Pancreatic Cancer

John P. Neoptolemos • Raul UrrutiaJames L. Abbruzzese • Markus W. BüchlerEditors

Pancreatic Cancer

Second Edition

With 244 Figures and 93 Tables

EditorsJohn P. NeoptolemosDepartment of GeneralVisceral and Transplantation SurgeryUniversity of HeidelbergHeidelberg, Germany

Raul UrrutiaDivision of ResearchDepartment of Surgery and GenomicSciences and Precision MedicineCenter (GSPMC)Medical College of WisconsinMilwaukee, WI, USA

James L. AbbruzzeseDivision of Medical OncologyDuke Cancer InstituteDuke University Medical CenterDurham, NC, USA

Markus W. BüchlerDepartment of GeneralVisceral and Transplantation SurgeryUniversity of HeidelbergHeidelberg, Germany

ISBN 978-1-4939-7191-6 ISBN 978-1-4939-7193-0 (eBook)ISBN 978-1-4939-7192-3 (print and electronic bundle)https://doi.org/10.1007/978-1-4939-7193-0

Library of Congress Control Number: 2018930882

1st edition: # Springer Science+Business Media, LLC 2010# Springer Science+Business Media, LLC, part of Springer Nature 2018This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of thematerial is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,broadcasting, reproduction on microfilms or in any other physical way, and transmission or informationstorage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodologynow known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoes not imply, even in the absence of a specific statement, that such names are exempt from the relevantprotective laws and regulations and therefore free for general use.The publisher, the authors and the editors are safe to assume that the advice and information in this bookare believed to be true and accurate at the date of publication. Neither the publisher nor the authors or theeditors give a warranty, express or implied, with respect to the material contained herein or for any errorsor omissions that may have been made. The publisher remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.

Printed on acid-free paper

This Springer imprint is published by the registered company Springer Science+Business Media, LLC partof Springer Nature.The registered company address is: 233 Spring Street, New York, NY 10013, U.S.A.

This work is dedicated to our wives Linda,Gwen, Marie, and Hedi and to our patientsand their relatives

Foreword

We have seen remarkable advances in the understanding of the epidemiologic,cellular, and molecular pathogenesis of pancreatic cancer since the First Edition ofPancreatic Cancer in 2010. Yet pancreatic cancer is still one of the most commoncauses of cancer-related death among men and women in the USA and many otherparts of the world, and the incidence is increasing relentlessly. The more we seem toknow, the bigger the challenge becomes. We said in 2010 “how do we get to the nextlevel?” That next level has now arrived.

In 2010, we were just introduced to FOLFIRINOX, a highly active chemotherapyregimen. That was soon followed by the finding that gemcitabine and albumin-bound paclitaxel is also very effective. As we have advanced these therapies frommetastatic to locally advanced to even resectable/borderline resectable disease, wesee the overall survival inching up. A small triumph perhaps, but worth noting. Ourchallenge now is how to insert more targeted agents and to position immuno-oncology into the arsenal against this very “cold” tumor.

Because of more effective therapy, more and more patients are undergoingresection even in settings where, previously, surgery would not be attempted.Despite the greater complexity of the surgical techniques, the operations themselvesremain safe. We are also seeing remarkable advances in laparoscopic and roboticsurgeries for selected cases with shorter hospital stay, allowing more patients to beeligible for adjuvant treatment.

Gene testing is now recommended for patients in whom we suspect mutationsbased on family history, but germline testing for inherited cancer susceptibilityseems to be gaining more traction. Recently, researchers at Johns Hopkins foundthe incidence of these mutations in patients with unremarkable family histories wasaround 4% and much higher than anyone would have anticipated. They sequenced32 genes in 854 patients and found 33 with a deleterious germline mutation,including BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2(2 patients), MLH1 (2 patients), CDKN2A (1 patient), TP53 (1 patient), BUB1B(1 patient), and BUB3 (1 patient). Some of these susceptibility gene mutations wouldbe missed if current family history guidelines for gene testing were to be applied.Although the proportion of affected individuals was small, the potential treatmentimpact on these individuals and screening implications for family members are bothmassive. Patients with germline mutations in DNA repair pathways enjoy exquisite

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responses to gemcitabine and cisplatin. PARP inhibitors can benefit patients withBRCA1/2 mutations, and pembrolizumab is effective for patients with microsatelliteinstability-high (MSI-H) cancer. In addition, we can use knowledge of germlinemutations to avoid certain treatments, such as radiation, for those with ATM or TP53mutations.

The Cancer Genome Atlas Research Network has also just recently performed anintegrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductaladenocarcinomas. Deep whole exome sequencing revealed recurrent somatic muta-tions in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS,RREB1, and PBRM1. Interestingly, KRAS wild-type tumors harbored alterations inother oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RASpathway genes. A subset of tumors was found to have multiple KRAS mutations,with some showing evidence of biallelic mutations. Going onto protein profiling afavorable prognosis subset was identified with low epithelial-mesenchymal transi-tion and high MTOR pathway activation. Associations of noncoding RNAs withtumor-specific mRNA subtypes were also identified. This is one of the key stepsproviding a roadmap for precision medicine.

This Second Edition textbook, Pancreatic Cancer, has maintained the momen-tum of a carefully composed compendium of state-of-the-art science in all aspects ofresearch of pancreatic cancer. The experts who were selected to provide contribu-tions are the best in their fields. The content is contemporary and comprehensive.This text is a necessary reference for anyone already doing research in pancreaticcancer.

Again I can only reiterate that I am truly grateful to my colleagues around theworld who have worked so hard and so tirelessly to create this reference. Dissem-inating the scientific breakthroughs that we know now will accelerate the progressthat will change the lives of more and more of our patients.

Margaret A. Tempero, M.D.University of California, San Francisco

viii Foreword

Preface

Pancreatic cancer has become an even greater challenge today than it was in 2010while paradoxically seeing exciting progress in its understanding with unforeseenadvances in its diagnosis and treatment. The First Edition proved to be a majorsuccess with over 30,000 downloads: it was up to date, evincing a deep butmanageable exposition of the relevant basic and translational science, complexedwithin a clinically relevant purpose. The forward momentum meant that a SecondEdition became an inevitability, but this has not simply meant just updating the sameelemental threads but a reworking of the perspective.

The incidence of pancreas cancer is rising around the world and is predicted tobecome the second commonest cause of death within a few years. Yet survival isbeginning to improve and in the case of potentially curable cases the 5-year survivalrates are 30% with postoperative adjuvant combination chemotherapy. By 2012 theestimated global incidence was 337,872 cases per year resulting in 330,391 deaths,and in Europe pancreatic cancer accounted for 103,773 new cases and 104,481deaths each year. In the USA in 2016, there were around 53,070 new cases ofpancreatic cancer diagnosed with 41,780 deaths. The American Cancer Society’sestimates for pancreatic cancer in the USA for 2017 were 53,670 (27,970 men and25,700 women) new cases with 43,090 (22,300 men and 20,790 women) deaths.Pancreatic cancer accounts for about 3% of all cancers in the USA and about 7% ofall cancer deaths. The 1-year survival rate of people with pancreatic cancer who donot have surgery has risen from around 10% to 30%, and the overall 5-year survivalrate has risen from 5% to 7%. In resected cases, the 5-year survival rates haveincreased from 8% with surgery alone to 30% with combination adjuvant chemo-therapy using gemcitabine and capecitabine.

Advances in surgical techniques now enable many more patients to be operated,and the application of neoadjuvant therapies may also render borderline and locallyadvanced pancreatic cancers more amenable to resection. But much is still needed tounderstand the biology of the cancer and how the microenvironment of both thepancreatic primary and its metastases influence this. We have expanded sections onstromal inflammatory cells in pancreatic cancer and tumor-stromal interactions ininvasion and metastases. There is enhanced discussion on the management ofpreneoplastic cystic neoplasms of the pancreas, including the controversial area ofintraductal papillary mucinous neoplasms. Advanced technologies for diagnosis and

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treatment now encompass cancer exosomes, liquid biopsies and circulating tumorcells, and vaccine therapy and immunotherapy.

The application of pancreatic cancer genetics has been progressed into precisionmedicine based on next-generation sequencing and master controllers. Other noveltherapeutic areas are now expounded in considerable depth including definingpancreatic cancer phenotypes via metabolomics, treatments based on the metabolismof pancreatic cancer, epigenetic pharmacology, differential therapy based on tumorheterogeneity, and multiparameter modalities applied in the setting of individualizedmedicine.

By drawing on many of the world’s recognized scientific authorities and practicalclinicians, we hope to inspire the current and future generations of active researchersto make clever and bold decisions on how we can successfully continue the fightagainst pancreatic cancer.

John P. NeoptolemosRaul Urrutia

James L. AbbruzzeseMarkus W. Büchler

x Preface

Acknowledgments

The Editors would like to dedicate their work to all the pancreatic cancer patients andtheir families.

The Editors wish to acknowledge the significant support offered by our individualeditorial assistants, who provided the day-to-day contacts, oversights, and manage-ment of manuscripts that were submitted in each international office.

We specifically wish to thank the assistance of Thilo Hackert in the office ofProfessor Büchler (Heidelberg, Germany) who made a great contribution as well asMia Rothwell in the office of Professor James Abbruzzese (Duke Cancer Institute,USA), and Dr. Gwen Lomberk in the office of Professor Raul Urrutia (Mayo Clinic,USA).

All of these people provided an invaluable service that is appreciated highly bythe Editors and allowed Springer to publish in a timely and organized fashion.

The Editors would also like to thank the assistance and organizational skills, andthe extraordinary attention and diligence of Springer’s Saskia Ellis andBarbara Wolf.

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Contents

Volume 1

Part I The Nature of Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . 1

Epidemiology and Prospects for Prevention of Pancreatic Cancer . . . . 3Patrick Maisonneuve and Albert Lowenfels

Cell Cycle Machinery and Its Alterations in Pancreatic Cancer . . . . . . 19Yusuke Kojima, Reeja S. Maskey, and Yuichi J. Machida

Pathologic Classification and Biological Behavior of PancreaticNeoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Olca Basturk, Michelle D. Reid, and N. Volkan Adsay

Developmental Molecular Biology of the Pancreas . . . . . . . . . . . . . . . . 89L. Charles Murtaugh, Ondine Cleaver, and Raymond J. MacDonald

The Molecular Pathology of Precursor Lesions of PancreaticCancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147Aatur D. Singhi and Anirban Maitra

Epigenetics and Its Applications to the Progression Model ofPancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177Gwen Lomberk and Raul Urrutia

Molecular Pathology of Pancreatic Endocrine Tumors . . . . . . . . . . . . . 209Gianfranco Delle Fave, Elettra Merola, Gabriele Capurso,Stefano Festa, Matteo Piciucchi, and Roberto Valente

Sporadic Pancreatic Endocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . 241Volker Fendrich and Detlef K. Bartsch

Molecular Pathology of Carcinomas of the Ampullary/PeriampullaryRegion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265Lena Haeberle, Jasmin Riemer, and Irene Esposito

xiii

Miscellaneous Nonpancreatic Nonendocrine Tumors . . . . . . . . . . . . . . 283Heather A. Lillemoe, John D. Abad, and Keith D. Lillemoe

Animal Modeling of Pancreatitis-to-Cancer Progression . . . . . . . . . . . . 313Paola Martinelli and Francisco X. Real

Pancreatic Cancer Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349Mackenzie Goodwin, Ethan V. Abel, Vinee Purohit, andDiane M. Simeone

Apoptosis: Signaling Pathways in Pancreatic Cancer Pathogenesis . . . 369David J. McConkey and Woonyoung Choi

EGFR (ErbB) Signaling Pathways in Pancreatic CancerPathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383Monique Williams, Gwen Lomberk, and Raul Urrutia

Hedgehog Signaling Plays a Dual Role in PancreaticCarcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409Tara L. Hogenson, Rachel L. O. Olson, and Martin E. Fernandez-Zapico

Smad4-TGF-β Signaling Pathways in Pancreatic CancerPathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431Murray Korc

Notch Signaling in Pancreatic Morphogenesis and PancreaticCancer Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457Gwen Lomberk and Raul Urrutia

Stromal Inflammation in Pancreatic Cancer: Mechanisms andTranslational Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481Kathleen A. Boyle, Michael A. James, Susan Tsai,Douglas B. Evans, and Michael B. Dwinell

Mouse Models of Pancreatic Exocrine Cancer . . . . . . . . . . . . . . . . . . . . 509Pedro A. Pérez-Mancera

Role of Tumor-Stromal Interactions in Pancreatic CancerInvasion and Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539Rachel L. O. Olson, Judith V. Forner, Pilar Navarro,Martin E. Fernandez-Zapico, and Ahmed M. Elamir

Familial Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553Nicholas J. Roberts and Alison P. Klein

Inherited Pancreatic Endocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . 573Jerena Manoharan, Jens Waldmann, Peter Langer, and Detlef K. Bartsch

xiv Contents

Volume 2

Part II Clinical Management of Pancreatic Cancer . . . . . . . . . . . . . 599

Clinical Decision-Making in Pancreatic Cancer . . . . . . . . . . . . . . . . . . . 601Robert A. Wolff

Paraneoplastic Syndromes in Pancreatic Cancer . . . . . . . . . . . . . . . . . . 633Jens Werner and Stephan Herzig

Diagnostic Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659Anne Macgregor-Das and Michael Goggins

Pancreatic Adenocarcinoma: CT and PET/CT . . . . . . . . . . . . . . . . . . . 681Götz M. Richter

MRI and MRCP for Diagnosis and Staging of Pancreatic Cancer . . . . 711Priya R. Healey

EUS and Its Role in Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 735Tobias Grote and Thomas Mathias Gress

Laparoscopic Staging in Patients with Newly Diagnosed PancreaticCancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753Timothy Gilbert, Ryan Baron, Paula Ghaneh, and Christopher Halloran

Palliative Management of Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . 771Rony Dev and Milind Javle

Therapeutic Endoscopy in the Management of Pancreatic Cancer . . . . 799Alyson McGhan and Rebecca Burbridge

Interventional Radiology for Pancreatic Cancer . . . . . . . . . . . . . . . . . . 815Ferga C. Gleeson and Michael J. Levy

Palliative Surgery in Advanced Pancreatic Cancer . . . . . . . . . . . . . . . . 857Florian Scheufele and Helmut Friess

Chemotherapy for Advanced Pancreatic Cancer . . . . . . . . . . . . . . . . . . 875Francesco Sclafani, David Cunningham, Alicia Okines,Gihan Ratnayake, and Ian Chau

Surgical Resection for Pancreatic Cancer Using the InternationalStudy Group of Pancreatic Surgery (ISGPS) Classifications . . . . . . . . . 923Thilo Hackert, Christoph W. Michalski, and Markus W. Büchler

Venous Resection in Pancreatic Cancer Surgery . . . . . . . . . . . . . . . . . . 941Yukihiro Yokoyama and Yuji Nimura

Controversies in Pathology Reporting and Staging . . . . . . . . . . . . . . . . 967Fiona Campbell and Caroline Sophie Verbeke

Contents xv

Staging and Postoperative Outcomes Using the InternationalStudy Group of Pancreatic Surgery (ISGPS) Classifications . . . . . . . . . 989T. Welsch and J. Weitz

Borderline Resectable Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . 1001Gauri R. Varadhachary

New Japanese Classification of Pancreatic Cancer . . . . . . . . . . . . . . . . 1021Shuji Isaji, Yasuhiro Murata, and Masashi Kishiwada

Adjuvant Chemotherapy in Pancreatic Cancer . . . . . . . . . . . . . . . . . . . 1039John P. Neoptolemos, David Cunningham, Francesco Sclafani, andPaula Ghaneh

Adjuvant Chemoradiation Therapy for Pancreatic Cancer . . . . . . . . . 1073Adeel Kaiser, William F. Regine, Naimish Pandya, andMichael C. Garofalo

Arterial Resection in Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . 1089Declan F. J. Dunne, Jörg Kleeff, Vincent S. Yip, Christopher Halloran,Paula Ghaneh, and John P. Neoptolemos

Treatment of Recurrent Pancreatic Cancer After Surgery . . . . . . . . . . 1105Oliver Strobel, Willem Niesen, and Markus W. Büchler

Management of Cystic Neoplasms of the PancreasIncluding IPMNs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131C. Tjaden, Thilo Hackert, and Markus W. Büchler

Laparoscopic Surgery for Pancreatic Neoplasms . . . . . . . . . . . . . . . . . 1157Santiago Sánchez Cabús and Laureano Fernández-Cruz

Modern Japanese Approach to Pancreatic Cancer . . . . . . . . . . . . . . . . 1169Takao Ohtsuka and Masao Tanaka

Neoadjuvant Chemotherapy in Pancreatic Cancer . . . . . . . . . . . . . . . . 1187Theodoros Michelakos and Cristina R. Ferrone

Differential Therapy Based on Tumor Heterogeneity in PancreaticCancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1203Juan Iovanna, Benjamin Bian, Martin Bigonnet, and Nelson Dusetti

Neoadjuvant Chemoradiation for Operable Pancreatic Cancer:The Importance of Local Disease Control . . . . . . . . . . . . . . . . . . . . . . . 1219Chad A. Barnes, Susan Tsai, William A. Hall, Beth A. Erickson, andDouglas B. Evans

xvi Contents

Volume 3

Part III New Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1239

Development of Novel Diagnostic Pancreatic Tumor Biomarkers . . . . . 1241Lucy Oldfield, Rohith Rao, Lawrence N. Barrera, and Eithne Costello

Development of Novel Therapeutic Response Biomarkers . . . . . . . . . . 1273Nils Elander, Karen Aughton, and William Greenhalf

Approaching Pancreatic Cancer Phenotypes via Metabolomics . . . . . . 1305Peter McGranaghan, Ulrike Rennefahrt, Beate Kamlage,Regina Reszka, Philipp Schatz, Bianca Bethan, Julia Mayerle, andMarkus M. Lerch

Circulating Tumor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1325Konstantinos L. Georgiadis, Kathryn Simpson, Mahmood Ayub,Ged Brady, Juan Valle, Claus Jorgensen, and Caroline Dive

Cancer Exosomes for Early Pancreatic Cancer Diagnosis andRole in Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361Murray Korc and Samantha Deitz McElyea

Metabolism in Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1379Ioannis Poursaitidis and Richard F. Lamb

Secondary Screening for Inherited Pancreatic DuctalAdenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1401Andrea Sheel, James Nicholson, Ioannis Sarantitis,John P. Neoptolemos, and William Greenhalf

Role of Radiotherapy in Locally Advanced Pancreatic Cancer . . . . . . . 1435Daphna Spiegel, Julian Hong, Manisha Palta, Brian Czito, andChristopher Willett

Vaccine Therapy and Immunotherapy for Pancreatic Cancer . . . . . . . 1461Lei Zheng and Elizabeth M. Jaffee

Evolution of Pancreatic Cancer Surgery . . . . . . . . . . . . . . . . . . . . . . . . 1507Christoph W. Michalski, Bing Liu, Markus W. Büchler, andThilo Hackert

Multiparameter Modalities for the Study of Patients in theSetting of Individualized Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1523Koji Miyabayashi, David A. Tuveson, and Kenneth H. Yu

Epigenetic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551Richard A. Burkhart, Anup R. Sharma, and Nita Ahuja

Contents xvii

Precision Medicine Based on Next-Generation Sequencingand Master Controllers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1577Katerina Dukleska, Charles J. Yeo, Michael J. Pishvaian, andJonathan R. Brody

Emerging Therapeutic Targets in Pancreatic Adenocarcinoma . . . . . . 1613Jennifer H. Choe and James L. Abbruzzese

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1643

xviii Contents

About the Editors

Professor John P. Neoptolemos was trained at theUniversity of Cambridge with a double degree in Natu-ral Sciences and Philosophy followed by clinical train-ing at Guy’s Hospital in London. He is Professor ofSurgery at the University of Heidelberg moving fromLiverpool University where he held the Chair of Surgeryfrom 1996 until 2017. As Chairman of ESPAC he suc-cessfully led the ESPAC-1, 3, and 4 trials, the results ofwhich have been adopted as guidelines for the treatmentof potentially curable pancreatic cancer around theworld. As Director, he received the Freedom of theCity of Liverpool in 2011 for the Liverpool CancerResearch UK Centre. In 2007, he established theNIHR Liverpool Pancreas Biomedical Research Unit(Scientific Director), the NIHR and Cancer ResearchUK, Liverpool Experimental Cancer Medicine Centre(Deputy Director), and the Liverpool Clinical Trialsand Cancer Research UK Cancer Trials Units (Director).In 2012, he was made an Honorary Member of theGerman Society of Surgery. In 2013, the Pancreas Unitwon the Acute Services Sector Health Services JournalNational Award. In 2013, he received a LifetimeAchievement Award from the European PancreaticClub at its 45th Meeting in Zurich. In 2014, he wasmade an Honorary Member of the Hungary Society ofSurgery and also an Honorary Professor of NanjingMedical University. He was awarded HirschbergAward for Pancreatic Cancer, American PancreaticAssociation in 2005, and the Ruth Brufsky Award forPancreas Cancer Research in 2017. Presently, he is onthe Medical Advisory Board for Pancreas CancerUK. He was elected Fellow of the Academy of MedicalSciences in 2007 and NIHR Senior Investigator in 2011.

xix

Dr. Raul Urrutia, M.D., was appointed as Director ofthe Genomic Sciences and Precision Medicine Center(GSPMC), the Warren P. Knowles Endowed Chair ofGenomic Sciences and Precision Medicine, and Profes-sor of Surgery at the Medical College of Wisconsin(MCW) from July 1, 2017. He remains Emeritus Pro-fessor at the Mayo Clinic, Rochester, MN, where hepreviously served as Professor in the Departments ofBiochemistry and Molecular Biology, Biophysics andMedicine at the Mayo Clinic College of Medicine inRochester, MN, and Director of Epigenomics Educationand Academic Relationships in the Epigenomics Pro-gram, Mayo Clinic Center for Individualized Medicine.Dr. Urrutia was also consultant for the Division ofGastroenterology and Hepatology, Department of Inter-nal Medicine, and consultant (joint appointment) for theDepartment of Physiology and Biomedical Engineering.

Dr. Urrutia received his M.D. degree from the Uni-versity of Cordoba Medical School in Cordoba, Argen-tina, in 1987. During medical school he undertookresearch in the Cell Biology Institute there, where hepublished studies on diet-induced genomic changes dur-ing the development of pancreatic cancer. From 1987 to1992, Dr. Urrutia held numerous positions at theNational Institutes of Health (NIH), including guestresearcher, visiting fellow, visiting associate, andtenure-track visiting scientist, during which he trainedin the fields of cell biology, molecular biophysics, pro-tein chemistry, and recombinant DNA techniques.

Dr. Urrutia’s career and activities combine interestsand expertise in the areas of genomics, epigenomics,and individualized medicine. Since joining the facultyat the Mayo Clinic College of Medicine in 1992,Dr. Urrutia has served as Director of the GI Unit, Direc-tor of the Ph.D. Program in Tumor Biology, AssociateDirector for Genomics at the Mayo Clinic General Clin-ical Research Center, and Director of the GI CancerResearch Program at the Mayo Cancer Center. Also atMayo, Dr. Urrutia established the first laboratory dedi-cated to epigenetics and chromatin dynamics in normalcell populations and in diseases, such as diabetes andpancreatic cancer. His laboratory has discovereddiabetes-causing genes such as KLF11, for which itsalterations are responsible for juvenile (MODY VII)and neonatal diseases, as well as KLF14 for insulin

xx About the Editors

resistance metabolic syndrome. Dr. Urrutia’s laboratoryhas made fundamental contributions by identifyingmembers and helping to put together the family ofKLF proteins, which are critical regulators of biology,pathobiology, and epigenetic reprogramming. In thearea of chromatin and epigenetics, the Urrutia laboratoryhas discovered new histone deacetylase (HDAC), his-tone acetyltransferase (HAT), and histonemethyltransferase (HMT) epigenetic pathways. Hiswork also led to the discovery of histone-proteins asso-ciated subcodes, which helps to interpret epigenomiccodes. All of these complexes are associated with thedevelopment of cancer, as well as many other diseases,and are currently being explored as an extremely prom-ising area in experimental therapeutics. His work hasbeen continuously funded by the NIH since the early1990s.

Dr. Urrutia has been past Chair for the PancreaticDiseases Section for the American GastroenterologicalAssociation (2005–2006), past President for the Amer-ican Pancreatic Association (2007), and a former mem-ber of the board of the International Association ofPancreatology.

James L. Abbruzzese, M.D., is the Chief of the DukeDivision of Medical Oncology and serves as the Asso-ciate Director for Clinical Research and Training for theDuke Cancer Institute (DCI). Dr. Abbruzzese is a lead-ing expert in the clinical study and treatment of pancre-atic cancer, and his management experience and visionfor clinical research and the division will substantiallysupport cancer care and research at Duke. Before mov-ing to Duke, he held the Waun Ki Hong DistinguishedChair in Translational Oncology, and he was Chairmanof the Department of Gastrointestinal Medical Oncol-ogy and Digestive Diseases at the University of TexasM.D. Anderson Cancer Center in Houston.

He earned his medical degree with honors from theUniversity of Chicago, Pritzker School of Medicine, andcompleted his residency in Internal Medicine at JohnsHopkins Hospital. He also completed clinical fellow-ships in Infectious Diseases at the Johns Hopkins and inMedical Oncology and Medical Oncology ResearchLaboratory of Neoplastic Disease Mechanisms at theDana-Farber Cancer Institute of Harvard Medical

About the Editors xxi

School. Before his recruitment to Duke University hespent most of his professional career at M.D. Anderson,where he progressed through the ranks to assume lead-ership positions as Chairman of the Department of Gas-trointestinal Medical Oncology and Associate Vice-Provost for Clinical Research.

Among his many accomplishments, Dr. Abbruzzeseis a Fellow of the American College of Physicians andFellow of the American Society of Clinical Oncology.He has coauthored more than 400 research publicationsand is the immediate past Chair of the Clinical Trials andTranslational Research Advisory Committee of theNational Cancer Institute. He currently serves as theChair of the NCI Pancreatic Ductal AdenocarcinomaProgress Working Group.

ProfessorMarkusW. Büchler is the Executive Directorand Professor of Surgery at the Department of Surgeryat Heidelberg University. After studying medicine inHeidelberg and Berlin, he started his surgical trainingat the University of Ulm where he became DeputyClinical Director in 1987. In 1993, he became Professorof Surgery and Clinical Director of General Surgery atthe University of Bern, Switzerland. In 2001, hereturned to Germany to start leading the surgical depart-ment in Heidelberg. Today, he additionally heads thesurgical departments at the Salem Hospital in Heidel-berg and at the general hospitals of Sinsheim, Eberbach,and Heppenheim. He is an internationally respectedexpert in the field of oncologic surgery, especially inthe field of pancreatic surgery. Professor Bü ̈chler haspublished more than 2000 scientific papers mainlyfocused on the translational features of GI cancer andpancreatic diseases as well as clinical surgical problems.Among others he has been President of the GermanSurgical Society, the European Pancreas Club, and theInternational Hepato-Pancreato-Biliary Association. Heis a member of the German Academy of SciencesLeopoldina and he is an Honorary Member of the Amer-ican Surgical Association, the American College ofSurgeons, and the Royal Colleges of Surgeons ofEngland and Scotland among many other societies. Pro-fessor Büchler has received multiple scientific awards,and he is a member of the editorial boards of many well-known scientific journals.

xxii About the Editors

Contributors

John D. Abad Feinberg School of Medicine, Northwestern University,Warrenville, IL, USA

James L. Abbruzzese Division of Medical Oncology, Duke Cancer Institute, DukeUniversity Medical Center, Durham, NC, USA

Ethan V. Abel Pancreatic Cancer Center, University of Michigan, Ann Arbor, MI,USA

Department of Translational Oncology Program, University of Michigan, AnnArbor, MI, USA

N. Volkan Adsay Department of Pathology, and Laboratory Medicine, EmoryUniversity School of Medicine and Winship Cancer Institute, Atlanta, GA, USA

Nita Ahuja Department of Surgery, Division of Surgical Oncology, Johns HopkinsHospital, Baltimore, MD, USA

Karen Aughton Molecular and Clinical Cancer Medicine, University of Liverpool,Liverpool, UK

Mahmood Ayub Clinical and Experimental Pharmacology Group, CancerResearch UK Manchester Institute, Manchester, UK

Chad A. Barnes Pancreatic Cancer Program, Department of Surgery, The MedicalCollege of Wisconsin, Milwaukee, WI, USA

Ryan Baron Department of Molecular and Clinical Cancer Medicine, Institute ofTranslational Medicine, University of Liverpool, Liverpool, UK

Lawrence N. Barrera Department of Molecular and Clinical Cancer Medicine,University of Liverpool, Liverpool, UK

Detlef K. Bartsch Klinik für Visceral- Thorax- und Gefäßchirurgie,Universitätsklinikum Gießen und Marburg, Baldingerstraße, Marburg, Germany

Olca Basturk Department of Pathology, Memorial Sloan Kettering Cancer Center,New York, NY, USA

xxiii

Bianca Bethan Metanomics Health, Berlin, Germany

Benjamin Bian Centre de Recherche en Cancérologie de Marseille (CRCM),INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France

Martin Bigonnet Centre de Recherche en Cancérologie de Marseille (CRCM),INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France

Kathleen A. Boyle Pancreatic Cancer Program, Department of Microbiology andImmunology, MCW Cancer Center, Medical College of Wisconsin, Milwaukee,WI, USA

Ged Brady Clinical and Experimental Pharmacology Group, Cancer Research UKManchester Institute, Manchester, UK

Jonathan R. Brody Departments of Surgery and the Jefferson Pancreas, Biliaryand Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, ThomasJefferson University, Philadelphia, PA, USA

Markus W. Büchler Department of General, Visceral and TransplantationSurgery, University of Heidelberg, Heidelberg, Germany

Rebecca Burbridge Division of Gastroenterology, Duke University Medical Cen-ter, Durham, NC, USA

Richard A. Burkhart Department of Surgery, Division of Hepatobiliary andPancreatic Surgery, Johns Hopkins Hospital, Baltimore, MD, USA

Fiona Campbell Royal Liverpool University Hospital, Liverpool, UK

Gabriele Capurso Digestive and Liver Disease Unit, II Medical School,“Sapienza,” University of Rome, S. Andrea Hospital, Rome, Italy

Ian Chau Department of Medicine, The Royal Marsden NHS Foundation Trust,London and Surrey, UK

Jennifer H. Choe Division of Medical Oncology, Duke Cancer Institute, DukeUniversity Medical Center, Durham, NC, USA

Woonyoung Choi Department of Urology, University of Texas, M.D. AndersonCancer Center, Houston, TX, USA

Ondine Cleaver Department of Molecular Biology, The University of TexasSouthwestern Medical Center, Dallas, TX, USA

Eithne Costello Department of Molecular and Clinical Cancer Medicine, Univer-sity of Liverpool, Liverpool, UK

xxiv Contributors

David Cunningham Department of Medicine, The Royal Marsden NHS Founda-tion Trust, London and Surrey, UK

Brian Czito Department of Radiation Oncology, Duke University, Durham, NC,USA

Gianfranco Delle Fave Digestive and Liver Disease Unit, II Medical School,“Sapienza,” University of Rome, S. Andrea Hospital, Rome, Italy

Rony Dev Symptom Control and Palliative Medicine, University of Texas MDAnderson Cancer Center, Houston, TX, USA

Caroline Dive Clinical and Experimental Pharmacology Group, Cancer ResearchUK Manchester Institute, Manchester, UK

Katerina Dukleska Departments of Surgery and the Jefferson Pancreas, Biliaryand Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, ThomasJefferson University, Philadelphia, PA, USA

Declan F. J. Dunne Department of Surgery, The Royal Liverpool and BroadgreenUniversity Hospitals NHS Trust, Liverpool, UK

Nelson Dusetti Centre de Recherche en Cancérologie de Marseille (CRCM),INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France

Michael B. Dwinell Pancreatic Cancer Program, Department of Microbiology andImmunology, MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI,USA

Pancreatic Cancer Program, Department of Surgery, MCW Cancer Center, MedicalCollege of Wisconsin, Milwaukee, WI, USA

Ahmed M. Elamir Clinical Oncology Department, Faculty of Medicine, CairoUniversity, Cairo, Egypt

Nils Elander Department of Oncology, Linköping University Hospital, Linköping,Sweden

Beth A. Erickson Pancreatic Cancer Program, Radiation Oncology, The MedicalCollege of Wisconsin, Milwaukee, WI, USA

Irene Esposito Institute of Pathology, Heinrich Heine University of Duesseldorf,Duesseldorf, Germany

Douglas B. Evans Pancreatic Cancer Program, Department of Surgery, MCWCancer Center, Medical College of Wisconsin, Milwaukee, WI, USA

Volker Fendrich Department of Surgery, University Hospital Marburg and Gies-sen, Marburg, Germany

Laureano Fernández-Cruz Universitat de Barcelona, Barcelona, Spain

Contributors xxv

Martin E. Fernandez-Zapico Schulze Center for Novel Therapeutics, MayoClinic, Rochester, MN, USA

Cristina R. Ferrone Department of Surgery, Massachusetts General Hospital,Harvard Medical School, Boston, MA, USA

Stefano Festa Digestive and Liver Disease Unit, II Medical School, “Sapienza,”University of Rome, S. Andrea Hospital, Rome, Italy

Judith V. Forner Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester,MN, USA

Cancer Research Programme, Hospital del Mar Medical Research Institute (IMIM),Barcelona, Spain

Helmut Friess Department of Surgery, Klinikum rechts der Isar, Technical Univer-sity of Munich, Munich, Germany

Michael C. Garofalo Department of Radiation Oncology, University of MarylandSchool of Medicine, Baltimore, MD, USA

Konstantinos L. Georgiadis Clinical and Experimental Pharmacology Group,Cancer Research UK Manchester Institute, Manchester, UK

Systems Oncology Group, Cancer Research UK Manchester Institute,Manchester, UK

Paula Ghaneh Department of Surgery, The Royal Liverpool and BroadgreenUniversity Hospitals NHS Trust, Liverpool, UK

Department of Molecular and Clinical Cancer Medicine, Institute of TranslationalMedicine, University of Liverpool, Liverpool, UK

Timothy Gilbert Department of Molecular and Clinical Cancer Medicine, Instituteof Translational Medicine, University of Liverpool, Liverpool, UK

Ferga C. Gleeson Division of Gastroenterology and Hepatology, Mayo ClinicCollege of Medicine, Rochester, MN, USA

Michael Goggins Department of Pathology, The Sol Goldman Pancreatic CancerResearch Center, Johns Hopkins University School of Medicine, Baltimore, MD,USA

Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center,Johns Hopkins University School of Medicine, Baltimore, MD, USA

Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center,Johns Hopkins University School of Medicine, Baltimore, MD, USA

Mackenzie Goodwin Pancreatic Cancer Center, University of Michigan, AnnArbor, MI, USA

Department of Translational Oncology Program, University of Michigan, AnnArbor, MI, USA

xxvi Contributors

William Greenhalf Department of Molecular and Clinical Cancer Medicine, Insti-tute of Translational Medicine, University of Liverpool, Liverpool, UK

Thomas Mathias Gress Department of Gastroenterology, Endocrinology, Metab-olism and Infectiology, Philipps University Marburg, Marburg, Germany

Tobias Grote Department of Gastroenterology, Endocrinology, Metabolism andInfectiology, Philipps University Marburg, Marburg, Germany

Thilo Hackert Department of General, Visceral and Transplantation Surgery, Hei-delberg University Hospital, Heidelberg, Germany

Lena Haeberle Institute of Pathology, Heinrich Heine University of Duesseldorf,Duesseldorf, Germany

William A. Hall Pancreatic Cancer Program, Radiation Oncology, The MedicalCollege of Wisconsin, Milwaukee, WI, USA

Christopher Halloran Department of Molecular and Clinical Cancer Medicine,Institute of Translational Medicine, University of Liverpool, Liverpool, UK

Priya R. Healey Royal Liverpool and Broadgreen University Hospital Trust,Liverpool, UK

Stephan Herzig Institute for Diabetes and Cancer, Helmholtz Center Munich,Neuherberg, Germany

Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, HeidelbergUniversity Hospital, Heidelberg, Germany

Tara L. Hogenson Schulze Center for Novel Therapeutics, Mayo Clinic, Roches-ter, MN, USA

Julian Hong Department of Radiation Oncology, Duke University, Durham, NC,USA

Juan Iovanna Centre de Recherche en Cancérologie de Marseille (CRCM),INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France

Shuji Isaji Hepatobiliary Pancreatic and Transplant Surgery, Mie UniversitySchool of Medicine, Tsu, Mie, Japan

Elizabeth M. Jaffee The Sidney Kimmel Cancer Center, Johns Hopkins UniversitySchool of Medicine, Baltimore, MD, USA

Michael A. James Pancreatic Cancer Program, Department of Surgery, MCWCancer Center, Medical College of Wisconsin, Milwaukee, WI, USA

Milind Javle Gastrointestinal Medical Oncology, University of Texas MD Ander-son Cancer Center, Houston, TX, USA

Contributors xxvii

Claus Jorgensen Systems Oncology Group, Cancer Research UK ManchesterInstitute, Manchester, UK

Adeel Kaiser Department of Radiation Oncology, University of Maryland Schoolof Medicine, Baltimore, MD, USA

Beate Kamlage Metanomics Health, Berlin, Germany

Masashi Kishiwada Hepatobiliary Pancreatic and Transplant Surgery, Mie Uni-versity School of Medicine, Tsu, Mie, Japan

Jörg Kleeff Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

Alison P. Klein The Johns Hopkins University School of Medicine, Baltimore,MD, USA

Yusuke Kojima Department of Oncology, Department of Molecular Pharmacologyand Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

Murray Korc Departments of Medicine, Biochemistry and Molecular Biology,Indiana University School of Medicine, the Melvin and Bren Simon Cancer Centerand the Pancreatic Cancer Signature Center, Indianapolis, IN, USA

Richard F. Lamb School of Health Sciences, Liverpool Hope University, HopePark Campus, Liverpool, UK

Peter Langer Klinikum Hanau Klinik für Allgemein-, Visceral- undThoraxchirurgie, Hanau, Germany

Markus M. Lerch Klinik für Innere Medizin A, Universitaetsmedizin der Ernst-Moritz-Arndt-Universitaet Greifswald, Greifswald, Germany

Michael J. Levy Division of Gastroenterology and Hepatology, Mayo ClinicCollege of Medicine, Rochester, MN, USA

Heather A. Lillemoe Vanderbilt University Medical Center, Nashville, TN, USA

Keith D. Lillemoe Massachusetts General Hospital, Harvard Medical School,Boston, MA, USA

Bing Liu Department of General, Visceral and Transplantation Surgery, HeidelbergUniversity Hospital, Heidelberg, Germany

Gwen Lomberk Division of Research, Department of Surgery, Medical College ofWisconsin, Milwaukee, WI, USA

Albert Lowenfels Department of Surgery and Department of Community andPreventive Medicine, New York Medical College, Valhalla, NY, USA

Raymond J. MacDonald Department of Molecular Biology, The University ofTexas Southwestern Medical Center, Dallas, TX, USA

xxviii Contributors

Anne Macgregor-Das Department of Pathology, The Sol Goldman PancreaticCancer Research Center, Johns Hopkins University School of Medicine, Baltimore,MD, USA

Yuichi J. Machida Department of Oncology, Department of Molecular Pharma-cology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

Patrick Maisonneuve Division of Epidemiology and Biostatistics, European Insti-tute of Oncology, Milan, Italy

Anirban Maitra Departments of Pathology and Translational Molecular Pathol-ogy, Sheikh Ahmed Pancreatic Cancer Research Center, University of Texas MDAnderson Cancer Center, Houston, TX, USA

Jerena Manoharan Klinik für Visceral- Thorax- und Gefäßchirurgie,Universitätsklinikum Gießen und Marburg, Baldingerstraße, Marburg, Germany

Paola Martinelli Cancer Progression and Metastasis Group, Institute for CancerResearch, Medical University Wien, Vienna, Austria

Reeja S. Maskey Department of Oncology, Department of Molecular Pharmacol-ogy and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

Julia Mayerle Klinik für Innere Medizin A, Universitaetsmedizin der Ernst-Moritz-Arndt-Universitaet Greifswald, Greifswald, Germany

Medizinische Klinik II, Klinikum der Universitaet Muenchen-Großhadern,Muenchen, Germany

David J. McConkey Johns Hopkins Greenberg Bladder Cancer Institute, Balti-more, MD, USA

Department of Urology, Brady Urological Institute, Johns Hopkins Medical Institu-tions, Baltimore, MD, USA

Samantha Deitz McElyea Department of Medicine, Indiana University Melvinand Bren Simon Cancer Center, Indianapolis, IN, USA

Alyson McGhan Division of Gastroenterology, Duke University Medical Center,Durham, NC, USA

Peter McGranaghan Metanomics Health, Berlin, Germany

Elettra Merola Universitätsklinikum Erlangen, Erlangen, Germany

Christoph W. Michalski Department of General, Visceral and TransplantationSurgery, Heidelberg University Hospital, Heidelberg, Germany

Theodoros Michelakos Department of Surgery, Massachusetts General Hospital,Harvard Medical School, Boston, MA, USA

Koji Miyabayashi Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

Contributors xxix

Yasuhiro Murata Hepatobiliary Pancreatic and Transplant Surgery, Mie Univer-sity School of Medicine, Tsu, Mie, Japan

L. Charles Murtaugh Department of Human Genetics, University of Utah, SaltLake City, UT, USA

Pilar Navarro Cancer Research Programme, Hospital del Mar Medical ResearchInstitute (IMIM), Barcelona, Spain

John P. Neoptolemos Department of General, Visceral and Transplantation Sur-gery, University of Heidelberg, Heidelberg, Germany

James Nicholson Molecular and Clinical Cancer Medicine, University of Liver-pool, Liverpool, UK

Willem Niesen Department of General, Visceral and Transplantation Surgery,Heidelberg University Hospital, Heidelberg, Germany

Yuji Nimura Division of Surgical Oncology, Department of Surgery, GraduateSchool of Medicine, Nagoya University, Nagoya, Aichi, Japan

Department of Digestive Surgery, Aichi Cancer Center Kanokoden, Nagoya, Japan

Takao Ohtsuka Department of Surgery and Oncology, Graduate School of Med-ical Sciences, Kyushu University, Fukuoka, Japan

Alicia Okines Department of Medicine, The Royal Marsden NHS FoundationTrust, London and Surrey, UK

Lucy Oldfield Department of Molecular and Clinical Cancer Medicine, Universityof Liverpool, Liverpool, UK

Rachel L. O. Olson Schulze Center for Novel Therapeutics, Mayo Clinic, Roch-ester, MN, USA

Center for Learning Innovation, University of Minnesota Rochester,Rochester, MN, USA

Manisha Palta Department of Radiation Oncology, Duke University, Durham, NC,USA

Naimish Pandya Department of Radiation Oncology, University of MarylandSchool of Medicine, Baltimore, MD, USA

Pedro A. Pérez-Mancera Department of Molecular and Clinical Cancer Medicine,University of Liverpool, Liverpool, UK

Matteo Piciucchi Digestive and Liver Disease Unit, II Medical School,“Sapienza,” University of Rome, S. Andrea Hospital, Rome, Italy

Michael J. Pishvaian Division of Hematology and Oncology, Lombardi Compre-hensive Cancer Center, Georgetown University, Washington, DC, USA

xxx Contributors

Ioannis Poursaitidis Department of Molecular and Clinical Cancer Medicine,Institute of Translational Medicine, University of Liverpool, Liverpool, UK

Vinee Purohit Pancreatic Cancer Center, University of Michigan, Ann Arbor, MI,USA

Department of Translational Oncology Program, University of Michigan, AnnArbor, MI, USA

Rohith Rao Department of Molecular and Clinical Cancer Medicine, University ofLiverpool, Liverpool, UK

Gihan Ratnayake Department of Medicine, The Royal Marsden NHS FoundationTrust, London and Surrey, UK

Francisco X. Real Epithelial Carcinogenesis Group, Spanish National CancerResearch Centre, CNIO, Madrid, Spain

Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra,Barcelona, Spain

CIBERONC, Madrid, Spain

William F. Regine Department of Radiation Oncology, University of MarylandSchool of Medicine, Baltimore, MD, USA

Michelle D. Reid Department of Pathology, and Laboratory Medicine, EmoryUniversity School of Medicine and Winship Cancer Institute, Atlanta, GA, USA

Ulrike Rennefahrt Metanomics Health, Berlin, Germany

Regina Reszka Metanomics Health, Berlin, Germany

Götz M. Richter Clinic for Diagnostic and Interventional Radiology, KlinikumStuttgart, Stuttgart, Germany

Jasmin Riemer Institute of Pathology, Heinrich Heine University of Duesseldorf,Duesseldorf, Germany

Nicholas J. Roberts The Sol Goldman Pancreatic Cancer Research Center, Depart-ment of Pathology, The Johns Hopkins University School of Medicine, Baltimore,MD, USA

Santiago Sánchez Cabús Department of HPB Surgery and Transplantation,ICMDiM, Hospital Clínic de Barcelona, Barcelona, Spain

Universitat de Barcelona, Barcelona, Spain

Ioannis Sarantitis Molecular and Clinical Cancer Medicine, University of Liver-pool, Liverpool, UK

Philipp Schatz Metanomics Health, Berlin, Germany

Florian Scheufele Department of Surgery, Klinikum rechts der Isar, TechnicalUniversity of Munich, Munich, Germany

Contributors xxxi

Francesco Sclafani Department of Medicine, The Royal Marsden NHS Founda-tion Trust, London and Surrey, UK

Anup R. Sharma Department of Surgery, Johns Hopkins University, Baltimore,MD, USA

Andrea Sheel Molecular and Clinical Cancer Medicine, University of Liverpool,Liverpool, UK

Diane M. Simeone The Department of Surgery, NYU Langone Medical Center,New York, USA

Department of Pathology, NYU Langone Medical Center, New York, USA

Perlmutter Cancer Center, NYU Langone Medical Center, New York, USA

Kathryn Simpson Clinical and Experimental Pharmacology Group, CancerResearch UK Manchester Institute, Manchester, UK

Aatur D. Singhi Department of Pathology, University of Pittsburgh Medical Cen-ter, Pittsburgh, PA, USA

Daphna Spiegel Department of Radiation Oncology, Duke University, Durham,NC, USA

Oliver Strobel Department of General, Visceral and Transplantation Surgery, Hei-delberg University Hospital, Heidelberg, Germany

Masao Tanaka Shimonoseki City Hospital, Shimonoseki, Japan

C. Tjaden Department of General, Visceral and Transplantation Surgery, Heidel-berg University Hospital, Heidelberg, Germany

Susan Tsai Pancreatic Cancer Program, Department of Surgery, MCW CancerCenter, Medical College of Wisconsin, Milwaukee, WI, USA

David A. Tuveson Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

Raul Urrutia Division of Research, Department of Surgery and Genomic Sciencesand Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwau-kee, WI, USA

Roberto Valente Digestive and Liver Disease Unit, II Medical School, “Sapienza,”University of Rome, S. Andrea Hospital, Rome, Italy

Juan Valle Institute of Cancer Sciences, University of Manchester, Manchester,UK

Gauri R. Varadhachary Department of Gastrointestinal Medical Oncology, Uni-versity of Texas, M.D. Anderson Cancer Center, Houston, TX, USA

Caroline Sophie Verbeke Oslo University Hospital, Oslo, Norway

Jens Waldmann Klinik für Visceral- Thorax- und Gefäßchirurgie,Universitätsklinikum Gießen und Marburg, Baldingerstraße, Marburg, Germany

xxxii Contributors

J. Weitz Department of Visceral, Thoracic and Vascular Surgery, University Hos-pital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

T. Welsch Department of Visceral, Thoracic and Vascular Surgery, UniversityHospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Jens Werner Department of Surgery, University Hospital, Ludwig-Maximilians-University, Munich, Germany

Christopher Willett Department of Radiation Oncology, Duke University, Dur-ham, NC, USA

Monique Williams Laboratory of Epigenetics and Chromatin Dynamics, Gastro-enterology Research Unit, Division of Gastroenterology and Hepatology, Depart-ment of Medicine, Mayo Clinic, Rochester, MN, USA

Robert A. Wolff Department of GI Medical Oncology, Division of Cancer Medi-cine, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA

Charles J. Yeo Departments of Surgery and the Jefferson Pancreas, Biliary andRelated Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, ThomasJefferson University, Philadelphia, PA, USA

Vincent S. Yip Department of Surgery, The Royal Liverpool and BroadgreenUniversity Hospitals NHS Trust, Liverpool, UK

Yukihiro Yokoyama Division of Surgical Oncology, Department of Surgery, Grad-uate School of Medicine, Nagoya University, Nagoya, Aichi, Japan

Kenneth H. Yu Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center andWeill Cornell Medical College, New York, NY, USA

Lei Zheng The Sidney Kimmel Cancer Center, Johns Hopkins University Schoolof Medicine, Baltimore, MD, USA

Contributors xxxiii