Pancreatic Cancer

Cover......Page 1
Foreword......Page 6
Preface......Page 8
Acknowledgements......Page 10
Table of Contents......Page 12
About the Editors......Page 18
List of Contributors......Page 22
Section 1: The Nature of Pancreatic Cancer......Page 30
1 Epidemiology and Prospects for Prevention of Pancreatic Cancer......Page 32
1 Epidemiology......Page 33
2.2 Hereditary Risk Factors......Page 34
2.3 Cigarette Smoking......Page 36
2.4 Obesity......Page 37
2.5 Diabetes Mellitus......Page 38
3.1 Alcohol......Page 39
3.2 Pancreatitis......Page 40
4.1 Meat......Page 41
4.3 Flavonoinds, Folate, Lycopene......Page 42
5.1 Infectious Agents......Page 43
5.2 Occupation......Page 44
5.4 Non-Steroidal Anti-Inflammatory Drugs......Page 45
Key Research Points......Page 46
References......Page 47
2 Development and Structure of the Pancreas......Page 56
1 Signals Toward the Pancreas Development......Page 57
2 Microscopic Structure and Functional Activity of the Pancreas......Page 60
2.1 Endocrine Pancreas......Page 61
2.2.1 Acini......Page 62
2.5 Concluding Remarks......Page 65
Clinical Implications......Page 66
References......Page 67
3 Pathologic Classification and Biological Behavior of Pancreatic Neoplasia......Page 68
1 Introduction......Page 69
2.1 Ductal Neoplasia......Page 70
2.1.1 Invasive Ductal Carcinoma......Page 72
2.1.2 Other Invasive Carcinomas of Ductal Lineage......Page 76
Undifferentiated Carcinoma with Osteoclast-Like Giant Cells......Page 77
Colloid Carcinoma (PureMucinous or Mucinous Non-Cystic Carcinoma)......Page 78
Pancreatic Intraepithelial Neoplasia......Page 79
Mass-Forming Preinvasive Neoplasia......Page 80
Intraductal Papillary Mucinous Neoplasms......Page 81
Mucinous Cystic Neoplasms......Page 83
2.2 Endocrine Neoplasia......Page 84
2.2.1 Pancreatic Endocrine Neoplasm......Page 85
2.3.1 Acinar Cell Carcinoma......Page 87
2.4 Neoplasms with Multiple Lineages (Pancreatoblastoma and Mixed Acinar-Endocrine Carcinoma)......Page 88
2.5.1 Solid Pseudopapillary Neoplasm......Page 90
2.7 Mesenchymal Tumors......Page 91
2.9 Secondary Tumors......Page 92
Key Practice Points......Page 93
Clinical Implications......Page 94
References......Page 95
4 Developmental Molecular Biology of the Pancreas......Page 100
1 Overview of Pancreatic Development......Page 101
2 Overview of Extrinsic and Intrinsic Developmental Factors......Page 104
Box 1 Extrinsic Developmental Factors (EFs): Cell-Cell Signaling Molecules......Page 105
2.1 Extrinsic Factors: Cell-Cell Signals......Page 106
2.2 Intrinsic Factors: DNA-Binding Transcription Factors......Page 110
3.1.1 Early Endoderm and Gut Tube Formation......Page 112
3.1.2 Anteroposterior Patterning of the Endoderm......Page 113
3.1.3 Dorsoventral Patterning of the Prepancreatic Endoderm......Page 114
3.1.4 Initiation of Pancreatic Budding......Page 115
3.2.1 Growth and Elaboration of Pancreatic Buds......Page 117
3.2.3.1 First Wave Endocrine Cells – Glucagon Cells Bud from the Epithelium......Page 118
3.2.5 Epithelial-Mesenchymal Crosstalk: Control of the‘‘Protodifferentiated’’ state......Page 120
3.3.1 The Secondary Transition......Page 123
3.3.1.1 Formation of Acini from the Multipotent Precursor Cells (MPCs)......Page 126
3.3.2 Ductal Development......Page 129
3.3.3 The Second Wave of Endocrine Cells – Formation of Primitive Islets......Page 130
3.3.3.1 Formation of Islet Precursor Cells by Delamination......Page 132
3.3.4 Comparison of First and Second Waves of Endocrine Cells......Page 134
3.4 Perinatal Growth and Differentiation (16 dpc to Neonate)......Page 135
4 End Note......Page 136
Key Research Points......Page 137
References......Page 138
5 Molecular Pathology of Precursor Lesions of Pancreatic Cancer......Page 148
2.1 Clinical and Histopathological Features of PanINs......Page 149
2.2 Molecular Genetics of PanINs......Page 150
2.2.1 Oncogene Mutations in PanIN Lesions......Page 151
2.2.2 Tumor Suppressor Gene Mutations in PanIN Lesions......Page 153
2.2.3 Caretaker Gene Mutations in PanIN Lesions......Page 154
2.2.5 Epigenetic Alterations in PanIN Lesions......Page 155
2.2.7 Cell Cycle and Proliferation Abnormalities in PanIN Lesions......Page 156
2.2.9 Aberrantly Activated Embryonic Signaling Pathwaysin PanIN Lesions......Page 157
2.2.10 Genetically Engineered Mouse Models and Murine PanINs(mPanINs)......Page 158
3.1 Clinical Features of IPMNs......Page 159
3.2 Histopathological Features of IPMNs......Page 160
3.4 Genetically Engineered Mouse Model of IPMNs......Page 161
4.1 Clinical Features of MCNs......Page 162
4.3 Molecular Genetics of MCNs......Page 163
4.5 Therapeutic Implications of MCNs......Page 164
Clinical Implications......Page 165
References......Page 166
6 Epigenetics and its Applications to a Revised Progression Model of Pancreatic Cancer......Page 172
2 Basic Concepts in Epigenetics......Page 173
3.2 The RNA Pol II Components and the General Transcription Factors......Page 174
3.4 The Promoter-Bashing Paradigm, Cis-Regulatory Sequences, and Sequence-Specific Transcription Factors......Page 175
3.5 The Coactivator-Corepressor Hypothesis......Page 176
3.6 Chromatin Dynamics Forms the Basis of Epigenetics......Page 177
3.6.2 Nucleosome Remodeling Machines......Page 179
3.6.3 Histone Chaperones......Page 180
3.7 Nuclear Shape and Nuclear Domains......Page 181
4 Epigenetics:Developing a Novel and Comprehensive Genomic-Epigenomic Model for Pancreatic Cancer that Includes Chromatin Dynamics and Nuclear Shape......Page 183
4.1 DNA Methylation......Page 185
4.2 Histone Acetylation and Deacetylation......Page 186
4.3 Histone H3-Methyl-K27 and Polycomb......Page 187
4.4 Histone H3-Methyl-K9 and Heterochromatin Protein 1......Page 188
4.6 MicroRNAs and Pancreatic Cancer......Page 189
5 Epigenetics, Chemoprevention and Chemotherapies......Page 190
6 Concluding Remarks......Page 192
Clinical Implications......Page 193
References......Page 194
7 Molecular Pathology of Pancreatic Endocrine Tumors......Page 200
2 Inherited Pancreatic Endocrine Tumors......Page 201
2.1 Multiple Endocrine Neoplasia Type I (MEN-I)......Page 202
2.2 Von Hippel-Lindau Disease (VHL)......Page 204
2.4 Tuberous Sclerosis Complex (TSC)......Page 205
3.1 Genome Wide Studies in Sporadic PETs......Page 206
3.2 Prognostic Relevance......Page 207
4.1 Oncogenes......Page 214
4.2 Tumor Suppressor Genes......Page 215
4.3 Growth Factors and Their Receptors (Receptor Tyrosine Kinases)......Page 216
5 Microarray Studies......Page 217
Clinical Implications......Page 220
References......Page 221
8 Sporadic Pancreatic Endocrine Tumors......Page 228
1 Introduction......Page 230
1.3 Pathological Features......Page 231
1.4 Natural History......Page 232
2.2 Differential Diagnosis......Page 233
2.3.2 Imaging......Page 234
2.4.1 Benign Insulinoma......Page 236
2.4.2 Malignant Insulinoma......Page 238
3.1 Clinical Symptoms......Page 240
3.3.1 Biochemical Testing......Page 241
3.3.2 Imaging......Page 242
3.4.1 Duodenal Gastrinomas......Page 243
3.4.2 Pancreatic Gastrinomas......Page 244
4.1 Clinical Symptoms......Page 245
5.1 Clinical Symptoms......Page 246
5.4 Prognosis......Page 247
6.4 Prognosis......Page 248
7.3.2 Imaging......Page 249
7.4 Treatment......Page 250
8.1.1 Liver Resection......Page 251
8.1.2 Liver Transplantation......Page 252
8.1.4 Embolization/Chemoembolization......Page 253
8.1.5 Peptide-receptor Radionuclide Therapy......Page 254
8.3 Chemotherapy......Page 256
Future Research Directions......Page 257
References......Page 258
9 Molecular Pathology of Ampullary, Intra-Pancreatic Bile Duct and Duodenal Cancers......Page 262
1 Introduction......Page 264
2.1.2 Prognosis......Page 266
2.1.5 Correlation Between Molecular Markers and HistologicalMorphology......Page 267
2.1.7 Cytogenetic Alterations......Page 269
2.1.8 Prognostic Markers......Page 270
2.1.10 Molecular Markers Characterising the Adenoma-CarcinomaSequence......Page 271
2.2.1 Epidemiology......Page 272
2.2.4 Molecular Alterations......Page 273
2.3.1 Epidemiology......Page 274
2.3.3 Molecular Alterations......Page 275
3.1.2 Prognosis......Page 276
4 Outlook......Page 277
Future Scientific Directions......Page 278
References......Page 279
10 Miscellaneous Non- Pancreatic Non- Endocrine Tumors......Page 284
2.1 Ampullary Neoplasms......Page 286
2.1.1 Benign Ampullary Tumors......Page 287
2.1.2 Malignant Ampullary Tumors......Page 288
2.2.1 Benign Distal Bile Duct Tumors......Page 290
2.2.2 Malignant Distal Bile Duct Tumors......Page 291
2.3.1 Benign Duodenal Tumors......Page 292
2.4.1 Mesenchymal Neoplasms......Page 293
3 Clinical Presentation......Page 294
4.2.1 Ultrasonography......Page 295
4.2.2 Computed Tomography......Page 296
4.2.4 Endoscopy/Endoscopic Ultrasound......Page 297
4.2.5 Endoscopic Retrograde Cholangiopancreatography......Page 299
4.2.6 Percutaneous Transhepatic Cholangiography......Page 300
4.3 Preoperative Staging......Page 301
5.2 Local Excision......Page 302
5.3 Pancreaticoduodenectomy......Page 304
6 Adjuvant and Neoadjuvant Therapy......Page 305
7 Survival......Page 306
Future Research Directions......Page 309
References......Page 310
11 Molecular Relationships Between Chronic Pancreatitis and Cancer......Page 314
2 Defining CP and PDAC......Page 316
3.2 CP is a Risk Factor for PDAC......Page 317
3.3 Both CP and PDAC Possess Preneoplastic Lesions......Page 319
3.4 CP and PDAC Share Genetic Alterations......Page 320
3.5 CP and PDAC Have Similar Patterns of Gene Expression......Page 321
3.6.3 Mouse Models Involving K-Ras Mutations......Page 323
4 Pancreatic Stellate Cells Link Pancreatitis and Pancreatic Carcinoma......Page 324
4.1 Identification of Pancreatic Stellate Cells in CP......Page 325
4.2 PSCs are Present in PDAC and Interact with Cancer Cells......Page 326
4.3 Pancreatic Cancer Cells Influence PSCs......Page 327
4.4 PSCs Influence Pancreatic Cancer Cells......Page 328
4.5 PSCs Contribute to Chemo- and Radiation- Resistance......Page 329
5.2 K-Ras Activity may be a Common Cause of Inflammation in CP and PDAC......Page 330
5.3 Modeling the Relationship Between CP and PDAC......Page 331
6.1 Targeting Stroma as a Therapy for Pancreatic Cancer......Page 333
6.3 Targeting Stroma as a Chemoprevention Strategy......Page 334
7.3 Influence of PSC on Immune Responses......Page 335
References......Page 336
12 Pancreatic Cancer Stem Cells......Page 346
1 Introduction......Page 347
2 Pancreatic Cancer and Cancer Stem Cells......Page 349
3 Origin of Cancer Stem Cells......Page 352
4 Developmental Signaling Pathways......Page 354
6 Cancer Stem Cells are Resistant to Standard Therapies......Page 355
Key Research Points......Page 357
References......Page 358
13 Cell Cycle Control in Pancreatic Cancer Pathogenesis......Page 362
1 The Cell Cycle......Page 364
1.1.1 G1......Page 365
1.1.2 S......Page 366
1.1.4 M......Page 368
1.2.1 Cell Cycle Regulatory Proteins......Page 370
1.2.2 D-Type Cyclins......Page 371
1.2.6 Regulation of Cdks......Page 372
1.2.7 Cdk Inhibitors......Page 373
1.2.8 Regulating the Regulators: Transcription......Page 374
1.2.9 Regulating the Regulators: Proteolytic Degradation......Page 375
1.2.10 Other Regulators......Page 376
1.3 Cell Cycle Checkpoints......Page 377
1.4 The DNA Damage Response......Page 378
2.1 Self-Sufficiency in Growth Signals......Page 380
2.2 Insensitivity to Anti-Growth Signals......Page 381
2.4 Reduced Apoptosis......Page 382
2.6 Consequences of Aberrant Cell Cycle Progression......Page 383
3 The Cell Cycle and Pancreatic Cancer......Page 385
3.1 KRAS......Page 386
3.2 MYC......Page 387
3.4 TP53......Page 388
3.5 TGF-beta Signaling......Page 389
3.6 MicroRNAs......Page 390
3.9 Targeting the Cell Cycle During Therapy......Page 391
Key Research Points......Page 392
Acknowledgments......Page 393
References......Page 394
14 Apoptosis Signaling Pathways in Pancreatic Cancer Pathogenesis......Page 398
2 Role of Apoptosis in the Outcome of Cancer Therapy......Page 399
3 Molecular Control of Apoptosis......Page 401
4 Expression of Canonical Apoptosis Regulators in Pancreatic Cancer......Page 402
5 Effects of the Major Genetic Alterations Observed in Pancreatic Cancer on Apoptosis......Page 403
6 Role of NFkappaB Activation......Page 405
7 Role of EMT......Page 406
9 Role of Wnt......Page 407
12 Summary and Conclusions......Page 408
Clinical Implications......Page 409
References......Page 410
15 EGFR Signaling Pathways in Pancreatic Cancer Pathogenesis......Page 416
2 EGF Ligands......Page 417
4 Post-receptor EGF Signaling......Page 419
5 Signaling Via the Canonical EGF-RAS-ERK Pathway......Page 422
6 EGF Signaling Via Other Important, Non-canonical Intracellular Pathways......Page 423
7 Anti-Erb-Mediated Therapy for Pancreatic Cancer......Page 426
8 Erb-Mediated Molecular Imaging Modalities......Page 427
Key Research Points......Page 428
Acknowledgments......Page 429
References......Page 430
16 Hedgehog Signaling Pathways in Pancreatic Cancer Pathogenesis......Page 432
1.1 The Hedgehog Signaling Pathway......Page 433
1.2 The Hedgehog Signaling Pathway in Cancer......Page 434
1.3 Different Modalities of Hedgehog Signaling Activation......Page 435
1.4 Pancreatic Adenocarcinoma......Page 437
1.5 Hedgehog Signaling in Pancreatic Adenocarcinoma......Page 438
1.6 Hedgehog Signaling in Tumor Stroma......Page 440
1.7 Hedgehog Signaling and Pancreatic Regeneration......Page 441
1.9 Hedgehog Signaling in Other Pancreatic Lesions and Tumors......Page 442
3 Clinical Implications......Page 443
Future Scientific Directions......Page 444
References......Page 445
17 Smad4/TGF-beta Signaling Pathways in Pancreatic Cancer Pathogenesis......Page 448
1.3 Overview of Molecular Alterations in PDAC......Page 449
2.2 TGF-beta Receptors......Page 450
2.3 Smad Proteins......Page 451
2.5 Consequences of Normal TGF-beta Signaling......Page 453
2.6 TGF-beta in Normal Development......Page 454
2.8 Smad-Independent Pathways of TGF-beta......Page 455
3.1 Noted Alterations......Page 456
3.2 Smad4 and Pancreatic Cancer......Page 457
3.3 TGF-beta and Acute Pancreatitis......Page 458
4.1 Overview......Page 459
4.3 TGF-beta in the Clinic......Page 460
4.4 The Future of TGF-beta......Page 461
References......Page 462
18 Notch Signaling in Pancreatic Morphogenesis and Pancreatic Cancer Pathogenesis......Page 470
1 Introduction......Page 471
2 Notch Receptor......Page 472
3 Notch Ligand......Page 474
4 Crosstalk with Other Signaling Cascades......Page 475
6 Notch-VEGF Interactions......Page 476
7 The Notch-Hes Pathway in Pancreatic Morphogenesis......Page 477
8 Notch and Pancreatic Cancer......Page 478
9 Pharmacological and Genetic Manipulation of the Notch Pathway......Page 479
10 Concluding Remarks......Page 480
Clinical Implications......Page 481
References......Page 482
19 Molecular Characterization of Pancreatic Cancer Cell Lines......Page 486
1 Introduction: Preclinical Models of Pancreatic Cancer......Page 487
2.1 "Cell Lines Are Genetically Scrambled"......Page 488
2.2 "The Effects of Drugs on Cancer Cells in Tissue Culture Cannot Predict their Activities in Patients"......Page 489
2.3 "Effects of Drugs in Two Dimensional Growth Conditions Have No Relationship to Their Effects in 3D and/or In Vivo"......Page 490
3 Heterogeneity in Human Pancreatic Cancer Cell Lines......Page 491
4 Characteristics of Orthotopic Xenografts Derived from Established Cell Lines......Page 493
Summary and Concluding Remarks......Page 495
Clinical Implications......Page 496
References......Page 497
20 Mouse Models of Pancreatic Exocrine Cancer......Page 500
2 The Origins of Human PDA......Page 501
3.1 Hamsters......Page 502
3.3 Mice......Page 505
4 Transplanted, Chemically-Induced Tumors......Page 506
5 Immunodeficient Models......Page 507
6.1 Early Transgenic Models......Page 508
7 Pancreatic Development......Page 510
8.1 The Cre-Lox System......Page 511
8.3 Activated KRAS and Ink4a/Arf Deficiency......Page 512
8.4 Activated KRAS and the p53 Pathway......Page 513
8.5 The Role of Inflammation......Page 515
8.6 Cystic Neoplasms: Activated KRAS and Smad4/TGF-beta Signaling......Page 516
10 The Future......Page 518
10.2 Improving Disease Detection and Treatment......Page 519
Key Research Points......Page 520
References......Page 521
21 Principles and Applications of Microarray Gene Expression in Pancreatic Cancer......Page 526
1 Introduction to DNA Array Technology......Page 527
2.1 Candidate Gene Selection......Page 529
2.2 Class Prediction and Class Discovery......Page 532
Future Scientific Directions......Page 534
References......Page 535
22 Principles and Applications of Proteomics in Pancreatic Cancer......Page 538
2.1 Choice of Sample......Page 539
2.2 What Control Samples Should Be Considered......Page 541
3.1.1 Albumin and Immunoglobulin Removal......Page 545
4.1.1 Two Dimensional Gel Electrophoresis......Page 547
4.1.2 Differential In-Gel Electrophoresis (DIGE)......Page 549
5.1 Isotope-Coded Affinity Tags (ICAT)......Page 550
5.2 Isobaric Tags for Relative and Absolute Quantification (iTRAQ)......Page 552
5.3 Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC)......Page 553
6 Surface Enhanced Laser Desorption Ionization (SELDI)......Page 554
7 Autoimmunoantibody Approaches......Page 556
9 Limitations and Cautionary Notes......Page 557
Key Research Points......Page 558
References......Page 559
23 Tumor-Stromal Interactions in Invasion and Metastases......Page 564
1 The Microenvironment of Pancreatic Ductal Adenocarcinoma......Page 565
2 Inflammation and Cancer......Page 567
3 Inflammation and Pancreatic Cancer......Page 568
4 Pancreatic Stellate Cells: Producers of Desmoplasia in Pancreatic Cancer......Page 569
5 Mutual Interactions of Pancreatic Cancer and Stellate Cells......Page 573
6 Neoangiogenesis in Pancreatic Cancer......Page 574
7 The Impact of the Tumor Microenvironment on Initiating Pancreatic Cancer Invasion and Metastasis......Page 576
8 Perineural Invasion in Pancreatic Ductal Adenocaricnoma......Page 581
9 Assessment of the Stromal Contribution to Pancreatic Cancer Behavior: The Activated Stroma Index......Page 584
10 Targetting Pancreatic Cancer - Stroma Interactions as a Therapy Option......Page 585
References......Page 588
24 Genetic Susceptibility and High Risk Groups for Pancreatic Cancer......Page 594
1 Introduction......Page 595
2.1 Oncogenes, Tumor Suppressors and Telomerase Activation: The Natural Order of Mutation......Page 596
2.2 Germ Line Mutations of Tumor Suppressors and DNA Repair Genes......Page 597
2.3.1 Jumping the Queue in the PanIN Progression......Page 598
2.3.3 Mutation: What, When and Where......Page 599
2.4 Pancreatitis and Progression Models......Page 601
2.5 Diabetes and Progression Models......Page 602
2.6.1 Monogenic Direct Predisposition......Page 606
2.6.2 Polygenic Direct Predisposition......Page 611
2.6.3 Monogenic Indirect Predisposition......Page 613
2.6.4 Polygenic Indirect Predisposition......Page 614
2.7 Screening Results and Progression......Page 615
3.1 Gene-Environment Interactions......Page 616
3.1.1 Tobacco......Page 617
3.2 Familial Pancreatic Cancer (FPC)......Page 618
4.1 Anticipation......Page 619
Key Practice Points......Page 620
References......Page 621
25 Inherited Pancreatic Endocrine Tumors......Page 630
1.1 Introduction......Page 632
1.2 Natural History of PETs in Patients with MEN1......Page 633
1.3 Clinical Management......Page 634
2.2 Diagnostic Procedures......Page 635
2.3 Treatment......Page 636
3.2 Clinical Symptoms......Page 637
3.3 Diagnostic Procedures......Page 638
3.4 Treatment......Page 639
5 Non-Functioning PETs......Page 640
6 Treatment of Liver Metastases in MEN1 Associated PETs......Page 641
7.1 Introduction......Page 642
7.3 Clinical Symptoms......Page 643
8.1 Introduction......Page 644
8.3 Clinical Spectrum and Symptoms......Page 645
8.5 Treatment......Page 646
Published Guidelines......Page 647
References......Page 648
Section 2: Clinical Management of Pancreatic Cancer......Page 652
26 Clinical Decision Making in Pancreatic Cancer......Page 654
2 Clinically Defined Stages of Pancreatic Cancer and Curative Potential......Page 656
3.1 Surgery at a High-Volume Center Improves Both Short-Term and Long-Term Survival......Page 657
3.3 Currently, Roughly Half of Patients Who Present with Potentially Resectable Pancreatic Cancer Undergo Adjuvant Therapy......Page 658
3.5 Pre-Operative CA 19-9 Determinations are Prognostic......Page 659
3.6 Adjuvant Therapy Improves Survival, but No Single Adjuvant Approach is Clearly Superior......Page 660
4 Clinical Decision-Making in the Setting of Borderline Resectable Disease......Page 661
4.3 Borderline Resectable Tumors Must be Recognized as Putting the Patient at High Risk for a Positive Surgical Margin......Page 662
4.4 Preoperative Therapy Should Be Seriously Considered as an Alternative to Upfront Surgery in the Setting of Borderline Resectable Disease......Page 663
5 Decision-Analysis in Patients with Locally-Advanced Pancreatic Cancer......Page 664
5.1 Chemotherapy may Serve as a Selection Mechanism to Identify Those Patients Most Apt to Benefit from the Delivery of Radiation......Page 665
5.2 Laparoscopic Staging is Only Relevant in Patients with Locally Advanced Disease Being Considered for Radiation......Page 666
5.3 Options for Less Invasive or Non-Operative Palliation of Biliary Obstruction and Gastric Outlet Obstruction are Expanding......Page 667
6.2 Patients with Good Performance Status Benefit from Cytotoxic Gemcitabine Doublets Compared with Gemcitabine Alone......Page 669
6.3 Patients with Poor Performance Status Do Not Benefit from Combination Chemotherapy and May Not Benefit from the Delivery of any Cytotoxic Therapy......Page 670
6.4 Second Line Therapy May Be Appropriate for Some Patients Who Progress After Front Line Therapy......Page 671
8 Conclusion......Page 672
Clinical Implications......Page 673
3 Tenets for Locally Advanced Pancreatic Cancer......Page 674
References......Page 675
27 Paraneoplastic Syndromes in Pancreatic Cancer......Page 680
1 Introduction......Page 681
3.1.1 Cachexia......Page 682
3.1.2 Fever......Page 683
3.4 Erythema Nodosum......Page 684
3.4.1 Acanthosis Nigrica......Page 685
3.8 Neurological Manifestation......Page 686
3.10 Polyneuropathies......Page 687
3.12 Endocrine Manifestation......Page 688
3.14.1 Classification of Diabetes Mellitus......Page 689
3.14.2 Control of Metabolism in Health and Diabetes Through Pancreatic Hormones......Page 690
3.14.3 Genetic Susceptibility to Diabetes......Page 693
3.14.4 Pancreatic Endocrine Tumors......Page 694
3.14.5 The Reverse Connection: Type II Diabetes as a Risk Factor for Pancreatic Ductal Adenocarcinoma......Page 695
References......Page 697
28 Diagnostic and Therapeutic Response Markers......Page 704
1 Introduction......Page 705
1.1.1 CA19–9......Page 707
1.1.2 CA242......Page 708
1.1.4 MUC1......Page 709
1.1.7 CEACAM1......Page 710
1.1.9 Tissue Polypeptide Specific Antigen......Page 711
1.3 p53......Page 712
1.3.1 Hypermethylated Genes......Page 713
1.4 Detecting Chromosomal Losses in Pancreatic Samples......Page 714
1.4.2 Micro RNA......Page 715
1.4.3 Telomerase......Page 716
1.4.4 Discovering Protein Markers Using Mass Spectrometry......Page 717
2 Therapeutic Response Markers......Page 718
2.1 Markers of Tumor Burden and Treatment Response......Page 719
Published Guidelines......Page 720
References......Page 721
29 CT and Fusion PET-CT for Diagnosis, Staging and Follow-Up......Page 732
3 Pancreatic Adenocarcinoma Staging......Page 734
4.2 Diagnosing Pancreatic Adenocarcinoma with 18F- Fluorodeoxyglucose (FDG)-PET......Page 736
5.1 Size of the Tumor with CT......Page 739
5.2 Post Processed Images......Page 740
5.3 Vascular Involvement......Page 741
6.1 N Staging with CT......Page 744
7.2 Peritoneal Spread......Page 745
7.3 Liver Metastases......Page 746
7.5 M Staging with FDG-PET......Page 747
7.6 Prognostic Significance of FDG-PET Findings......Page 748
8.2 Recurrent Disease Detection with FDG-PET......Page 749
9 Strengths and Pitfalls of Imaging Pancreatobiliary Disease with FDG-PET......Page 750
10 Pancreatic Cancer and Image Fusion with PET-CT......Page 751
12 Published Guidelines and Websites......Page 753
References......Page 754
30 MRI and MRCP for Diagnosis and Staging of Pancreatic Cancer......Page 760
3 Appearance of the Normal Pancreas on MRI......Page 762
3.1 Arterial Anatomy......Page 763
3.1.2 Venous Anatomy and Variants......Page 764
4.1 Planes of Imaging......Page 765
4.3 T2-Weighted Imaging......Page 766
4.4 MRCP......Page 767
4.4.1 Breath-hold Versus Respiratory Triggering......Page 768
4.4.2 Thick Versus Thin Section Imaging......Page 769
4.5 Dynamic Imaging......Page 770
4.7 1.5 T Versus. 3 T Imaging......Page 771
5.1 Sensitivity and Specificity of MRI......Page 772
6 Appearance of Tumor on MRCP......Page 773
7.1 Chronic Pancreatitis......Page 775
7.2 Groove Pancreatitis......Page 776
7.4 Metastases to the Pancreas......Page 777
8 Staging......Page 778
9.1.1 Arterial Invasion......Page 779
9.2 Nodal Disease......Page 781
9.3 Liver Metastases......Page 782
9.3.1 Gadolinium......Page 783
9.3.2.2 Superparamagnetic Iron Oxide Particles......Page 784
9.4 Peritoneal Metastases......Page 785
Future Research Directions......Page 786
References......Page 787
31 EUS for Diagnosis and Staging of Pancreatic Cancer......Page 792
1 Introduction......Page 793
2.2 Endosonographic Fine-Needle Aspiration (EUS-FNA) of the Pancreas: Technique of EUS-Guided FNA......Page 794
3.1 Visualization of Pancreatic Cancer with EUS......Page 796
3.2 Is EUS (Still) the Method of Choice to Diagnose Pancreatic Cancer......Page 798
3.3 EUS or Transabdominal US in the Diagnosis of Pancreatic Cancer......Page 802
3.5 EUS or MRI/MRCP in the Diagnosis of Pancreatic Cancer......Page 803
3.7.1 EUS-Elastography and Other Technical Advances......Page 804
3.8 EUS-FNA in Diagnosis of Pancreatic Cancer. Results and Clinical Application......Page 805
3.9 Optimizing EUS-FNA Technique......Page 807
4.1 EUS Staging in Pancreatic Cancer - Principles......Page 809
4.2.1.1 TNM Staging......Page 810
4.2.1.3 EUS versus CT-Based Staging in Pancreatic Cancer......Page 811
4.2.1.4 Tumor Resectability and Vascular Invasion Assessment......Page 812
4.2.1.5 Endosonographic Assessment of Lymph Nodes......Page 813
4.4 EUS or MRI in the Staging of Pancreatic Cancer......Page 814
4.5 EUS or PET in the Staging of Pancreatic Cancer......Page 815
5.1 EUS and EUS-FNA: Impact in Decision Making in Pancreatic Cancer......Page 816
5.2 EUS-Associated Complications: Complications of Pancreatic EUS and EUS-FNA......Page 817
5.3 EUS for Detection of Distant Metastases......Page 819
5.4 EUS-Guided Therapy: Overview and Perspectives......Page 820
Summary......Page 821
Published Guidelines......Page 822
References......Page 823
32 Laparoscopy and Laparoscopic Ultrasound for Diagnosis and Staging......Page 830
1 Staging and Assessment by Radiological Imaging......Page 832
2 L/LUS in Potentially Resectable Patients......Page 833
3 Peritoneal Cytology at L/LUS......Page 836
Key Practice Points......Page 837
References......Page 838
33 Palliative Management of Pancreatic Cancer......Page 842
1 Introduction......Page 844
4 Establishing Goals of Care......Page 845
6 Pain Assessment and Management......Page 848
7 Principles of Medical Pain Management......Page 849
9 Depression......Page 850
11 Diagnosis of Gastroparesis......Page 852
11.4 Erythromycin......Page 853
15 Jejunostomy......Page 854
17 Jaundice......Page 855
19 Management of Cachexia......Page 856
20 Nutritional Management......Page 858
21 Constipation......Page 859
22 Malignant Ascites......Page 860
23 Vascular Thrombosis......Page 861
Key Practice Points......Page 863
References......Page 864
34 Diagnostic and Therapeutic Endoscopy in Pancreatic Cancer......Page 868
1.1 Endoscopic Features......Page 869
1.2 Tissue Collection......Page 870
1.3 Brush Cytology......Page 871
2 Stricture Biopsy......Page 872
2.1 Pancreatic Juice Aspiration for Measurement of Tumor Markers......Page 873
3 Therapy......Page 874
4.1 The Emergence of the Plastic Biliary Stent......Page 875
4.2 Quality of Life Assessments with Endoscopic Stent Placement......Page 876
4.4 Type of Stent......Page 877
4.5 Which Stent for Which Patient......Page 878
5.2 Designer Biliary Stents......Page 880
Summary......Page 881
Published Guidelines......Page 882
References......Page 883
35 Interventional Radiology for Pancreatic Cancer......Page 888
2 Bile Duct Drainage......Page 890
2.1 Endoscopic Retrograde Cholangiography (ERCP) Guided Drainage......Page 891
2.2 Interventional Radiology (IR) Guided Drainage......Page 892
2.3.1 Transpapillary/Transanastomotic Drainage......Page 893
2.3.2.1 Technical Success, Outcomes and Complications (For EUS Guided Bile Duct Drainage)......Page 895
3 Duodenal Lumen Stenting......Page 896
3.2 Endoscopic Guided Duodenal Stenting......Page 898
4.1 Percutaneous Guided Celiac Plexus Neurolysis......Page 900
4.2 Endoscopic Ultrasound Guided Celiac Plexus Neurolysis......Page 901
4.3 Endoscopic Ultrasound Guided Celiac Ganglia Neurolysis......Page 904
5 Locally Injected Anti-Tumor Therapies......Page 907
5.1.2 Computed Tomography Injection......Page 908
5.2.1 Allogenic Mixed Lymphocyte Culture (Cytoimplant)......Page 909
5.2.4 Oncogel (ReGel/Paclitaxel)......Page 910
6.1.1 Traditional Brachytherapy......Page 911
6.1.2 EUS Guided Delivery of Fiducial Markers and Brachytherapy......Page 912
6.2.2 EUS Guided Photodynamic Therapy......Page 913
6.3.2 EUS Guided Radiofrequency Ablation......Page 914
Key Research Points......Page 915
Future Research/Directions......Page 916
References......Page 917
36 Palliative Surgery in Advanced Pancreatic Cancer......Page 924
1 Introduction......Page 925
3 Endoscopic Stenting for Jaundice......Page 926
5 Gastric Outlet Obstruction......Page 930
6 "Surgical" Treatment of Pain......Page 933
7 Pancreatic Resection for Palliation......Page 934
8 Laparoscopic Palliation......Page 936
Key Practice Points......Page 937
References......Page 938
37 Chemotherapy for Advanced Pancreatic Cancer......Page 942
2.1 5-FU Monotherapy......Page 943
2.2 Gemcitabine Monotherapy......Page 944
2.2.1 Fixed Dose Rate Gemcitabine......Page 945
2.3.1 Gemcitabine with 5-FU......Page 946
2.3.2 Gemcitabine and Capecitabine......Page 948
2.3.3 Gemcitabine and S-1......Page 951
2.3.5 Gemcitabine and Platinum Agents......Page 952
2.3.7 Gemcitabine and Taxanes......Page 956
2.3.8 Gemcitabine with Other Agents......Page 957
2.5 Three or More Drug Regimens......Page 958
3 2nd line Chemotherapy......Page 959
3.3 Other Chemotherapy Combinations......Page 960
4.1.1 Erlotinib......Page 961
4.1.3 Cetuximab......Page 965
4.2.1 Bevacizumab......Page 966
4.3 Other Biological Agents......Page 967
Key Practice Points......Page 969
Published Guidelines......Page 970
Conflicts of Interest......Page 971
References......Page 972
38 Developments in Chemoradiation for Advanced Pancreatic Cancer......Page 980
2 Chemoradiation Trials in Locally Advanced Pancreatic Cancer......Page 981
2.1 Chemoradiation Trials with Novel Agents......Page 984
3 Radiation Dose Escalation in Locally Advanced Pancreatic Cancer?......Page 986
3.1 Limitations and Challenges to Radiation Dose Intensification in Pancreatic Cancer......Page 987
4.1 Imaging Technology......Page 988
4.2 Intensity-Modulated Radiotherapy......Page 989
4.3 Image-Guided and Stereotactic Body Radiotherapy......Page 990
4.4 Particle Beam Therapy......Page 993
5 Conclusion......Page 995
Published Guidelines......Page 996
References......Page 997
39 Surgical Resection for Pancreatic Cancer......Page 1000
1 Introduction......Page 1001
2 Diagnostic Evaluation and Assessment for Resectability......Page 1002
4 Development of Surgery for Pancreatic Cancer......Page 1004
5 Kausch-Whipple Partial Pancreatoduodenectomy......Page 1005
6 Left (Distal) Pancreatectomy......Page 1009
7 Total Pancreatectomy......Page 1011
8 Extended Lymphadenectomy......Page 1012
9 Vascular Resection......Page 1013
11 Short-Term Outcome......Page 1014
11.1 Pancreatic Fistula......Page 1015
11.3 Delayed Gastric Emptying......Page 1017
11.4 Postpancreatectomy Hemorrhage......Page 1018
11.5 Complication Severity......Page 1019
Key Practice Points......Page 1020
References......Page 1021
40 Venous Resection in Pancreatic Cancer Surgery......Page 1026
1 Introduction......Page 1027
2.1 Partial Resection and Reconstruction......Page 1028
2.2 Segmental Resection and Reconstruction......Page 1029
3.1 Morbidity and Mortality......Page 1031
3.2 Survival......Page 1032
4 Discussion......Page 1037
Future Research Directions......Page 1040
References......Page 1041
41 Pathological Reporting and Staging Following Pancreatic Cancer Resection......Page 1044
1 Introduction: Cancer Staging and Pathology Reporting......Page 1045
2.1 The Past and the Present......Page 1046
2.2 The Future......Page 1050
2.2.1 Definition of Relevant Margins......Page 1051
2.2.3 The Dissection Protocol......Page 1053
2.2.5 Comparison with other Methods......Page 1055
2.2.6 The Clinical Significance......Page 1058
3 Conclusive Remarks......Page 1059
Pathology Reporting......Page 1060
References......Page 1061
42 Japanese Pancreas Society Staging Systems for Pancreatic Cancer......Page 1064
2 JPS and UICC Staging Systems for Pancreatic Cancer......Page 1065
2.1 T Category......Page 1066
2.2 N Category......Page 1067
3 Clinical Review of the Staging System Using Data from National Pancreatic Cancer Registry in Japan......Page 1069
Key Practice Points......Page 1075
Future Research Direction......Page 1078
References......Page 1079
43 Adjuvant Chemotherapy in Pancreatic Cancer......Page 1080
1 Introduction......Page 1081
3 Randomized Controlled Trials of Adjuvant Chemotherapy......Page 1082
3.3 Kosuge et al.......Page 1084
3.4 ESPAC-1......Page 1085
3.5 CONKO-001......Page 1086
4 Rationale for Adjuvant Chemoradiation......Page 1087
5.1 EORTC 40891......Page 1088
5.2 ESPAC-1......Page 1090
7.1 GITSG 9173......Page 1091
7.3 Future Studies......Page 1093
9 The Role of Neoadjuvant Therapy......Page 1094
10 Meta-Analysis......Page 1096
11 Conclusions......Page 1098
Useful Websites......Page 1101
References......Page 1102
44 Adjuvant Chemoradiation Therapy for Pancreatic Cancer......Page 1108
2 Rationale for Adjuvant Chemoradiation in Pancreatic Cancer......Page 1109
2.1.1 GITSG Trial......Page 1110
2.1.3 ESPAC-1 Trial......Page 1111
2.1.4 RTOG 97-04 Trial......Page 1112
2.1.5 CONKO-001 Trial......Page 1115
2.2 Non-Randomized Trials......Page 1116
3 Conclusion......Page 1117
Key Research Points......Page 1118
References......Page 1119
45 Neoadjuvant Treatment in Pancreatic Cancer......Page 1122
1 Introduction......Page 1123
3 Advantages of Neo-Adjuvant Therapy......Page 1124
4.1 Resectable (T1-3) Lesions......Page 1126
4.2 Borderline Resectable (T3/4) Tumors......Page 1130
4.2.1 Challenges to the Routine use of Neoadjuvant Therapy......Page 1131
4.2.2 The Importance of Multidisciplinary Therapy......Page 1132
4.2.3 Conclusion......Page 1133
Published Guidelines......Page 1134
Bibliography......Page 1135
46 Borderline Resectable Pancreatic Cancer......Page 1138
2 Preoperative Staging and the Role of the Multidetector CT Scan......Page 1139
3 Pancreaticoduodenectomy and the Retroperitoneal Margin......Page 1141
5.1 Vascular Abutment on the Superior Mesenteric Artery......Page 1143
6 Expanded Criteria for Borderline Resectable Pancreatic Cancer - Definition of MDACC Types B and C......Page 1145
7 Role of Preoperative Therapy in Patients with Borderline Resectable (Types A, B, C) Pancreatic Cancer......Page 1146
8 Barriers to Preoperative Therapy for Borderline Resectable Cancer......Page 1149
References......Page 1151
47 Management of Cystic Neoplasms of the Pancreas......Page 1154
2 Serous Cystadenomas......Page 1155
3 Mucinous Cystic Neoplasms......Page 1157
4.1 Main-Duct IPMN......Page 1159
4.2 Branch Duct IPMN......Page 1162
5 Benign Cysts......Page 1164
Key Practice Points......Page 1165
Future Research Directions......Page 1166
References......Page 1167
48 Laparoscopic Surgery for Pancreatic Neoplasms......Page 1170
1 Laparoscopic Pancreaticoduodenectomy......Page 1171
2.2 Cystic Tumors......Page 1173
2.4.1 Short Summary......Page 1174
3 Conclusions......Page 1177
Future Research Directions......Page 1178
References......Page 1179
49 Modern Japanese Approach to Pancreas Cancer......Page 1182
1 Clinical Guidelines for Management of Pancreatic Cancer......Page 1183
2 Clues to Early Diagnosis of Pancreatic Cancer......Page 1189
2.1 Dilatation of Pancreatic Duct......Page 1190
2.3 Intraductal Papillary Mucinous Neoplasm (IPMN)......Page 1193
3.1 Extended Resection versus Standard Resection......Page 1194
3.2 Adjuvant Treatment......Page 1196
References......Page 1197
Section 3: New Directions......Page 1202
50 Development of Novel Pancreatic Tumor Biomarkers......Page 1204
1 Introduction......Page 1205
2 Marker Sensitivity and Disease Heterogeneity......Page 1206
3 Markers of Precursor Neoplasms......Page 1207
4 Evaluating Candidate Diagnostic Markers......Page 1209
5 Phases of Biomarker Discovery......Page 1211
6 Pitfalls in Marker Studies......Page 1212
7 DNA Mutations......Page 1213
8 DNA Methylation......Page 1215
9 Gene Expression Analysis of Pancreatic Neoplasms......Page 1216
10 MicroRNAs......Page 1217
11 Autoantibodies......Page 1218
12 Proteomics Approaches to Identify Protein Markers......Page 1219
14 Conclusion......Page 1220
Acknowledgment......Page 1221
References......Page 1222
51 Inherited Genetics of Pancreatic Cancer and Secondary Screening......Page 1232
1 Introduction......Page 1233
2.1 What Does a Family History of Cancer Mean?......Page 1234
2.1.2 Risk Assessment: Family Structure Rather than Number of Cases......Page 1235
3.1 Age-Dependent Risk......Page 1236
4 Whether to Screen?......Page 1238
4.1 An Example of Risk Assessment......Page 1239
5.1 Imaging......Page 1240
5.2.1 Serum Antigens......Page 1241
5.2.3 Circulating DNA......Page 1242
5.2.4.1 Forms of Molecular Analysis......Page 1243
5.2.4.3 Analysis of K-Ras Mutations......Page 1246
5.2.4.5 Cancer Associated Methylation......Page 1248
5.2.4.6 Release from the Cell: Promoter Methylation and Freedom......Page 1250
5.2.4.7 Methylation of Other Sequences......Page 1252
5.2.4.8 Combination of Methylation Levels......Page 1253
5.2.4.10 Telomerase in Pancreatic Juice......Page 1254
6.1 Washington......Page 1255
6.4 EUROPAC and FaPaCa......Page 1256
8 General Resources......Page 1258
Future Research Directions......Page 1259
References......Page 1260
52 Gene Therapy for Pancreatic Cancer......Page 1266
2 Gene Delivery System......Page 1268
2.2 Retrovirus......Page 1271
2.4 Lentivirus......Page 1272
2.7 Polymer and Dendrimer......Page 1273
3.1 RAS......Page 1274
3.1.1 RNA-Directed Strategies......Page 1275
3.1.2 Dominant-Negative Mutant......Page 1276
3.4 Insulin-Like Growth Factor and Focal Adhesion Kinase......Page 1277
3.7 NOTCH Signaling......Page 1278
3.9 Telomerase......Page 1279
3.10.1 TP53......Page 1280
3.10.4 LSM1......Page 1281
3.11.2 AS-3......Page 1282
3.12 MicroRNA......Page 1283
4.2 Cytosine Deaminase......Page 1284
5.1 Adenovirus......Page 1285
5.2 Herpes Simplex Virus......Page 1287
5.3 Reovirus......Page 1288
6.2 GM-CSF......Page 1289
6.4 Carcinoembryonic Antigen......Page 1290
Key Research Points......Page 1291
References......Page 1292
53 Vaccine Therapy and Immunotherapy for Pancreatic Cancer......Page 1298
1.1 Tumor Antigen Recognition and Immune Surveillance......Page 1300
1.3.1 Alteration in T Cell Signal Transduction and Cytokine Regulation......Page 1302
1.3.1.1 TGF-beta......Page 1303
1.3.2 Tolerance Induced by Regulatory DCs......Page 1304
1.3.4.1 CTLA-4......Page 1305
1.3.4.3 B7-H3 and B7-H4......Page 1307
1.3.5 Regulatory T Cells Represent a Cellular Checkpoint of Immune Activity......Page 1308
1.3.7 Altered Metabolism in Immune Cells......Page 1309
1.3.8 Tumor Microenvironment is the Site Where Immune Tolerance is Established......Page 1310
2.1.1 Monoclonal Antibodies......Page 1312
2.1.2 Adoptive T Cell Transfer......Page 1313
2.2 Vaccine Strategies for Cancer Treatment......Page 1314
2.2.1.1 Autologous Whole Cell Vaccines......Page 1315
2.2.1.2 Allogeneic Whole Cell Vaccines......Page 1316
2.2.2.2.1 Listeria-Based Recombinant Vaccines......Page 1317
2.2.2.3 DC-Based Vaccines......Page 1319
2.3.1 Chemotherapy as Immune Modulator......Page 1320
2.3.2.1 Targeting CTLA-4......Page 1322
2.3.2.2 Targeting PD-1......Page 1323
2.3.2.5 Targeting Tregs......Page 1324
3.1.1 Monoclonal Antibodies for Pancreatic Cancer Treatments......Page 1325
3.2.1.1 Tumor Markers as Vaccine Antigens......Page 1326
3.2.1.2 Oncoproteins as Vaccine Antigens......Page 1328
3.2.3 Mixed Antigens as Vaccine Targets......Page 1329
3.2.4 Allogeneic Whole-Cell Pancreatic Vaccines......Page 1330
4.1 New Strategies for Pancreatic Tumor Whole Cell Vaccine......Page 1332
4.3 Ongoing Human Pancreatic Studies of Recombinant Vaccines......Page 1333
5.1 Identification of new Pancreatic Cancer Antigen......Page 1337
5.2.1 Focus on Targeting Immune Checkpoints......Page 1338
5.2.2 Focus on Combinatory Therapies......Page 1339
5.3 Optimal Predictors of Antitumor Immune Response......Page 1340
5.4 Evaluating Clinical Response in the Immunotherapy Studies......Page 1341
Future Scientific Directions......Page 1342
References......Page 1343
54 Emerging Therapeutic Targets for Pancreatic Cancer......Page 1348
2.1 Nuclear Factor-Kappa B......Page 1349
2.2 Specificity Protein 1......Page 1351
2.3 Transforming Growth Factor Beta (TGF-beta)......Page 1352
2.4 Hedgehog and GLI Signaling......Page 1353
3 Hepatocyte Growth Factor (HGF) and c-Met......Page 1355
4.1 BRCA2......Page 1357
4.2 CHEK-1/2......Page 1358
5 Bortezomib and Endoplasmic Reticulum Stress......Page 1359
6 Gene Therapy......Page 1360
Clinical Implications......Page 1361
References......Page 1362
Color Insert......Page 1366
Index......Page 1414