the p15, p14ARF, and p16 genes. CONCLUSIONS: Our results strongly support that the deletion of RD may represent a novel mechanism to simultaneously downregulate p15, p14ARF, and p16, thus contributing to the development of human pancreatic cancers.

6 Article Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. 2014

Basturk, Olca / Tang, Laura / Hruban, Ralph H / Adsay, Volkan / Yang, Zhaohai / Krasinskas, Alyssa M / Vakiani, Efsevia / La Rosa, Stefano / Jang, Kee-Taek / Frankel, Wendy L / Liu, Xiuli / Zhang, Lizhi / Giordano, Thomas J / Bellizzi, Andrew M / Chen, Jey-Hsin / Shi, Chanjuan / Allen, Peter / Reidy, Diane L / Wolfgang, Christopher L / Saka, Burcu / Rezaee, Neda / Deshpande, Vikram / Klimstra, David S. ·Departments of *Pathology ***Surgery †††Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY †Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center ‡‡‡Department of Surgery, Johns Hopkins University, Baltimore, MD ‡Department of Pathology, Emory University, Atlanta, GA §Department of Pathology, Penn State Hershey MC, Hershey ∥Department of Pathology, University of Pittsburgh, Pittsburgh, PA **Department of Pathology, Ohio State University, Columbus ††Department of Pathology, Cleveland Clinic, Cleveland, OH ‡‡Department of Pathology, Mayo Clinic, Rochester, MN §§Department of Pathology, University of Michigan, Ann Arbor, MI ∥∥Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA ¶¶Department of Pathology, Indiana University, Indianapolis, IN ##Department of Pathology, Vanderbilt University, Nashville, TN §§§Department of Pathology, Massachusetts General Hospital, Boston, MA ¶Department of Pathology, Ospedale di Circolo, Varese, Italy #Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. ·Am J Surg Pathol · Pubmed #24503751.

ABSTRACT: BACKGROUND: In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited. DESIGN: A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed. RESULTS: The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively. CONCLUSIONS: Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.

7 Article A differential microRNA profile distinguishes cholangiocarcinoma from pancreatic adenocarcinoma. 2014

Collins, Amy L / Wojcik, Sylwia / Liu, James / Frankel, Wendy L / Alder, Hansjuerg / Yu, Lianbo / Schmittgen, Thomas D / Croce, Carlo M / Bloomston, Mark. ·Department of Surgery, The Ohio State University, Columbus, OH, USA. ·Ann Surg Oncol · Pubmed #24046106.

ABSTRACT: BACKGROUND: Cancers of the bile duct and the pancreas are virtually indistinguishable using conventional histopathological and clinical characteristics. We sought to use microRNA (miR) profiling to differentiate these two cancers. METHODS: RNA was harvested from the tumors of patients undergoing curative resection for cholangiocarcinoma or pancreatic adenocarcinoma and compared with adjacent normal bile duct or pancreas, respectively. There were 31 pairs of cholangiocarcinoma with matched tumor and adjacent bile duct and nine pairs of pancreatic cancer with matched tumor and adjacent uninvolved pancreas that had sufficient quantity of RNA that were included in the final analysis. Differential microRNA expression profiles were determined using the nCounter System from nanoString Technologies (Seattle, WA,USA). RESULTS: A total of 41 differentially expressed miRs were identified in cholangiocarcinoma (25 overexpressed, 16 underexpressed) and 52 differentially expressed miRs were found in pancreatic adenocarcinoma (30 overexpressed, 22 underexpressed) relative to adjacent normal tissue. Of these two profiles, 15 miRs were commonly dysregulated between tumor types. Also, eight miRs were similarly overexpressed or underexpressed in cholangiocarcinoma and pancreatic adenocarcinoma, whereas the other seven miRs had inverse expression levels. CONCLUSIONS: Cholangiocarcinoma has a distinct miR profile from pancreatic adenocarcinoma. Discrimination between these two tumor types may be possible with as few as seven miRs.

8 Article Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. 2013

Mace, Thomas A / Ameen, Zeenath / Collins, Amy / Wojcik, Sylwia / Mair, Markus / Young, Gregory S / Fuchs, James R / Eubank, Tim D / Frankel, Wendy L / Bekaii-Saab, Tanios / Bloomston, Mark / Lesinski, Gregory B. ·Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. ·Cancer Res · Pubmed #23514705.

ABSTRACT: Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide prosurvival signals to tumors; however, little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n = 7) were generated from human specimens and phenotypically confirmed via expression of vimentin, α-smooth muscle actin (α-SMA), and glial fibrillary acidic protein (GFAP). Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1). Culture of peripheral blood mononuclear cells [peripheral blood mononuclear cell (PBMC), n = 3 donors] with PSC supernatants or IL-6/granulocyte macrophage colony-stimulating factor (GM-CSF; positive control) for 7 days promoted PBMC differentiation into an MDSC (CD11b+CD33+) phenotype and a subpopulation of polymorphonuclear CD11b+CD33+CD15+ cells. The resulting CD11b+CD33+ cells functionally suppressed autologous T-lymphocyte proliferation. In contrast, supernatants from HPF did not induce an MDSC phenotype in PBMCs. Culture of normal PBMCs with PSC supernatants led to STAT3 but not STAT1 or STAT5 phosphorylation. IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation. Finally, the FLLL32 STAT3 inhibitor abrogated PSC supernatant-mediated MDSC differentiation, PSC viability, and reduced autocrine IL-6 production indicating these processes are STAT3 dependent. These results identify a novel role for PSC in driving immune escape in pancreatic cancer and extend the evidence that STAT3 acts as a driver of stromal immunosuppression to enhance its interest as a therapeutic target.

9 Article Cancer risks for relatives of patients with serrated polyposis. 2012

Win, Aung Ko / Walters, Rhiannon J / Buchanan, Daniel D / Jenkins, Mark A / Sweet, Kevin / Frankel, Wendy L / de la Chapelle, Albert / McKeone, Diane M / Walsh, Michael D / Clendenning, Mark / Pearson, Sally-Ann / Pavluk, Erika / Nagler, Belinda / Hopper, John L / Gattas, Michael R / Goldblatt, Jack / George, Jill / Suthers, Graeme K / Phillips, Kerry D / Woodall, Sonja / Arnold, Julie / Tucker, Kathy / Field, Michael / Greening, Sian / Gallinger, Steve / Aronson, Melyssa / Perrier, Renee / Woods, Michael O / Green, Jane S / Walker, Neal / Rosty, Christophe / Parry, Susan / Young, Joanne P. ·Centre for MEGA Epidemiology, School of Population Health, University of Melbourne, Carlton, Victoria, Australia. ·Am J Gastroenterol · Pubmed #22525305.

ABSTRACT: OBJECTIVES: Serrated polyposis (hyperplastic polyposis) is characterized by multiple polyps with serrated architecture in the colorectum. Although patients with serrated polyposis are known to be at increased risk of colorectal cancer (CRC) and possibly extracolonic cancers, cancer risk for their relatives has not been widely explored. The aim of this study was to estimate the risks of CRC and extracolonic cancers for relatives of patients with serrated polyposis. METHODS: A cohort of the 1,639 first- and second-degree relatives of 100 index patients with serrated polyposis recruited regardless of a family history of polyps or cancer from genetic clinics in Australia, New Zealand, Canada, and the USA, were retrospectively analyzed to estimate the country-, age-, and sex-specific standardized incidence ratios (SIRs) for relatives compared with the general population. RESULTS: A total of 102 CRCs were observed in first- and second-relatives (SIR 2.25, 95% confidence interval (CI) 1.75-2.93; P<0.001), with 54 in first-degree relatives (SIR 5.16, 95% CI 3.70-7.30; P<0.001) and 48 in second-degree relatives (SIR 1.38, 95% CI 1.01-1.91; P=0.04). Six pancreatic cancers were observed in first-degree relatives (SIR 3.64, 95% CI 1.70-9.21; P=0.003). There was no statistical evidence of increased risk for cancer of the stomach, brain, breast, or prostate. CONCLUSIONS: Our finding that relatives of serrated polyposis patients are at significantly increased risk of colorectal and pancreatic cancer adds to the accumulating evidence that serrated polyposis has an inherited component.

10 Article DOG1 (clone K9) is seldom expressed and not useful in the evaluation of pancreatic neoplasms. 2012

Hemminger, Jessica / Marsh, William L / Iwenofu, Obiajulu Hans / Frankel, Wendy L. ·Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA. ·Appl Immunohistochem Mol Morphol · Pubmed #22495382.

ABSTRACT: DOG1, a transmembrane calcium-regulated chloride channel protein, is a sensitive and specific marker for gastrointestinal stromal tumors compared with other spindle cell and epithelioid neoplasms. Overexpression has also been described in a variety of both benign and malignant epithelial neoplasms. Recently, DOG1 immunoreactivity has been reported in pancreatic solid pseudopapillary tumors (SPT), suggesting a role as a marker for SPT. Utilizing immunohistochemistry, we evaluated DOG1 expression in pancreatic neoplasms to determine the prevalence of staining and establish diagnostic utility. Multiple tissue microarrays (TMA) were created from cores of formalin-fixed paraffin-embedded blocks containing pancreatic adenocarcinomas (n=112), neuroendocrine tumors (n=99), serous cystadenomas (n=28), and SPT (n=14) as well as normal pancreas (n=12). Immunoreactivity for DOG1 (clone K9) was assessed for intensity (1 to 3+), percentage of tumor positivity and location. Of the 99 cases of neuroendocrine tumors, only 2 (2%) were focally positive. Patchy staining was identified in 8 cases (7%) of adenocarcinoma of 1 to 2+ intensity, involving 15% to 80% of the tumor cells and primarily seen in a membranous and luminal distribution. In contrast to a previous report, no DOG1 positivity was observed in SPT, evaluated by both TMA and full sections. The TMAs of serous cystadenomas and normal pancreas were negative for DOG1. Rarely, pancreatic islets displayed granular, cytoplasmic staining. DOG1 antibody clone K9 is not a useful marker for SPT or other primary pancreatic neoplasms. Additional studies may be helpful to evaluate differences between clones of DOG1.

11 Article Osteopontin expression is associated with improved survival in patients with pancreatic adenocarcinoma. 2012

Collins, Amy L / Rock, Jonathan / Malhotra, Lavina / Frankel, Wendy L / Bloomston, Mark. ·Department of Surgery, The Ohio State University, Columbus, OH, USA. ·Ann Surg Oncol · Pubmed #22461132.

ABSTRACT: BACKGROUND: Osteopontin (OPN) is a secreted protein of the extracellular matrix. It has been used as a marker for tumor aggressiveness and correlated with clinical outcomes in several solid tumors, such as liver, lung, and breast. We determined the OPN expression and its influence on survival in patients with resected pancreatic adenocarcinoma. METHODS: Tissue microarrays were constructed from 245 resected pancreatic adenocarcinomas. Immunohistochemical staining for OPN was undertaken and compared to normal pancreas (n = 12). OPN expression was then correlated with patient demographics, tumor size, grade, node, and margin status. Survival curves were created by the Kaplan-Meier method and compared by log rank analysis. RESULTS: In total, 181 (74 %) of pancreatic adenocarcinoma tissues expressed OPN compared to 7 (58 %) of normal controls (p = 0.004). Expression was observed predominantly in the cytoplasm of the tumor cells. The median and 2 year overall survival was longer when OPN was expressed (17.1 vs. 11.6 months, and 38 vs. 24 %, respectively, p = 0.04). Multivariate analysis showed OPN expression and T stage to be independent predictors of overall survival, while other histopathologic factors such as tumor grade, tumor size, and nodal status were not. CONCLUSIONS: These results suggest that the presence of OPN expression in pancreatic adenocarcinoma may have a protective effect independent of tumor stage. This emphasizes the importance of the interaction between pancreatic cancer cells and their stromal elements.

12 Article The spectrum of hematologic malignancies involving the pancreas: potential clinical mimics of pancreatic adenocarcinoma. 2012

Rock, Jonathan / Bloomston, Mark / Lozanski, Gerard / Frankel, Wendy L. ·Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210-1218, USA. ·Am J Clin Pathol · Pubmed #22338053.

ABSTRACT: Hematologic malignancies often involve the pancreas, causing potential diagnostic pitfalls and, rarely, potentially avoidable surgical resection. We review the spectrum of hematologic malignancies involving the pancreas and describe features useful in preoperative distinction from adenocarcinoma. Archived clinical, pathologic, and radiologic data (1965 to present) for hematologic malignancies involving the pancreas were reviewed and compared with the data for 157 surgically resected pancreatic adenocarcinomas. Of 42 cases, 27 (64%) were clinically "suspicious" for hematologic malignancies. Of the remaining 15 cases, 4 patients underwent resection for presumed pancreatic adenocarcinoma. Isolated pancreatic masses proved most difficult to identify clinically. Significant factors in distinguishing hematologic malignancies from adenocarcinoma included history of hematologic malignancy, young age, large tumor size, low CA19-9 level, B symptoms, and lack of jaundice or diabetes mellitus. Various hematologic malignancies involve the pancreas, most commonly diffuse large B-cell lymphoma. Pancreatic masses are usually correctly identified clinically. Preoperative and operative sampling is strongly recommended when hematologic malignancies cannot be excluded.

13 Article The mTOR pathway is frequently activated in pancreatic ductal adenocarcinoma and chronic pancreatitis. 2010

Bellizzi, Andrew M / Bloomston, Mark / Zhou, Xiao-Ping / Iwenofu, Obiajulu Hans / Frankel, Wendy L. ·Departments of Pathology, The Ohio State University Medical Center, Columbus, OH 43210-1218, USA. ·Appl Immunohistochem Mol Morphol · Pubmed #20661135.

ABSTRACT: INTRODUCTION: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase critical to cell growth and proliferation through its effects on protein translation. Activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway has been described in various tumor types. Earlier studies have demonstrated loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function in some pancreatic ductal adenocarcinomas (PDAs). We performed immunohistochemistry for PTEN and p-RPS6 (major downstream mTOR effector) in a group of PDAs. An assessment of chronic pancreatitis (CP) and normal pancreas (NL) was performed in parallel. MATERIALS AND METHODS: Tissue microarrays were constructed from 49 PDA, 27 CP, and 12 NL. Cases were scored as follows: PTEN (intact: ≥ 5% staining and lost: < 5%) and p-RPS6 (0, 1+: modest intensity in ≥ 5% of cells and 2+: strong intensity ≥ 5% of cells). RESULTS: Forty-one percent of PDAs demonstrated loss of PTEN, and 75% demonstrated p-RPS6 immunoreactivity (1+ in 22 and 2+ in 3). PTEN was uniformly intact in NL and CP. Although p-RPS6 immunoreactivity was only noted in 1 NL control (8%), 1+ positivity was observed in 62% of CP. CONCLUSIONS: mTOR pathway activation, as evidenced by p-RPS6 immunoreactivity, is frequent in PDA. p-RPS6 expression was also frequent in CP, highlighting the importance of this pathway in both neoplastic and inflammatory processes. Given evidence of pathway activation and the existence of specific anti-mTOR therapeutics, mTOR represents a logical target for directed biologic therapy.