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Pancreatic Neoplasms: HELP
Articles by William E. Fisher
Based on 45 articles published since 2009
(Why 45 articles?)
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Between 2009 and 2019, W. Fisher wrote the following 45 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Intraperitoneal Drainage and Pancreatic Resection. 2018

Fisher, William E. ·Division of General Surgery, Michael E. DeBakey Department of Surgery, Elkins Pancreas Center, Baylor College of Medicine, 6620 Main Street, Suite 1425, Houston, TX 77030, USA. Electronic address: wfisher@bcm.edu. ·Adv Surg · Pubmed #30098613.

ABSTRACT: -- No abstract --

2 Review Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer. 2018

Eibl, Guido / Cruz-Monserrate, Zobeida / Korc, Murray / Petrov, Maxim S / Goodarzi, Mark O / Fisher, William E / Habtezion, Aida / Lugea, Aurelia / Pandol, Stephen J / Hart, Phil A / Andersen, Dana K / Anonymous1831515. · ·J Acad Nutr Diet · Pubmed #28919082.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.

3 Review Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection. 2017

Gilliland, Taylor M / Villafane-Ferriol, Nicole / Shah, Kevin P / Shah, Rohan M / Tran Cao, Hop S / Massarweh, Nader N / Silberfein, Eric J / Choi, Eugene A / Hsu, Cary / McElhany, Amy L / Barakat, Omar / Fisher, William / Van Buren, George. ·The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Taylor.Gilliland@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Nicole.Villafane@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Kevin.Shah@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Rohan.Shah@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Hop.TranCao@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Nader.Massarweh@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. ejs@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Eugene.Choi@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Cary.Hsu@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Amy.McElhany@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Omar.Barakat@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. wfisher@bcm.edu. · The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. George.vanburen@bcm.edu. ·Nutrients · Pubmed #28272344.

ABSTRACT: Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3) enteral nutrition (EN) should be preferred as a nutritional intervention over total parenteral nutrition (TPN) postoperatively; and, (4) a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life.

4 Review Genomic profiling guides the choice of molecular targeted therapy of pancreatic cancer. 2015

Frank, Thomas S / Sun, Xiaotian / Zhang, Yuqing / Yang, Jingxuan / Fisher, William E / Gingras, Marie-Claude / Li, Min. ·The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA. · The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1262A, Oklahoma City, OK 73104, USA; Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. · Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1262A, Oklahoma City, OK 73104, USA. · Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. · Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, N1519, Houston, TX 77030, USA. Electronic address: mgingras@bcm.edu. · The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1262A, Oklahoma City, OK 73104, USA. Electronic address: min-li@ouhsc.edu. ·Cancer Lett · Pubmed #25890222.

ABSTRACT: Pancreatic cancer has the worst five-year survival rate of all malignancies due to its aggressive progression and resistance to therapy. Current therapies are limited to gemcitabine-based chemotherapeutics, surgery, and radiation. The current trend toward "personalized genomic medicine" has the potential to improve the treatment options for pancreatic cancer. Gene identification and genetic alterations like single nucleotide polymorphisms and mutations will allow physicians to predict the efficacy and toxicity of drugs, which could help diagnose pancreatic cancer, guide neoadjuvant or adjuvant treatment, and evaluate patients' prognosis. This article reviews the multifaceted roles of genomics and pharmacogenomics in pancreatic cancer.

5 Review Pancreatic cancer disparities in African Americans. 2015

Khawja, Shumaila N / Mohammed, Somala / Silberfein, Eric J / Musher, Benjamin L / Fisher, William E / Van Buren, George. ·From the *Michael E. DeBakey Department of Surgery, †The Elkins Pancreas Center, ‡Dan L. Duncan Cancer Center, and §Department of Medicine, Baylor College of Medicine, Houston, TX. ·Pancreas · Pubmed #25872128.

ABSTRACT: OBJECTIVES: Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. The incidence of pancreatic cancer in African Americans is 50% to 90% higher than the incidence in other racial groups. African Americans also have the worst prognosis. This is an evidence-based review of pancreatic cancer in African Americans with particular emphasis on baseline characteristics, treatment, and survival. METHODS: We queried PubMed in search for articles describing racial disparities in pancreatic cancer. Two categories of terms were "anded" together: pancreatic cancer terms and race terms. The last search was performed on November 14, 2013. RESULTS: We summarized the data on pancreatic cancer baseline characteristics, treatment, and survival for African Americans that we obtained from the following databases: (1) Surveillance, Epidemiology, and End Results, 1988-2008; (2) California Cancer Registry 1988-1998; (3) Cancer Survivor Program of Orange County/San Diego Imperial Organization for Cancer Control, 1988-1998; and (4) Harris County, 1998-2010. CONCLUSIONS: Overall, pancreatic cancer survival of African Americans has not significantly improved over the past several decades despite advances in multimodality therapy; African Americans continue to face worse outcomes than whites. Although baseline characteristics, treatment, and biological factors offer some explanation, they do not completely explain the disparities in incidence and survival.

6 Review Pancreatic cancer: advances in treatment. 2014

Mohammed, Somala / Van Buren, George / Fisher, William E. ·Somala Mohammed, George Van Buren II, William E Fisher, The Elkins Pancreas Center, Michael E DeBakey Department of Surgery, and Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, United States. ·World J Gastroenterol · Pubmed #25071330.

ABSTRACT: Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents.

7 Review Quality metrics in pancreatic surgery. 2013

Mohammed, Somala / Fisher, William E. ·Division of General Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Suite 404D, Houston, TX 77030, USA. ·Surg Clin North Am · Pubmed #23632153.

ABSTRACT: As the practice of pancreatic surgery evolves to encompass a wider array of clinical indications, incorporate increasingly complex technologies, and provide care to an aging population with many comorbid conditions, systematic assessment of quality and outcomes in an effort to improve the quality of care is imperative. This article discusses the volume-outcomes relationship that exists in pancreatic surgery, trends in centralization of practice within the field, common outcomes measures, and the complexity of assessing quality metrics. It also highlights surgical outcomes from several high-volume institutions and recent developments in quality metrics within pancreatic surgery.

8 Review Value of pancreatic resection for cancer metastatic to the pancreas. 2010

Sweeney, Alex D / Fisher, William E / Wu, Meng-Fen / Hilsenbeck, Susan G / Brunicardi, F Charles. ·Michael E DeBakey Department of Surgery, Baylor College of Medicine, The Elkins Pancreas Center, Houston, Texas, USA. ·J Surg Res · Pubmed #20422750.

ABSTRACT: BACKGROUND: Cancer metastatic to the pancreas from other primary sites is uncommon, and it has been treated with an aggressive surgical approach in fit patients when the primary tumor is controlled and the pancreas is the only site of metastatic disease. The value of pancreatic resection in this setting is unclear. The purpose of this study was to review cases of cancer metastatic to the pancreas. METHODS: We reviewed our experience with cancer metastatic to the pancreas and the literature regarding resection of pancreatic metastases. Patient and tumor characteristics were summarized using descriptive statistics. RESULTS: A total of 220 patients with pancreatic metastasis were analyzed. Three patients were selected from our own experience, and 217 were selected from a literature review. In the 127 patients whose symptoms were recorded at the time of presentation, the most common presenting symptoms were jaundice (n = 32, 25.2%) and abdominal pain (n = 25, 19.7%). In the 189 patients for whom the location of the metastasis in the pancreas was revealed, the most common location was the head of the pancreas (n = 79, 41.8%). The primary tumor site was most commonly kidney (n = 155, 70.5%). Surgical resection was attempted in 177 of 220 patients; 135 patients suffering from RCC metastasis also underwent pancreatic resection. In the latter group, a median survival of 70 months was seen, as well as 78% and 65% 2- and 5-year survival rates, respectively. CONCLUSION: Survival after resection of RCC with isolated metastasis to the pancreas is favorable. However, a more detailed analysis considering outcomes without surgery for each primary tumor site is needed before the value of this aggressive surgical approach can be completely assessed in the general occurrence of pancreatic metastasis.

9 Article SRC-3 inhibition blocks tumor growth of pancreatic ductal adenocarcinoma. 2019

Song, Xianzhou / Chen, Hui / Zhang, Chengwei / Yu, Yang / Chen, Zhongyuan / Liang, Han / Van Buren, George / McElhany, Amy L / Fisher, William E / Lonard, David M / O'Malley, Bert W / Wang, Jin. ·Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, 77030, USA. · Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Department of Statistics, Rice University, Houston, TX, 77030, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, USA. · Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address: dlonard@bcm.edu. · Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address: berto@bcm.edu. · Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address: wangj@bcm.edu. ·Cancer Lett · Pubmed #30423406.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and lethal disease with few treatment options. Steroid receptor coactivator-3 (SRC-3, also known as NCOA3, AIB1, pCIP, ACTR, RAC3, TRAM1) sits at the nexus of many growth signaling pathways and has been pursued as a therapeutic target for breast, prostate and lung cancers. In this study, we find that SRC-3 is overexpressed in PDAC and inversely correlates with patient overall survival. Knockdown of SRC-3 reduces pancreatic cancer cell proliferation, migration and invasion in vitro. Additionally, inhibition of SRC-3 using either shRNA or a small molecule inhibitor can significantly inhibit tumor growth in orthotopic pancreatic cancer mouse models. Collectively, this study establishes SRC-3 as a promising therapeutic target for pancreatic cancer treatment.

10 Article A Prospective Study to Establish a New-Onset Diabetes Cohort: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. 2018

Maitra, Anirban / Sharma, Ayush / Brand, Randall E / Van Den Eeden, Stephen K / Fisher, William E / Hart, Phil A / Hughes, Steven J / Mather, Kieren J / Pandol, Stephen J / Park, Walter G / Feng, Ziding / Serrano, Jose / Rinaudo, Jo Ann S / Srivastava, Sudhir / Chari, Suresh T / Anonymous1551565. ·Division of Gastroenterology, Department of Medicine, Mayo Clinic, Rochester, MN. · Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA. · Division of Research, Kaiser Permanente Northern California, Oakland, CA. · Division of Gastroenterology, Baylor College of Medicine, Houston, TX. · Division of Gastroenterology, The Ohio State University Wexner Medical Center, Columbus, OH. · Department of Surgery, College of Medicine, University of Florida Health Science Center, Gainesville, FL. · Division of Endocrinology and Metabolism, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN. · Division of Gastroenterology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA. · Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA. · Department of Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, WA. · Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. · Division of Cancer Prevention, National Cancer Institute, Rockville, MD. ·Pancreas · Pubmed #30325864.

ABSTRACT: The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

11 Article PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies: Rationale and Study Design for PROCEED From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. 2018

Yadav, Dhiraj / Park, Walter G / Fogel, Evan L / Li, Liang / Chari, Suresh T / Feng, Ziding / Fisher, William E / Forsmark, Christopher E / Jeon, Christie Y / Habtezion, Aida / Hart, Phil A / Hughes, Steven J / Othman, Mohamed O / Rinaudo, Jo Ann S / Pandol, Stephen J / Tirkes, Temel / Serrano, Jose / Srivastava, Sudhir / Van Den Eeden, Stephen K / Whitcomb, David C / Topazian, Mark / Conwell, Darwin L / Anonymous1531565. ·Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA. · Digestive and Liver Disorders, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN. · Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. · Biostatistics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA. · Division of General Surgery, Baylor College of Medicine, Houston, TX. · Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL. · Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA. · Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH. · Department of Surgery, University of Florida, Gainesville, FL. · Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX. · Cancer Biomarker Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD. · Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA. · Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN. · Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. · Division of Research, Kaiser Permanente Northern California, Oakland, CA. ·Pancreas · Pubmed #30325862.

ABSTRACT: Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis (CP) in the United States. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in CP. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of CP-controls, suspected CP, and definite CP. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid, and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of CP. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of CP.

12 Article Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. 2018

Fisher, William E / Cruz-Monserrate, Zobeida / McElhany, Amy L / Lesinski, Gregory B / Hart, Phil A / Ghosh, Ria / Van Buren, George / Fishman, Douglas S / Rinaudo, Jo Ann S / Serrano, Jose / Srivastava, Sudhir / Mace, Thomas / Topazian, Mark / Feng, Ziding / Yadav, Dhiraj / Pandol, Stephen J / Hughes, Steven J / Liu, Robert Y / Lu, Emily / Orr, Robert / Whitcomb, David C / Abouhamze, Amer S / Steen, Hanno / Sellers, Zachary M / Troendle, David M / Uc, Aliye / Lowe, Mark E / Conwell, Darwin L / Anonymous1521565. ·Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH. · Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University, Atlanta, GA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center. · Department of Pediatrics, Baylor College of Medicine, Houston, TX. · Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville. · Division of Digestive Diseases and Nutrition, National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. · Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. · Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA. · Department of Surgery, University of Florida College of Medicine, Gainesville, FL. · Clinical Research Support Center, The University of Texas MD Anderson Cancer Center, Houston, TX. · Indiana Clinical and Translational Sciences Institute, Specimen Storage Facility, Indianapolis, IN. · Clinical and Translational Sciences, University of Florida, Gainesville, FL. · Departments of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA. · Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Lucile Packard Children's Hospital and Stanford University School of Medicine, Stanford, CA. · Department of Pediatrics, University of Texas Southwestern Medical School, Dallas, TX. · Stead Family Department of Pediatrics, University of Iowa, Stead Family Children's Hospital, Iowa City, IA. · Department of Pediatrics, Washington University School of Medicine, St Louis, MO. ·Pancreas · Pubmed #30325860.

ABSTRACT: High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.

13 Article Venous thrombosis following pancreaticoduodenectomy with venous resection. 2018

Mohammed, Somala / Mendez-Reyes, Jose E / McElhany, Amy / Gonzales-Luna, Daniel / Van Buren, George / Bland, Daniel S / Villafane-Ferriol, Nicole / Pierzynski, Jeanne A / West, Charles A / Silberfein, Eric J / Fisher, William E. ·Baylor College of Medicine, The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, Houston, Texas. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Baylor College of Medicine, The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, Houston, Texas. Electronic address: wfisher@bcm.edu. ·J Surg Res · Pubmed #29907222.

ABSTRACT: BACKGROUND: Addition of en bloc segmental venous reconstruction (VR) to pancreaticoduodenectomy (PD) for venous involvement of pancreatic tumors increases the complexity of the operation and may increase complications. The long-term mesenteric venous patency rate and oncologic outcome has not been well defined. METHODS: Our prospective database was reviewed to assess 90-day postoperative outcomes for patients who underwent PD or PD + VR (September 2004-June 2016). Two independent observers reviewed CT scans to determine long-term vein patency. In patients with pancreatic ductal adenocarcinoma, the impact of VR on 5-year overall survival was assessed using multivariate Cox proportional hazards regression. Student's t-test was used to evaluate continuous variables and the chi-square test for categorical variables. RESULTS: Three hundred ninety-three patients underwent PD (51 PD + VR). Patients undergoing PD + VR had longer operations (561 ± 119 versus 433 ± 89 min, P < 0.00001) and greater blood loss (768 ± 812 versus 327 ± 423 cc, P < 0.00001). There was no difference in 90-day mortality, overall postoperative complication rates, complication severity grades, reoperation, readmission, or length of stay. 26.7% experienced venous thrombosis. Most thromboses occurred in the first year after surgery, but we also observed late thrombosis in 1 patient after 89-month follow-up. Among 135 patients with pancreatic ductal adenocarcinoma, survival was significantly longer in the PD-alone group (31.3 months [95% confidence interval: 22.9-40.0] versus 17.0 [95% confidence interval: 13.0-19.1], p CONCLUSIONS: PD + VR does not increase short-term morbidity, but venous thrombosis is frequent and can occur long after surgery. Survival is inferior when VR is required especially in the absence of neoadjuvant chemotherapy.

14 Article Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment. 2018

Sukumaran, Sujita / Watanabe, Norihiro / Bajgain, Pradip / Raja, Kanchana / Mohammed, Somala / Fisher, William E / Brenner, Malcolm K / Leen, Ann M / Vera, Juan F. ·Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas. · Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas. · Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. · Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas. jfvera@txch.org. ·Cancer Discov · Pubmed #29880586.

ABSTRACT: The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in "on-target, off-tumor" toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize prostate stem cell antigen, TGFβ, and IL4, and whose endodomains recapitulate physiologic T-cell signaling by providing signals for activation, costimulation, and cytokine support, produce potent antitumor effects selectively at the tumor site. In addition, this strategy has the benefit of rendering our cells resistant to otherwise immunosuppressive cytokines (TGFβ and IL4) and can be readily extended to other inhibitory molecules present at the tumor site (e.g., PD-L1, IL10, and IL13).

15 Article Value of lymph node positivity in treatment planning for early stage pancreatic cancer. 2017

Tran Cao, Hop S / Zhang, Qianzi / Sada, Yvonne H / Silberfein, Eric J / Hsu, Cary / Van Buren, George / Chai, Christy / Katz, Matthew H G / Fisher, William E / Massarweh, Nader N. ·Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX. Electronic address: hop.trancao@bcm.edu. · Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX. · Department of Medicine, Baylor College of Medicine, Houston, TX; VA HSR&D Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, TX. · Division of Surgical Oncology, U.T. MD Anderson Cancer Center, Houston, TX. · Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX; VA HSR&D Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, TX. ·Surgery · Pubmed #28666686.

ABSTRACT: BACKGROUND: Multimodal therapy is recommended for early stage pancreatic cancer, although whether all patients benefit and the optimal timing of chemotherapy remain unclear. METHODS: Retrospective cohort study of patients aged 18-79 years with stage I-II pancreatic ductal adenocarcinoma in the National Cancer Database (2004-2012). Patients were grouped based on treatment strategy as surgery only, adjuvant, and preoperative. Accuracy of nodal staging and rate of nodal downstaging were ascertained using pretreatment clinical and postresection pathologic nodal status data. Association between overall risk of death and treatment strategy was evaluated with multivariable Cox regression. RESULTS: Among 19,031 patients, 31.1% underwent surgery only, 59.6% received adjuvant, and 9.3% preoperative therapy. Based on patients receiving upfront surgery, clinical nodal staging bore sensitivity, specificity, positive predictive value, and negative predictive value of 46.2%, 95.7%, 95.1%, and 49.8%, respectively. Preoperative therapy downstaged 38% of cN1 patients to ypN0; 5-year overall survival for this group was 27.2% vs 12.3% for ypN1 patients (P < .001). Relative to surgery only, adjuvant (HR 0.75, 95% CI [0.71-0.78]) and preoperative therapy (HR 0.66 [0.60-0.73]) were associated with lower risk of death among patients with pN1, but not pN0 (adjuvant-HR 1.01 [0.94-1.09]; preoperative-HR 1.10 [0.99-1.22]), disease. CONCLUSION: Our data provide strong support for preoperative chemotherapy for patients with node-positive pancreatic cancer, one third of whom may be downstaged. Among those with seemingly node-negative disease, half will be understaged with current clinical staging modalities. These results should be considered when planning treatment for patients with early stage pancreatic cancer.

16 Article Pancreatic endometrial cyst mimics mucinous cystic neoplasm of the pancreas. 2017

Mederos, Michael A / Villafañe, Nicole / Dhingra, Sadhna / Farinas, Carlos / McElhany, Amy / Fisher, William E / Van Buren Ii, George. ·Michael A Mederos, Nicole Villafañe, Amy McElhany, William E Fisher, George Van Buren II, Department of General Surgery, Baylor College of Medicine, Houston, TX 77030, United States. ·World J Gastroenterol · Pubmed #28246486.

ABSTRACT: Pancreatic cysts include a variety of benign, premalignant, and malignant lesions. Endometrial cysts in the pancreas are exceedingly rare lesions that are difficult to diagnose pre-operatively. This report describes the findings in a 43-year-old patient with a recent episode of acute pancreatitis who presented with a large cyst in the tail of the pancreas. Imaging demonstrated a loculated pancreatic cyst, and cyst fluid aspiration revealed an elevated amylase and carcinoembryonic antigen. The patient experienced an interval worsening of abdominal pain, fatigue, diarrhea, and a 15-pound weight loss 3 mo after the initial episode of pancreatitis. With concern for a possible pre-malignant lesion, the patient underwent a laparoscopic distal pancreatectomy with splenectomy, which revealed a 16 cm × 12 cm × 4 cm lesion. Final histopathology was consistent with an intra-pancreatic endometrial cyst. Here we discuss the overlapping imaging and laboratory features of pancreatic endometrial cysts and mucinous cystic neoplasms of the pancreas.

17 Article Whole-genome landscape of pancreatic neuroendocrine tumours. 2017

Scarpa, Aldo / Chang, David K / Nones, Katia / Corbo, Vincenzo / Patch, Ann-Marie / Bailey, Peter / Lawlor, Rita T / Johns, Amber L / Miller, David K / Mafficini, Andrea / Rusev, Borislav / Scardoni, Maria / Antonello, Davide / Barbi, Stefano / Sikora, Katarzyna O / Cingarlini, Sara / Vicentini, Caterina / McKay, Skye / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / McLean, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Wilson, Peter J / Anderson, Matthew J / Fink, J Lynn / Newell, Felicity / Waddell, Nick / Holmes, Oliver / Kazakoff, Stephen H / Leonard, Conrad / Wood, Scott / Xu, Qinying / Nagaraj, Shivashankar Hiriyur / Amato, Eliana / Dalai, Irene / Bersani, Samantha / Cataldo, Ivana / Dei Tos, Angelo P / Capelli, Paola / Davì, Maria Vittoria / Landoni, Luca / Malpaga, Anna / Miotto, Marco / Whitehall, Vicki L J / Leggett, Barbara A / Harris, Janelle L / Harris, Jonathan / Jones, Marc D / Humphris, Jeremy / Chantrill, Lorraine A / Chin, Venessa / Nagrial, Adnan M / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia / Rooman, Ilse / Toon, Christopher / Wu, Jianmin / Pinese, Mark / Cowley, Mark / Barbour, Andrew / Mawson, Amanda / Humphrey, Emily S / Colvin, Emily K / Chou, Angela / Lovell, Jessica A / Jamieson, Nigel B / Duthie, Fraser / Gingras, Marie-Claude / Fisher, William E / Dagg, Rebecca A / Lau, Loretta M S / Lee, Michael / Pickett, Hilda A / Reddel, Roger R / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Epari, Krishna / Nguyen, Nam Q / Zeps, Nikolajs / Falconi, Massimo / Simbolo, Michele / Butturini, Giovanni / Van Buren, George / Partelli, Stefano / Fassan, Matteo / Anonymous7980896 / Khanna, Kum Kum / Gill, Anthony J / Wheeler, David A / Gibbs, Richard A / Musgrove, Elizabeth A / Bassi, Claudio / Tortora, Giampaolo / Pederzoli, Paolo / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Medical Oncology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Italy. · Department of Medicine, Section of Endocrinology, University and Hospital Trust of Verona, Verona, Italy. · The University of Queensland, School of Medicine, Brisbane 4006, Australia. · Pathology Queensland, Brisbane 4006, Australia. · Royal Brisbane and Women's Hospital, Department of Gastroenterology and Hepatology, Brisbane 4006, Australia. · Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital &Institute, Beijing 100142, China. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · Department of Anatomical Pathology. St Vincent's Hospital, Sydney, New South Wales 2010, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · Department of Pathology, Queen Elizabeth University Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA. · Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia. · Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney. Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · School of Medicine, Western Sydney University, Penrith, New South Wales 2175, Australia. · Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, Western Australia 6009, Australia. · St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia. · University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia. ·Nature · Pubmed #28199314.

ABSTRACT: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

18 Article Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer. 2017

Mohammed, Somala / Sukumaran, Sujita / Bajgain, Pradip / Watanabe, Norihiro / Heslop, Helen E / Rooney, Cliona M / Brenner, Malcolm K / Fisher, William E / Leen, Ann M / Vera, Juan F. ·Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA; Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. · Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA. · Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. · Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. · Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Electronic address: jfvera@txch.org. ·Mol Ther · Pubmed #28129119.

ABSTRACT: The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced tumor responses, even in patients with refractory diseases. To target pancreatic cancer, we generated CAR T cells directed against prostate stem cell antigen (PSCA) and demonstrated specific tumor lysis. However, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit CAR T cell persistence and function. Thus, to protect our cells from the immunosuppressive cytokine IL-4, we generated an inverted cytokine receptor in which the IL-4 receptor exodomain was fused to the IL-7 receptor endodomain (4/7 ICR). Transgenic expression of this molecule in CAR-PSCA T cells should invert the inhibitory effects of tumor-derived IL-4 and instead promote T cell proliferation. We now demonstrate the suppressed activity of CAR T cells in tumor-milieu conditions and the ability of CAR/ICR T cells to thrive in an IL-4-rich microenvironment, resulting in enhanced antitumor activity. Importantly, CAR/ICR T cells remained both antigen and cytokine dependent. These findings support the benefit of combining the 4/7 ICR with CAR-PSCA to treat pancreatic cancer, a PSCA-expressing tumor characterized by a dense immunosuppressive environment rich in IL-4.

19 Article Overexpression of Semaphorin-3E enhances pancreatic cancer cell growth and associates with poor patient survival. 2016

Yong, Lin-Kin / Lai, Syeling / Liang, Zhengdong / Poteet, Ethan / Chen, Fengju / van Buren, George / Fisher, William / Mo, Qianxing / Chen, Changyi / Yao, Qizhi. ·Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, USA. · Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. · Department of Pathology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA. · Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. · Department of Medicine, Baylor College of Medicine, Houston, TX, USA. · Michael E. DeBakey Department of Surgery, Division of General Surgery, Baylor College of Medicine, Houston, TX, USA. · Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX, USA. ·Oncotarget · Pubmed #27911862.

ABSTRACT: Semaphorin-3E (Sema3E) is a member of an axon guidance gene family, and has recently been reported to contribute to tumor progression and metastasis. However, its role in pancreatic cancer is yet unknown and uncharacterized. In this study, we showed that Sema3E is overexpressed in human pancreatic cancer, and that high Sema3E levels are associated with tumor progression and poor survival. Interestingly, we also observed Sema3E expression in the nucleus, even though Sema3E is reported to be a secreted protein. Overexpression of Sema3E in pancreatic cancer cells promoted cell proliferation and migration in vitro, and increased tumor incidence and growth in vivo. Conversely, knockout of Sema3E suppressed cancer cell proliferation and migration in vitro, and reduced tumor incidence and size in vivo. Moreover, Sema3E induced cell proliferation via acting through the MAPK/ERK pathway. Collectively, these results reveal an undiscovered role of Sema3E in promoting pancreatic cancer pathogenesis, suggesting that Sema3E may be a suitable prognostic marker and therapeutic target for pancreatic cancer.

20 Article Biologic effect of neurogenesis in pancreatic cancer. 2016

He, Dandan / Manzoni, Adriana / Florentin, Diego / Fisher, William / Ding, Yi / Lee, MinJae / Ayala, Gustavo. ·Department of Internal Medicine, Detroit Medical Center, Sinai-Grace Hospital, Wayne State University, Detroit, MI 48235, USA. · Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77401 USA. · Department of Surgery, Baylor College of Medicine, Houston, TX, 77401 USA. · Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center Medical School, Houston, TX, 77401 USA. · Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, TX 77401. · Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center Medical School, Houston, TX, 77401 USA. Electronic address: Gustavo.E.Ayala@uth.tmc.edu. ·Hum Pathol · Pubmed #26980040.

ABSTRACT: Pancreatic cancer (PaCA) is a deadly disease with few systemic therapeutic options. The head of the pancreas is the most innervated part and most common location of cancer. However, little is known about the contribution of the nerve-cancer interaction to facilitate pancreatic progression. To quantify PaCA axonogenesis, we used a 3-dimensional in vitro neurogenesis model. In addition, neurogenesis in human PaCA was analyzed using PGP9.5 immunohistochemistry, deconvolution imaging, and image segmentation and analysis. There was a significant increase of the total area of neurites in the in vitro coculture with dorsal root ganglia group than control. The nerve density in PaCA tissue was significantly higher than normal pancreatic tissue. To study the functional role of nerves in PaCA, male athymic nude (Nu-Nu) mice were divided into 3 groups: (A) animals were coinjected with MIA PaCa-2 cells and 20U/kg weight units of Botulinum toxin (Botox) (n=10); (B) first injected with Botox and 6weeks later MIA PaCa-2 cancer cells (n=4); and (C) control animals were injected with equivalent amounts of saline fluid (n=9). Animals were sacrificed 6weeks later. Tumor size and apoptotic count (terminal deoxynucleotidyl transferase dUTP nick-end labeling) were measured. Tumor size was decreased and apoptotic rate increased in Botox-treated PaCA. Our data indicate that neural microenvironment may play an important role in the progression of PaCA. It may lead to novel nerve-targeted coadjuvant therapies for PaCA.

21 Article Genomic analyses identify molecular subtypes of pancreatic cancer. 2016

Bailey, Peter / Chang, David K / Nones, Katia / Johns, Amber L / Patch, Ann-Marie / Gingras, Marie-Claude / Miller, David K / Christ, Angelika N / Bruxner, Tim J C / Quinn, Michael C / Nourse, Craig / Murtaugh, L Charles / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourbakhsh, Ehsan / Wani, Shivangi / Fink, Lynn / Holmes, Oliver / Chin, Venessa / Anderson, Matthew J / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Xu, Qinying / Wilson, Peter J / Cloonan, Nicole / Kassahn, Karin S / Taylor, Darrin / Quek, Kelly / Robertson, Alan / Pantano, Lorena / Mincarelli, Laura / Sanchez, Luis N / Evers, Lisa / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chantrill, Lorraine A / Mawson, Amanda / Humphris, Jeremy / Chou, Angela / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia V / Giry-Laterriere, Marc / Rooman, Ilse / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Moran-Jones, Kim / Jamieson, Nigel B / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Grützmann, Robert / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Corbo, Vincenzo / Bassi, Claudio / Rusev, Borislav / Capelli, Paola / Salvia, Roberto / Tortora, Giampaolo / Mukhopadhyay, Debabrata / Petersen, Gloria M / Anonymous91128 / Munzy, Donna M / Fisher, William E / Karim, Saadia A / Eshleman, James R / Hruban, Ralph H / Pilarsky, Christian / Morton, Jennifer P / Sansom, Owen J / Scarpa, Aldo / Musgrove, Elizabeth A / Bailey, Ulla-Maja Hagbo / Hofmann, Oliver / Sutherland, Robert L / Wheeler, David A / Gill, Anthony J / Gibbs, Richard A / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. · Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. · School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. · Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. · Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. · School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. · Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. · Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. · Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. · Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. · The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. · Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. · University of Melbourne, Parkville, Victoria 3010, Australia. ·Nature · Pubmed #26909576.

ABSTRACT: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

22 Article Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation. 2016

Gingras, Marie-Claude / Covington, Kyle R / Chang, David K / Donehower, Lawrence A / Gill, Anthony J / Ittmann, Michael M / Creighton, Chad J / Johns, Amber L / Shinbrot, Eve / Dewal, Ninad / Fisher, William E / Anonymous1060856 / Pilarsky, Christian / Grützmann, Robert / Overman, Michael J / Jamieson, Nigel B / Van Buren, George / Drummond, Jennifer / Walker, Kimberly / Hampton, Oliver A / Xi, Liu / Muzny, Donna M / Doddapaneni, Harsha / Lee, Sandra L / Bellair, Michelle / Hu, Jianhong / Han, Yi / Dinh, Huyen H / Dahdouli, Mike / Samra, Jaswinder S / Bailey, Peter / Waddell, Nicola / Pearson, John V / Harliwong, Ivon / Wang, Huamin / Aust, Daniela / Oien, Karin A / Hruban, Ralph H / Hodges, Sally E / McElhany, Amy / Saengboonmee, Charupong / Duthie, Fraser R / Grimmond, Sean M / Biankin, Andrew V / Wheeler, David A / Gibbs, Richard A. ·Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: mgingras@bcm.edu. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, NSW 2170, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. · The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, TX 77030, USA. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. · The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA. · Department of Surgery, TU Dresden, 01307 Dresden, Germany. · Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; Academic Unit of Surgery, Institute of Cancer Sciences, Glasgow Royal Infirmary, Level 2, New Lister Building, University of Glasgow, Glasgow G31 2ER, UK. · Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, TU Dresden, 01307 Dresden, Germany. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Department of Pathology, Southern General Hospital, Greater Glasgow and Clyde NHS, Glasgow G51 4TF, UK. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wheeler@bcm.edu. ·Cell Rep · Pubmed #26804919.

ABSTRACT: The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

23 Article Risk-adjusted Outcomes of Clinically Relevant Pancreatic Fistula Following Pancreatoduodenectomy: A Model for Performance Evaluation. 2016

McMillan, Matthew T / Soi, Sameer / Asbun, Horacio J / Ball, Chad G / Bassi, Claudio / Beane, Joal D / Behrman, Stephen W / Berger, Adam C / Bloomston, Mark / Callery, Mark P / Christein, John D / Dixon, Elijah / Drebin, Jeffrey A / Castillo, Carlos Fernandez-Del / Fisher, William E / Fong, Zhi Ven / House, Michael G / Hughes, Steven J / Kent, Tara S / Kunstman, John W / Malleo, Giuseppe / Miller, Benjamin C / Salem, Ronald R / Soares, Kevin / Valero, Vicente / Wolfgang, Christopher L / Vollmer, Charles M. ·*Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania†Department of Surgery, Mayo Clinic, Jacksonville, Florida‡Department of Surgery, University of Calgary, Calgary, Canada§Department of Surgery, University of Verona, Verona, Italy¶Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana||Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee**Department of Surgery, Jefferson Medical College, Philadelphia, Pennsylvania††Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio‡‡Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts§§Department of Surgery, University of Alabama School of Medicine, Birmingham, Alabama¶¶Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts||||Department of Surgery, Baylor College of Medicine, Houston, Texas***Department of Surgery, University of Florida College of Medicine, Gainesville, Florida†††Department of Surgery, Yale School of Medicine, New Haven, Connecticut‡‡‡Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland. ·Ann Surg · Pubmed #26727086.

ABSTRACT: OBJECTIVE: To evaluate surgical performance in pancreatoduodenectomy using clinically relevant postoperative pancreatic fistula (CR-POPF) occurrence as a quality indicator. BACKGROUND: Accurate assessment of surgeon and institutional performance requires (1) standardized definitions for the outcome of interest and (2) a comprehensive risk-adjustment process to control for differences in patient risk. METHODS: This multinational, retrospective study of 4301 pancreatoduodenectomies involved 55 surgeons at 15 institutions. Risk for CR-POPF was assessed using the previously validated Fistula Risk Score, and pancreatic fistulas were stratified by International Study Group criteria. CR-POPF variability was evaluated and hierarchical regression analysis assessed individual surgeon and institutional performance. RESULTS: There was considerable variability in both CR-POPF risk and occurrence. Factors increasing the risk for CR-POPF development included increasing Fistula Risk Score (odds ratio 1.49 per point, P < 0.00001) and octreotide (odds ratio 3.30, P < 0.00001). When adjusting for risk, performance outliers were identified at the surgeon and institutional levels. Of the top 10 surgeons (≥15 cases) for nonrisk-adjusted performance, only 6 remained in this high-performing category following risk adjustment. CONCLUSIONS: This analysis of pancreatic fistulas following pancreatoduodenectomy demonstrates considerable variability in both the risk and occurrence of CR-POPF among surgeons and institutions. Disparities in patient risk between providers reinforce the need for comprehensive, risk-adjusted modeling when assessing performance based on procedure-specific complications. Furthermore, beyond inherent patient risk factors, surgical decision-making influences fistula outcomes.

24 Article Antiproliferative effects and mechanisms of liver X receptor ligands in pancreatic ductal adenocarcinoma cells. 2014

Candelaria, Nicholes R / Addanki, Sridevi / Zheng, Jine / Nguyen-Vu, Trang / Karaboga, Husna / Dey, Prasenjit / Gabbi, Chiara / Vedin, Lise-Lotte / Liu, Ka / Wu, Wanfu / Jonsson, Philip K / Lin, Jean Z / Su, Fei / Bollu, Lakshmi Reddy / Hodges, Sally E / McElhany, Amy L / Issazadeh, Mehdi A / Fisher, William E / Ittmann, Michael M / Steffensen, Knut R / Gustafsson, Jan-Åke / Lin, Chin-Yo. ·Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America. · Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. · Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America; Center for Diabetes Research, Houston Methodist Research Institute, Houston, Texas, United States of America. · Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America; The Elkins Pancreas Center at Baylor College of Medicine, Houston, Texas, United States of America. · Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America. · Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America; Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, Huddinge, Sweden. ·PLoS One · Pubmed #25184494.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.

25 Article A tumorigenic factor interactome connected through tumor suppressor microRNA-198 in human pancreatic cancer. 2013

Marin-Muller, Christian / Li, Dali / Bharadwaj, Uddalak / Li, Min / Chen, Changyi / Hodges, Sally E / Fisher, William E / Mo, Qianxing / Hung, Mien-Chie / Yao, Qizhi. ·Authors' Affiliations: Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Department of Molecular Virology and Microbiology, Duncan Cancer Center, Baylor College of Medicine; and Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas. ·Clin Cancer Res · Pubmed #23989979.

ABSTRACT: PURPOSE: The majority of pancreatic cancers overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion, and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors and explored the potential of MSLN-regulated miR-198 treatment in vivo. EXPERIMENTAL DESIGN: The expression and functional regulation of the tumorigenic factors MSLN, NF-κB, and the homeobox transcription factors (TF) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in pancreatic cancer cell lines, patient tumor samples, and xenograft pancreatic cancer mouse models. RESULTS: We found that miR-198 is downregulated in pancreatic cancer and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-κB-mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in pancreatic cancer cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival. CONCLUSIONS: miR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in pancreatic cancer, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point.

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