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Pancreatic Neoplasms: HELP
Articles by Rebekah R. White
Based on 24 articles published since 2009
(Why 24 articles?)
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Between 2009 and 2019, Rebekah White wrote the following 24 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Editorial Neoadjuvant chemotherapy for localized pancreatic cancer: too little or too long? 2014

White, Rebekah R / Evans, Douglas B. ·Department of Surgery, Duke University School of Medicine, Durham, NC, USA, rebekah.white@duke.edu. ·Ann Surg Oncol · Pubmed #24452411.

ABSTRACT: -- No abstract --

2 Review Clinical Management: Resectable Disease. 2017

White, Rebekah R / Lowy, Andrew M. · ·Cancer J · Pubmed #29189330.

ABSTRACT: Despite the identification of more active systemic therapy combinations for pancreatic cancer, cures remain elusive and feasible only in patients with localized, operable disease. When examining outcome data from phase III adjuvant trials conducted during the past decade, the survival for patients with localized disease has improved, likely owing to a combination of factors including more active adjuvant therapy and improved surgical and perioperative care. Perhaps the greatest recent change in the care of patients with localized pancreatic cancer has been the extension of surgery to tumors previously thought to be inoperable because of involvement of major blood vessels. These so-called "borderline resectable pancreatic cancers" have now been objectively defined, and their management is being studied in randomized trials. This has been made feasible by the availability of more active systemic therapy combinations that are increasingly being used in the neoadjuvant setting. Given the increasing activity of systemic regimens, the challenges in delivering such therapy in the postoperative setting, and the numerous novel agents in late stages of clinical development, it is reasonable to hypothesize that the neoadjuvant setting may eventually become the standard of care for patients with resectable disease.

3 Review Aptamers: potential applications to pancreatic cancer therapy. 2011

Rialon, Kristy L / White, Rebekah R. ·Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. ·Anticancer Agents Med Chem · Pubmed #21492073.

ABSTRACT: There is an unquestionable need for more effective therapies for pancreatic cancer. Aptamers are single-stranded DNA or RNA oligonucleotide ligands whose 3-dimensional structures are dictated by their sequences. Aptamers have been generated against numerous purified protein targets using an iterative in vitro selection technique known as Systematic Evolution of Ligands by EXponential enrichment (SELEX). Several biochemical properties make them attractive tools for use in an array of biological research applications and as potential pharmacologic agents. Isolated aptamers may directly affect target protein function, or they may also be modified for use as delivery agents for other therapeutic cargo or as imaging agents. More complex selections, using whole cancer cells or tumor tissue, may simultaneously identify novel or unexpected targets and aptamers to inhibit them. This review summarizes recent advances in the field of aptamers and discusses aptamer targets that have relevance to pancreatic cancer.

4 Article A Syngeneic Pancreatic Cancer Mouse Model to Study the Effects of Irreversible Electroporation. 2018

Shankara Narayanan, Jayanth S / Ray, Partha / Naqvi, Ibtehaj / White, Rebekah. ·Moores Cancer Center, University California San Diego. · Duke University School of Medicine. · Moores Cancer Center, University California San Diego; rewhite@ucsd.edu. ·J Vis Exp · Pubmed #29939178.

ABSTRACT: Pancreatic cancer (PC), a disease which kills approximately 40,000 patients each year in the US, has successfully evaded several therapeutic approaches including the promising immunotherapeutic strategies. Irreversible electroporation (IRE) is a non-thermal ablation technique that induces tumor cell death without destruction of adjacent collagenous structures, thus enabling the procedure to be performed in tumors very close to blood vessels. Unlike thermal ablation techniques, IRE results in gradual apoptotic cell death, along with immediate ablation induced necrosis, and is currently in clinical use for selected patients with locally advanced PC. An ablative, non-target specific procedure like IRE can induce a myriad of responses in the tumor microenvironment. A few studies have addressed the effects of IRE on tumor growth in other tumor types, but none have focused on PC. We have developed a syngeneic mouse model of PC in which subcutaneous (SQ) and orthotopic tumors can be successfully treated with IRE in a highly controlled setting, facilitating various longitudinal studies post procedure. This animal model serves as a robust system to study the effects of IRE and ways to improve the clinical efficacy of IRE.

5 Article Integrated Analysis of Exosomal Protein Biomarkers on Alternating Current Electrokinetic Chips Enables Rapid Detection of Pancreatic Cancer in Patient Blood. 2018

Lewis, Jean M / Vyas, Ankit D / Qiu, Yuqi / Messer, Karen S / White, Rebekah / Heller, Michael J. · ·ACS Nano · Pubmed #29570265.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) typically has nonspecific symptoms and is often found too late to treat. Because diagnosis of PDAC involves complex, invasive, and expensive procedures, screening populations at increased risk will depend on developing rapid, sensitive, specific, and cost-effective tests. Exosomes, which are nanoscale vesicles shed into blood from tumors, have come into focus as valuable entities for noninvasive liquid biopsy diagnostics. However, rapid capture and analysis of exosomes with their protein and other biomarkers have proven difficult. Here, we present a simple method integrating capture and analysis of exosomes and other extracellular vesicles directly from whole blood, plasma, or serum onto an AC electrokinetic microarray chip. In this process, no pretreatment or dilution of sample is required, nor is it necessary to use capture antibodies or other affinity techniques. Subsequent on-chip immunofluorescence analysis permits specific identification and quantification of target biomarkers within as little as 30 min total time. In this initial validation study, the biomarkers glypican-1 and CD63 were found to reflect the presence of PDAC and thus were used to develop a bivariate model for detecting PDAC. Twenty PDAC patient samples could be distinguished from 11 healthy subjects with 99% sensitivity and 82% specificity. In a smaller group of colon cancer patient samples, elevated glypican-1 was observed for metastatic but not for nonmetastatic disease. The speed and simplicity of ACE exosome capture and on-chip biomarker detection, combined with the ability to use whole blood, will enable seamless "sample-to-answer" liquid biopsy screening and improve early stage cancer diagnostics.

6 Article Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis. 2018

Naqvi, Ibtehaj / Gunaratne, Ruwan / McDade, Jessica E / Moreno, Angelo / Rempel, Rachel E / Rouse, Douglas C / Herrera, Silvia Gabriela / Pisetsky, David S / Lee, Jaewoo / White, Rebekah R / Sullenger, Bruce A. ·Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Medical Scientist Training Program, Duke University, Durham, NC 27710, USA; Department of Surgery, Duke University, Durham, NC 27710, USA. · Department of Surgery, Duke University, Durham, NC 27710, USA. · Division of Laboratory Animal Resources, Duke University, Durham, NC 27710, USA. · Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27514, USA. · Department of Medicine, Duke University, Durham, NC 27710, USA. · Department of Surgery, Duke University, Durham, NC 27710, USA; Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: rewhite@ucsd.edu. · Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Surgery, Duke University, Durham, NC 27710, USA. Electronic address: bruce.sullenger@duke.edu. ·Mol Ther · Pubmed #29550075.

ABSTRACT: Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatory agents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupus erythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC). In addition, extracellular DNA and RNA circulate on or within lipid microvesicles, such as microparticles or exosomes, which also promote metastasis by inducing pro-tumorigenic signaling in cancer cells and pre-conditioning secondary sites for metastatic establishment. Here, we explore the use of an NABP, the 3

7 Article TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3. 2016

Hesler, Rachel A / Huang, Jennifer J / Starr, Mark D / Treboschi, Victoria M / Bernanke, Alyssa G / Nixon, Andrew B / McCall, Shannon J / White, Rebekah R / Blobe, Gerard C. ·Department of Pharmacology and Cancer Biology. · Division of Medical Oncology, Department of Medicine. · Department of Pathology and. · Department of Surgery, Duke University, B354 LSRC Research Drive , Box 91004, Durham, NC 27708 , USA. ·Carcinogenesis · Pubmed #27604902.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 . We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

8 Article Feeding jejunostomy tube placement in patients undergoing pancreaticoduodenectomy: an ongoing dilemma. 2014

Nussbaum, Daniel P / Zani, Sabino / Penne, Kara / Speicher, Paul J / Stinnett, Sandra S / Clary, Bryan M / White, Rebekah R / Tyler, Douglas S / Blazer, Dan G. ·Department of Surgery, Duke University Medical Center, Box 3443, Durham, NC, 27710, USA, daniel.nussbaum@duke.edu. ·J Gastrointest Surg · Pubmed #24961442.

ABSTRACT: BACKGROUND: Concomitant placement of feeding jejunostomy tubes (FJT) during pancreaticoduodenectomy is common, yet there are limited data regarding catheter-specific morbidity and associated outcomes. This information is crucial to appropriately select patients for feeding tube placement and to optimize perioperative nutrition strategies. METHODS: A review of all patients undergoing pancreaticoduodenectomy with FJT placement was completed. Patients were grouped by the occurrence of FJT-related morbidity. Multivariable logistic regression was performed to identify predictors of FJT morbidity; these complications were then further defined. Finally, associated postoperative outcomes were compared between groups. RESULTS: In total, 126 patients were included, of which 18 (14 %) had complications directly related to their FJT, including pericatheter infection (n = 6), pneumatosis intestinalis (n = 4), severe tube feed intolerance (n = 3), and primary catheter malfunction (n = 7). Following adjustment with logistic regression, preoperative hypoalbuminemia was identified as the only independent predictor of FJT complications (OR 2.23, p = 0.035). Patients with FJT complications were more likely to be initiated on total parenteral nutrition (TPN; 55.6 vs. 7.4 %, p -0.035) and to require TPN at discharge (16.7 vs. 0%, p = 0.003). Correspondingly, these patients resumed an oral diet later (14 vs. 8 days, p = 0.06). Both reoperation (50.0 vs. 6.5%, p < 0.001) and readmission (50.0 vs. 22.4%, p = 0.041) rates were higher among patients with FJT complications. CONCLUSIONS: FJT-related morbidity is common among patients undergoing pancreaticoduodenectomy and is associated with inferior outcomes and other performance metrics. Preoperative malnutrition appears to predict FJT complications, creating an ongoing dilemma regarding FJT placement. In the future, it will be important to better define criteria for FJT placement during pancreaticoduodenectomy.

9 Article Defining the learning curve for team-based laparoscopic pancreaticoduodenectomy. 2014

Speicher, Paul J / Nussbaum, Daniel P / White, Rebekah R / Zani, Sabino / Mosca, Paul J / Blazer, Dan G / Clary, Bryan M / Pappas, Theodore N / Tyler, Douglas S / Perez, Alexander. ·Department of Surgery, Duke University Medical Center, Durham, NC, USA, paul.speicher@duke.edu. ·Ann Surg Oncol · Pubmed #24923222.

ABSTRACT: BACKGROUND: The purpose of this study was to define the learning curves for laparoscopic pancreaticoduodenectomy (LPD) with and without laparoscopic reconstruction, using paired surgical teams consisting of advanced laparoscopic-trained surgeons and advanced oncologic-trained surgeons. METHODS: All patients undergoing PD without vein resection at a single institution were retrospectively analyzed. LPD was introduced by initially focusing on laparoscopic resection followed by open reconstruction (hybrid) for 18 months prior to attempting a totally LPD (TLPD) approach. Cases were compared with Chi square, Fisher's exact test, and Kruskal-Wallis analysis of variance (ANOVA). RESULTS: Between March 2010 and June 2013, 140 PDs were completed at our institution, of which 56 (40 %) were attempted laparoscopically. In 31/56 procedures we planned to perform only the resection laparoscopically (hybrid), of which 7 (23 %) required premature conversion before completion of resection. Following the first 23 of these hybrid cases, a total of 25 TLPDs have been performed, of which there were no conversions to open. For all LPD, a significant reduction in operative times was identified following the first 10 patients (median 478.5 vs. 430.5 min; p = 0.01), approaching open PD levels. After approximately 50 cases, operative times and estimated blood loss were consistently lower than those for open PD. CONCLUSIONS: In our experience of building an LPD program, the initial ten cases represent the biggest hurdle with respect to operative times. For an experienced teaching center using a staged and team-based approach, LPD appears to offer meaningful reductions in operative time and blood loss within the first 50 cases.

10 Article Further characterization of the target of a potential aptamer biomarker for pancreatic cancer: cyclophilin B and its posttranslational modifications. 2013

Ray, Partha / Sullenger, Bruce A / White, Rebekah R. ·Department of Surgery, Duke University School of Medicine , Durham, North Carolina. ·Nucleic Acid Ther · Pubmed #24152208.

ABSTRACT: Posttranslational modifications on proteins can serve as useful biomarkers for disease. However, their discovery and detection in biological fluids is challenging. Aptamers are oligonucleotide ligands that demonstrate high affinity toward their target proteins and can discriminate closely related proteins with superb specificity. Previously, we generated a cyclophilin B aptamer (M9-5) that could discriminate sera from pancreatic cancer patients and healthy volunteers with high specificity and sensitivity. In our present work we further characterize the aptamer and the target protein, cyclophilin B, and demonstrate that the aptamer could discriminate between cyclophilin B expressed in human cells versus bacteria. Using mass-spectrometric analysis, we discovered post-translational modifications on cyclophilin B that might be responsible for the M9-5 selectivity. The ability to distinguish between forms of the same protein with differing post-translational modifications is an important advantage of aptamers as tools for identification and detection of biomarkers.

11 Article Trends in racial disparities in pancreatic cancer surgery. 2013

Shah, Anand / Chao, K S Clifford / Ostbye, Truls / Castleberry, Anthony W / Pietrobon, Ricardo / Gloor, Beat / Clary, Bryan M / White, Rebekah R / Worni, Mathias. ·Department of Radiation Oncology, Columbia University Medical Center, New York, NY, USA. ·J Gastrointest Surg · Pubmed #24002757.

ABSTRACT: OBJECTIVES: We tested three hypotheses: (1) blacks with pancreatic cancer are recommended surgical resection less often than whites; (2) when recommended surgical resection, blacks refuse surgery more often than whites; and lastly, (3) racial differences in refusal of surgical resection have decreased over time. METHODS: A retrospective cohort study was conducted on patients with potentially resectable, nonmetastatic pancreatic adenocarcinoma of the Surveillance, Epidemiology, and End Results registry from 1988 to 2009. Univariate and multivariable logistic regression analyses were performed to assess whether differences in the proportion of whites versus blacks refusing surgery among patients recommended for resection changed over time. RESULTS: A total of 35,944 patients were included; most were white (87.6 %). After adjusting for covariates including tumor stage, pancreatic cancer resection was less often recommended to and performed in blacks compared with whites (adjusted odds ratio (aOR) 0.88, 95 % confidence interval (CI) 0.82-0.95; aOR 0.83, 95 % CI 0.76-0.91, respectively). Blacks also underwent surgical resection less often when surgery was recommended (aOR 0.73, 95 % CI 0.64-0.85). Racial disparities in surgery recommendation and its performance did not decrease from 1988 to 2009. In multivariable adjusted analyses, blacks refused surgery more often when it was recommended (aOR in 1988 4.75, 95 % CI 2.51-9.01); this disparity decreased over time (aOR 0.93 per year, 95 % CI 0.89-0.97). CONCLUSIONS: Although racial disparities in pancreatic cancer surgery refusal have diminished over the past two decades, significant disparities in the recommendation and performance of surgery persist. It is likely that both provider- and patient-level factors have a substantial impact on surgery recommendation and its acceptance. The identification of such factors is critical to design a framework for eliminating disparities in cancer-directed surgery for pancreatic cancer.

12 Article Modest improvement in overall survival for patients with metastatic pancreatic cancer: a trend analysis using the surveillance, epidemiology, and end results registry from 1988 to 2008. 2013

Worni, Mathias / Guller, Ulrich / White, Rebekah R / Castleberry, Anthony W / Pietrobon, Ricardo / Cerny, Thomas / Gloor, Beat / Koeberle, Dieter. ·From the *Department of Surgery, Duke University Medical Center, Durham, NC; †Department of Visceral Surgery and Medicine, University of Bern, Bern; and ‡Department of Medical Oncology and Hematology, Cantonal Hospital St Gallen, Gallen, Switzerland. ·Pancreas · Pubmed #23867367.

ABSTRACT: OBJECTIVES: Patients with pancreatic adenocarcinoma often present with distant metastatic disease. We aimed to assess whether improvements in survival of clinical trials translated to a population-based level. METHODS: The US Surveillance, Epidemiology, and End Results registry was queried. Adult patients with distant metastatic adenocarcinoma of the pancreas were included from 1988 to 2008. Overall survival was analyzed using Kaplan-Meier curves as well as multivariable-adjusted Cox proportional hazards models. RESULTS: In total, 32,452 patients were included. Mean age was 67.6 (SD: 11.7) years, and 15,341 (47.3%) were female. Median overall survival was 3 months (95% confidence interval [CI], 3-3 months), which increased from 2 (CI, 2-2) months in 1988 to 3 (CI, 3-4) months in 2008. After adjustment for multiple covariates, the hazard ratio (HR) decreased by 0.977 per year (CI, 0.975-0.980). In multivariable-adjusted survival analyses, tumor location in the pancreatic body/tail (HR, 1.10), male sex (HR, 1.09), increasing age (HR, 1.016), African American ethnicity (HR, 1.16), nonmarried civil status (HR, 1.18), and absence of radiotherapy (HR, 1.41) were associated with worse survival (P < 0.001 for all predictors). CONCLUSIONS: The improvement in overall survival over the past 2 decades among patients with metastatic pancreatic adenocarcinoma is modest and disappointing. More effective therapeutic strategies for advanced disease are desperately needed.

13 Article Concomitant vascular reconstruction during pancreatectomy for malignant disease: a propensity score-adjusted, population-based trend analysis involving 10,206 patients. 2013

Worni, Mathias / Castleberry, Anthony W / Clary, Bryan M / Gloor, Beat / Carvalho, Elias / Jacobs, Danny O / Pietrobon, Ricardo / Scarborough, John E / White, Rebekah R. ·Department of Visceral Surgery and Medicine, University of Bern, Inselspital, Bern, Switzerland. ·JAMA Surg · Pubmed #23715922.

ABSTRACT: OBJECTIVE: To assess trends in the frequency of concomitant vascular reconstructions (VRs) from 2000 through 2009 among patients who underwent pancreatectomy, as well as to compare the short-term outcomes between patients who underwent pancreatic resection with and without VR. DESIGN: Single-center series have been conducted to evaluate the short-term and long-term outcomes of VR during pancreatic resection. However, its effectiveness from a population-based perspective is still unknown. Unadjusted, multivariable, and propensity score-adjusted generalized linear models were performed. SETTING: Nationwide Inpatient Sample from 2000 through 2009. PATIENTS: A total of 10,206 patients were involved. MAIN OUTCOME MEASURES: Incidence of VR during pancreatic resection, perioperative in-hospital complications, and length of hospital stay. RESULTS: Overall, 10,206 patients were included in this analysis. Of these, 412 patients (4.0%) underwent VR, with the rate increasing from 0.7% in 2000 to 6.0% in 2009 (P < .001). Patients who underwent pancreatic resection with VR were at a higher risk for intraoperative (propensity score-adjusted odds ratio, 1.94; P = .001) and postoperative (propensity score-adjusted odds ratio, 1.36; P = .008) complications, while the mortality and median length of hospital stay were similar to those of patients without VR. Among the 25% of hospitals with the highest surgical volume, patients who underwent pancreatic surgery with VR had significantly higher rates of postoperative complications and mortality than patients without VR. CONCLUSIONS: The frequency of VR during pancreatic surgery is increasing in the United States. In contrast with most single-center analyses, this population-based study demonstrated that patients who underwent VR during pancreatic surgery had higher rates of adverse postoperative outcomes than their counterparts who underwent pancreatic resection only. Prospective studies incorporating long-term outcomes are warranted to further define which patients benefit from VR.

14 Article Aptamer-mediated delivery of chemotherapy to pancreatic cancer cells. 2012

Ray, Partha / Cheek, Marcus A / Sharaf, Mariam L / Li, Na / Ellington, Andrew D / Sullenger, Bruce A / Shaw, Barbara Ramsay / White, Rebekah R. ·Department of Surgery, Duke University School of Medicine, Durham, NC, USA. ·Nucleic Acid Ther · Pubmed #23030589.

ABSTRACT: Gemcitabine is a nucleoside analog that is currently the best available single-agent chemotherapeutic drug for pancreatic cancer. However, efficacy is limited by our inability to deliver sufficient active metabolite into cancer cells without toxic effects on normal tissues. Targeted delivery of gemcitabine into cancer cells could maximize effectiveness and concurrently minimize toxic side effects by reducing uptake into normal cells. Most pancreatic cancers overexpress epidermal growth factor receptor (EGFR), a trans-membrane receptor tyrosine kinase. We utilized a nuclease resistant RNA aptamer that binds and is internalized by EGFR on pancreatic cancer cells to deliver gemcitabine-containing polymers into EGFR-expressing cells and inhibit cell proliferation in vitro. This approach to cell type-specific therapy can be adapted to other targets and to other types of therapeutic cargo.

15 Article The impact of vascular resection on early postoperative outcomes after pancreaticoduodenectomy: an analysis of the American College of Surgeons National Surgical Quality Improvement Program database. 2012

Castleberry, Anthony W / White, Rebekah R / De La Fuente, Sebastian G / Clary, Bryan M / Blazer, Dan G / McCann, Richard L / Pappas, Theodore N / Tyler, Douglas S / Scarborough, John E. ·Department of Surgery, Duke University Medical Center, Durham, NC, USA. anthony.castleberry@duke.edu ·Ann Surg Oncol · Pubmed #22932857.

ABSTRACT: BACKGROUND: Several single-center reports suggest that vascular resection (VR) during pancreaticoduodenectomy (PD) for patients with pancreatic adenocarcinoma is feasible without affecting early postoperative mortality or morbidity. Our objective is to review the outcomes associated with VR during PD using a large multicenter data source. METHODS: A retrospective cohort analysis was performed using the National Surgical Quality Improvement Program Participant User Files for 2005-2009. All patients undergoing PD for a postoperative diagnosis of malignant neoplasm of the pancreas were included. Forward stepwise multivariate regression analysis was used to determine the association between VR during PD and 30-day postoperative mortality and morbidity after adjustment for patient demographics and comorbidities. RESULTS: 3,582 patients were included for analysis, 281 (7.8 %) of whom underwent VR during PD. VR during PD was associated with significantly greater risk-adjusted 30-day postoperative mortality [5.7 % with VR versus 2.9 % without VR, adjusted odds ratio (AOR) 2.1, 95 % confidence interval (CI) 1.22-3.73, P = 0.008] and overall morbidity (39.9 % with VR versus 33.3 % without VR, AOR 1.36, 95 % CI 1.05-1.75, P = 0.02). There was no significant difference in risk-adjusted postoperative mortality or morbidity between those patients undergoing VR by the primary surgical team versus those patients undergoing VR by a vascular surgical team. CONCLUSIONS: Contrary to the findings of several previously published single-center analyses, the current study demonstrates increased 30-day postoperative morbidity and mortality in PD with VR when compared with PD alone.

16 Article Targeting eNOS in pancreatic cancer. 2012

Lampson, Benjamin L / Kendall, S Disean / Ancrile, Brooke B / Morrison, Meghan M / Shealy, Michael J / Barrientos, Katharine S / Crowe, Matthew S / Kashatus, David F / White, Rebekah R / Gurley, Susan B / Cardona, Diana M / Counter, Christopher M. ·Departments of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA. ·Cancer Res · Pubmed #22738914.

ABSTRACT: Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS, NOS3, or NOS III) has been implicated recently in the pathogenesis of PDACs. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDACs. Genetic deficiency in eNOS limited the development of preinvasive pancreatic lesions and trended toward an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor N(G)-nitro-L-arginine methyl ester (l-NAME). Similarly, other transgenic models of oncogenic KRas-driven tumors responded to l-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which l-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose l-NAME for clinical investigations in treatment of PDACs and possibly other KRas-driven human cancers.

17 Article Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker. 2012

Ray, Partha / Rialon-Guevara, Kristy L / Veras, Emanuela / Sullenger, Bruce A / White, Rebekah R. ·Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710, USA. partha.ray@duke.edu ·J Clin Invest · Pubmed #22484812.

ABSTRACT: Most cases of pancreatic cancer are not diagnosed until they are no longer curable with surgery. Therefore, it is critical to develop a sensitive, preferably noninvasive, method for detecting the disease at an earlier stage. In order to identify biomarkers for pancreatic cancer, we devised an in vitro positive/negative selection strategy to identify RNA ligands (aptamers) that could detect structural differences between the secretomes of pancreatic cancer and non-cancerous cells. Using this molecular recognition approach, we identified an aptamer (M9-5) that differentially bound conditioned media from cancerous and non-cancerous human pancreatic cell lines. This aptamer further discriminated between the sera of pancreatic cancer patients and healthy volunteers with high sensitivity and specificity. We utilized biochemical purification methods and mass-spectrometric analysis to identify the M9-5 target as cyclophilin B (CypB). This molecular recognition-based strategy simultaneously identified CypB as a serum biomarker and generated a new reagent to recognize it in body fluids. Moreover, this approach should be generalizable to other diseases and complementary to traditional approaches that focus on differences in expression level between samples. Finally, we suggest that the aptamer we identified has the potential to serve as a tool for the early detection of pancreatic cancer.

18 Article Does preoperative therapy optimize outcomes in patients with resectable pancreatic cancer? 2012

Papalezova, Katia T / Tyler, Douglas S / Blazer, Dan G / Clary, Bryan M / Czito, Brian G / Hurwitz, Herbert I / Uronis, Hope E / Pappas, Theodore N / Willett, Christopher G / White, Rebekah R. ·Department of Surgery, Montefiore Medical Center, Bronx, NY, USA. kpapalez@montefiore.org ·J Surg Oncol · Pubmed #22311829.

ABSTRACT: The objective of this study was to compare survival between all patients with radiographically resectable adenocarcinoma of the proximal pancreas who underwent preoperative chemoradiation therapy (PRE-OP CRT) or surgical exploration first (SURGERY) with "intention to resect." Pancreatic cancer patients who undergo resection after PREOP CRT live longer than patients who undergo resection without PREOP CRT, a difference that may be attributable to patient selection. We retrospectively identified 236 patients with pancreatic head adenocarcinoma seen between 1999 and 2007 with sufficient data to be confirmed medically and radiographically resectable. The outcomes of 144 patients who underwent PREOP CRT were compared to those of 92 patients who proceeded straight to SURGERY. The groups were similar in age and gender. Tumors were slightly larger in the PREOP CRT group (mean 2.5 cm vs. 2.1 cm, P < 0.01), and there were trends toward more venous abutment (54% vs. 39%, P = 0.06) and a higher Charlson comorbidity index (P = 0.1). In the PREOP CRT group, 76 patients (53%) underwent resection, 28 (19%) had metastatic and 17 (12%) locally unresectable disease after PREOP CRT, and 23 (16%) were not explored due to performance status or loss to follow-up. In the SURGERY group, 68 patients (74%) underwent resection. Sixteen patients (17%) had metastatic and eight patients (9%) locally unresectable disease at exploration. In patients who underwent resection, the PREOP CRT group had smaller pathologic tumor size and lower incidence of positive lymph nodes than the SURGERY group but no difference in positive margins or need for vascular resection. Median overall survival (OS) in patients undergoing resection was 27 months in the PREOP CRT group and 17 months in the SURGERY group (P = 0.04). Median OS in all patients treated with PREOP CRT or surgically explored with intention to resect was 15 and 13 months, respectively, with superimposable survival curves. Despite a lower resection rate, the PREOP CRT group as a whole had a similar OS to the SURGERY group as a whole. For patients who underwent resection, those in the PREOP CRT had longer survival than those in the SURGERY group, suggesting that PREOP CRT allows better patient selection for resection. PREOP CRT should be considered an acceptable alternative for most patients with resectable pancreatic cancer.

19 Article Vascular surgery collaboration during pancreaticoduodenectomy with vascular reconstruction. 2012

Turley, Ryan S / Peterson, Kirk / Barbas, Andrew S / Ceppa, Eugene P / Paulson, Erik K / Blazer, Dan G / Clary, Bryan M / Pappas, Theodore N / Tyler, Douglas S / McCann, Richard L / White, Rebekah R. ·Department of Surgery, Duke University, Durham, NC 27710, USA. ·Ann Vasc Surg · Pubmed #22305864.

ABSTRACT: BACKGROUND: Once thought to have unresectable disease, pancreatic cancer patients with portal venous involvement are now reported to have comparable survival after pancreaticoduodenectomy (PD) with vascular reconstruction (VR) as compared with patients without vascular involvement. We hypothesize that a multidisciplinary approach involving a vascular surgeon will minimize morbidity and improve patency of VRs. METHODS: We identified 204 patients who underwent PD for pancreatic adenocarcinoma from 1997 to 2008. Patients who underwent PD with VR (N = 42) were compared with those who underwent standard PD (N = 162). VRs were performed by a vascular surgeon and involved primary repair (N = 8), vein patch (N = 25), or interposition grafting (N = 9) with femoral or other venous conduit. RESULTS: Patients undergoing PD with VR had larger tumors (3.0 cm vs. 2.5 cm, P < 0.01) but did not have different rates of tumor-free margins (73% vs. 72%, P = 0.84) or lymph nodes metastases (50% vs. 38%, P = 0.14). The VR group had higher median blood loss (875 mL vs. 550 mL, P = 0<0.01), but no differences in mortality, complication rates, length of stay, or readmission rates were found in a median follow-up of 29 months. Overall survival rates were similar. Predictors of mortality on multivariate analysis included increasing histological grade (P = 0.01), positive lymph nodes (P = 0.01), and increasing tumor size (P = 0.01), but not VR (P = 0.28). When evaluated by computed tomography scans within 6 months postoperatively, 97% of reconstructions remained patent. CONCLUSIONS: The need for VR is not a contraindication to potentially curative resection in patients with pancreatic adenocarcinoma. Assistance of a vascular surgeon during VR may allow moderate-volume centers to achieve outcomes comparable with high-volume centers.

20 Article Resected pancreatic neuroendocrine tumors: patterns of failure and disease-related outcomes with or without radiotherapy. 2012

Zagar, Timothy M / White, Rebekah R / Willett, Christopher G / Tyler, Douglas S / Papavassiliou, Paulie / Papalezova, Katia T / Guy, Cynthia D / Broadwater, Gloria / Clough, Robert W / Czito, Brian G. ·Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA. ·Int J Radiat Oncol Biol Phys · Pubmed #22270161.

ABSTRACT: PURPOSE: Pancreatic neuroendocrine tumors (NET) are rare and have better disease-related outcomes compared with pancreatic adenocarcinoma. Surgical resection remains the standard of care, although many patients present with locally advanced or metastatic disease. Little is known regarding the use of radiotherapy in the prevention of local recurrence after resection. To better define the role of radiotherapy, we performed an analysis of resected patients at our institution. METHODS: Between 1994 and 2009, 33 patients with NET of the pancreatic head and neck underwent treatment with curative intent at Duke University Medical Center. Sixteen patients were treated with surgical resection alone while an additional 17 underwent resection with adjuvant or neoadjuvant radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months. RESULTS: Thirteen patients (39%) experienced treatment failure. Eleven of the initial failures were distant, one was local only and one was local and distant. Two-year overall survival was 77% for all patients. Two-year local control for all patients was 87%: 85% for the CMT group and 90% for the surgery alone group (p = 0.38). Two-year distant metastasis-free survival was 56% for all patients: 46% and 69% for the CMT and surgery patients, respectively (p = 0.10). CONCLUSIONS: The primary mode of failure is distant which often results in mortality, with local failure occurring much less commonly. The role of radiotherapy in the adjuvant management of NET remains unclear.

21 Article Comparison of outcomes and the use of multimodality therapy in young and elderly people undergoing surgical resection of pancreatic cancer. 2012

Barbas, Andrew S / Turley, Ryan S / Ceppa, Eugene P / Reddy, Srinevas K / Blazer, Dan G / Clary, Bryan M / Pappas, Theodore N / Tyler, Douglas S / White, Rebekah R / Lagoo, Sandhya A. ·Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. andrew.barbas@duke.edu ·J Am Geriatr Soc · Pubmed #22211710.

ABSTRACT: OBJECTIVES: To compare outcomes and the use of multimodality therapy in young and elderly people with pancreatic cancer undergoing surgical resection. DESIGN: Retrospective, single-institution study. SETTING: National Cancer Institute/National Comprehensive Cancer Network cancer center. PARTICIPANTS: Two hundred three individuals who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma at Duke University Medical Center comprised the study population. Participants were divided into three groups based on age (<65, n = 97; 65-74, n = 74; ≥75, N = 32). MEASUREMENTS: Perioperative outcomes, the use of multimodality therapy, and overall survival of the different age groups were compared. RESULTS: Similar rates of perioperative mortality and morbidity were observed in all age groups, but elderly adults were more likely to be discharged to a rehabilitation or skilled nursing facility. A similar proportion of participants received neoadjuvant therapy, but a smaller proportion of elderly participants received adjuvant therapy. Overall survival was similar between the age groups. Predictors of poorer overall survival included coronary artery disease, positive resection margin, and less-differentiated tumor histology. Treatment with neoadjuvant and adjuvant therapy were predictors of better overall survival. CONCLUSION: Carefully selected elderly individuals experience similar perioperative outcomes and overall survival to those of younger individuals after resection of pancreatic cancer. There appears to be a significant disparity in the use of adjuvant therapy between young and elderly individuals.

22 Article A decision model of therapy for potentially resectable pancreatic cancer. 2012

VanHouten, Jacob P / White, Rebekah R / Jackson, Gretchen Purcell. ·Vanderbilt University Medical Center, Nashville, Tennessee, USA. ·J Surg Res · Pubmed #22079845.

ABSTRACT: BACKGROUND: Optimal treatment for potentially resectable pancreatic cancer is controversial. Resection is considered the only curative treatment, but neoadjuvant chemoradiotherapy may offer significant advantages. MATERIALS AND METHODS: We developed a decision model for potentially resectable pancreatic cancer. Initial therapeutic choices were surgery, neoadjuvant chemoradiotherapy, or no treatment; subsequent decisions offered a second intervention if not prohibited by complications or death. Payoffs were calculated as the median expected survival. We gathered evidence for this model through a comprehensive MEDLINE search. One-way sensitivity analyses were performed. RESULTS: Neoadjuvant chemoradiation is favored over initial surgery, with expected values of 18.6 and 17.7 mo, respectively. The decision is sensitive to the probabilities of treatment mortality and tumor resectability. Threshold probabilities are 7.0% mortality of neoadjuvant chemoradiotherapy, 69.2% resectability on imaging after neoadjuvant therapy, and 73.7% resectability at exploration after neoadjuvant therapy, 92.2% resectability at initial resection, and 9.9% surgical mortality following chemoradiotherapy. The decision is sensitive to the utility of time spent in chemoradiotherapy, with surgery favored for utilities less than 0.3 and -0.8, for uncomplicated and complicated chemoradiotherapy, respectively. CONCLUSIONS: The ideal treatment for potentially resectable pancreatic cancer remains controversial, but recent evidence supports a slight benefit for neoadjuvant therapy. Our model shows that the decision is sensitive to the probability of tumor resectability and chemoradiation mortality, but not to rates of other treatment complications. With minimal benefit of one treatment over another based on survival alone, patient preferences will likely play an important role in determining best treatment.

23 Article Pancreatic neuroendocrine tumors: selection, selection, selection…. 2011

White, Rebekah R. ·Department of Surgery, Duke University Medical Center, DUMC Box 3247, Durham, NC 27710, USA. ·J Surg Res · Pubmed #20855087.

ABSTRACT: -- No abstract --

24 Article Defining criteria for selective operative management of pancreatic cystic lesions: does size really matter? 2010

Ceppa, Eugene P / De la Fuente, Sebastian G / Reddy, Srinevas K / Stinnett, Sandra S / Clary, Bryan M / Tyler, Douglas S / Pappas, Theodore N / White, Rebekah R. ·Department of Surgery, Duke University Medical Center, P.O. Box 3247, Durham, NC 27710, USA. ·J Gastrointest Surg · Pubmed #19911240.

ABSTRACT: INTRODUCTION: Proposed criteria for resection of pancreatic cystic lesions have included symptoms, size (>3 cm), and suspicious features by endoscopic ultrasound (EUS). The objective of this study was to evaluate risk factors for malignancy in a large series of patients undergoing resection of suspected pancreatic cystic neoplasms. METHODS: Medical records of patients selected for resection of pancreatic cystic lesions at Duke University Medical Center from 2000 to 2008 were reviewed. Lesions with solid components on cross-sectional imaging were excluded. Malignancy was defined as invasive or in situ carcinoma. RESULTS: After review, 101 patients were confirmed to have undergone resection for suspected cystic neoplasms of the pancreas. Preoperative EUS was performed in 71 patients. Sixteen patients (16%) had malignant lesions (preoperative size 1.5-5.9 cm). There was no clear association between size and malignancy. Male gender, biliary ductal dilatation (BDD), pancreatic ductal dilatation (PDD), and suspicious cytology (but not age, symptoms, or size) were associated with increased risk of malignancy. When factors available for all patients were incorporated into a multivariate model, only BDD and PDD were independent risk factors for malignancy. Only one patient with malignancy had neither BDD nor PDD but did have solid components by EUS. CONCLUSIONS: In patients selected for resection, size was not an independent risk factor for malignancy. While size might be appropriate for stratification of asymptomatic patients with simple cysts, size should not be used as a selection criterion for patients who have cysts with solid components or with associated BDD or PDD.