Textbook of Pancreatic Cancer : Principles and Practice of Surgical Oncology

Foreword Foreword from ESSO Foreword from the President of IHPBA Foreword from the President of the AHPBA Preface Contents Contributors Part I: Pancreatic Cancer Disease Burden Chapter 1: Risk Factors for Pancreatic Cancer 1.1 Introduction 1.2 Age, Gender and Race 1.3 Pancreatitis (Acute, Chronic and Hereditary) 1.3.1 Chronic Pancreatitis 1.3.2 Acute Pancreatitis 1.3.3 Hereditary Pancreatitis 1.4 Tobacco Smoking 1.5 Alcohol Consumption 1.6 Body Mass Index and Obesity 1.7 Diabetes Mellitus 1.8 Dietary Patterns 1.9 Poor Oral Hygiene 1.10 ABO Blood Group 1.11 Potential Risk Factors 1.12 Study Design and Ongoing Epidemiological Projects 1.13 Conclusions References Chapter 2: Epidemiology of Pancreatic Cancer 2.1 Introduction 2.2 Worldwide Incidence 2.3 Trends in Incidence 2.3.1 Data from The Netherlands 2.3.2 Data from Austria 2.3.3 Data from Canada 2.3.4 Data from Puerto Rico 2.3.5 Data from the USA 2.4 Worldwide Mortality 2.4.1 Data from The Netherlands 2.4.2 Data from Austria 2.4.3 Data from Canada 2.4.4 Data from Puerto Rico 2.4.5 Data from the USA 2.5 Conclusion References Chapter 3: Hereditary Syndromes and Pancreatic Cancer 3.1 Introduction 3.2 Hereditary Tumour Predisposition Syndromes 3.2.1 Peutz-Jeghers Syndrome 3.2.2 Familial Atypical Multiple Mole Melanoma and Pancreatic Cancer Syndrome (FAMMM) 3.2.3 Hereditary Breast and Ovarian Cancer Syndrome 3.2.4 PALB2 Gene Mutations 3.2.5 ATM Gene Mutations 3.2.6 Lynch Syndrome 3.3 Hereditary Pancreatitis 3.4 Other Tumour Predisposition Syndromes 3.4.1 Li Fraumeni Syndrome 3.4.2 Familial Adenomatous Polyposis 3.4.3 Germline Mutations in Other Cancer Genes 3.5 Testing and Tools 3.6 Surveillance/Screening Recommendations 3.7 Conclusion References Chapter 4: Familial Pancreatic Cancer 4.1 Introduction 4.2 Familial Pancreatic Cancer 4.3 Pancreatic Cancer Susceptibility Genes in Patients with Familial Pancreatic Cancer 4.3.1 ATM 4.3.2 BRCA1, BRCA2, PALB2 4.3.3 CDKN2A 4.3.4 Hereditary Pancreatitis Genes 4.3.5 Other Inherited Syndromes 4.4 Pancreatic Cancer Susceptibility Genes in Patients with Sporadic PDAC 4.5 Pancreatic Cancer Susceptibility Genes in Patients with Pancreatic Cancer Precursor Lesions 4.6 Screening for Patients with Pathogenic Germline Variants 4.7 Conclusion References Part II: Education, Training and Quality of Care Chapter 5: Education and Training in Pancreatic Surgery 5.1 Structure of Training Pathways 5.1.1 North-American Training Programmes 5.1.2 European Training Programmes 5.1.3 Australasian Programmes 5.1.4 Effect of Training Programmes on Clinical Outcomes 5.1.5 Workforce Prediction 5.2 Standards of Training 5.2.1 Period of Training 5.2.2 Curriculum 5.3 Clinical Experience and Skills Acquisition 5.3.1 Volume and Training 5.3.2 Minimal Invasive HPB Surgery 5.3.3 Human Factors 5.4 Research 5.5 Fellowship Satisfaction: The Trainee Experience 5.6 Technologies: Online Learning Platforms and Social Media References Chapter 6: Quality of Care Indicators in Pancreatic Cancer 6.1 Introduction 6.2 Defining Quality of Care 6.3 Variations in Quality of Care 6.4 Monitoring Quality of Care 6.4.1 Clinical Indicators 6.4.2 Development and Implementation of Clinical Quality Indicators in Pancreatic Cancer 6.4.2.1 Step 1: Synthesis of Evidence 6.4.2.2 Step 2: Monitoring and Analysis 6.4.2.3 Step 3: Implementation and Review 6.4.3 Value-Based Health Care 6.4.4 Patient-Reported Outcome Measures (PROMs) in Pancreatic Cancer 6.4.5 Evaluating Quality of Care 6.5 Feedback and Reporting 6.6 Examining Variation 6.7 Conclusions References Chapter 7: The Quantity and Quality of Surgical Trials in Pancreatic Cancer 7.1 Introduction 7.2 Quantity of Surgical Trials in Pancreatic Cancer 7.3 Quality of Surgical Trials in Pancreatic Cancer 7.4 Evolution over Time 7.5 The Way Forward 7.5.1 Research Prioritization 7.5.2 Collaborative, Pragmatic Surgical Trials 7.5.3 Focus on Methodology and Training Programs 7.5.4 Transfer of Knowledge to Clinical Practice 7.6 Conclusions References Chapter 8: Mandatory Reporting Measurements in Trials for Potentially Resectable Pancreatic Cancer 8.1 Introduction 8.2 Baseline Characteristics in Trials of Patients with Potentially Resectable Pancreatic Cancer 8.3 Prognostic Factors in Trials of Patients with Potentially Resectable Pancreatic Cancer 8.4 Conclusion References Chapter 9: Regionalization to Improve Outcomes in Pancreatic Surgery 9.1 Introduction 9.2 The Volume-Outcome Debate 9.3 Measuring Quality of Care Beyond Simple Metrics 9.4 Context over Numbers 9.4.1 Benefits from Anatomically Related Procedures and Outcomes 9.4.2 Improved Outcomes over Time 9.4.3 Readmissions 9.5 Current State of Regionalization 9.5.1 Nordic Countries 9.5.2 Rest of Europe 9.5.3 “Take the Volume Pledge” in the United States 9.6 Barriers to Regionalization 9.6.1 The Patient 9.6.2 Healthcare Systems 9.6.3 Hospital/Surgeon 9.6.4 Political/Government 9.7 Conclusion References Chapter 10: Oncopolitics in Pancreatic Cancer 10.1 Introduction 10.2 Ongoing Oncopolicy Initiatives 10.3 European Commission Initiated Actions in Cancer Health and Research 10.3.1 Oncopolicy for Pancreatic Cancer 10.4 Action Plans to Increase Awareness of Pancreatic Cancer 10.4.1 Pancreatic Cancer Action 10.4.2 Pancreatic Cancer Europe 10.4.3 Digestive Cancers Europe 10.4.4 United European Gastroenterology 10.4.5 Pancreatic Cancer Action Network 10.5 Research and Funding 10.6 Conclusion References Part III: The Pancreas Chapter 11: Anatomy and Embryology of the Pancreatic Gland 11.1 Introduction 11.2 Basic Description of the Pancreas 11.3 Development of the Pancreas 11.4 Cellular Development of the Pancreas 11.5 Macroscopy and Topography 11.6 Vascular Supply and Lymphatic Drainage of the Pancreas 11.7 Innervation of the Pancreas 11.8 Conclusion References Chapter 12: Vascular Supply: Important Arterial and Venous Variants 12.1 Introduction 12.2 Arterial Supply: Development of Normal and Variant Anatomy 12.3 Venous Supply: Development of Normal and Variant Anatomy 12.4 Pancreatoduodenectomy: Standard Anatomy 12.5 Pancreatoduodenectomy: Impact of Venous Drainage 12.6 Pancreatoduodenectomy: Variant Anatomy 12.7 Left Pancreatectomy: Standard Anatomy 12.8 Left Pancreatectomy: Variant Anatomy 12.9 Conclusion References Chapter 13: The Lymphatic System and Lymph Nodes of the Pancreas 13.1 Introduction 13.2 The Lymph System and Its Role 13.3 The Lymphatic Network of the Pancreas 13.4 Clinical-Anatomical Classification 13.4.1 Radiologic Imaging 13.4.2 Sentinel Lymph Node 13.5 Tumors of the Pancreatic Head 13.6 Tumors of the Body and Tail 13.6.1 Neoadjuvant Treatment and Lymph Node Yield 13.7 Conclusion References Part IV: Understanding Disease Biology Chapter 14: The Hallmarks of Pancreatic Cancer 14.1 Introduction 14.1.1 Precursor Lesions and the Pancreatic Cancer Progression Model 14.1.2 Sustaining Proliferative Signaling in Pancreatic Cancer 14.1.3 Avoiding Immune Destruction 14.1.4 Evading Growth Suppressors 14.1.4.1 CDKN2A 14.1.4.2 SMAD4 14.1.5 Genome Instability and Mutation 14.1.6 Reprogramming of Energy Metabolism and Stroma in Pancreatic Carcinoma 14.1.6.1 Cancer-Associated Fibroblasts 14.1.7 Metastasis of Pancreatic Cancer 14.2 Conclusions References Chapter 15: Pathobiology of Precursors to Pancreatic Cancer 15.1 Introduction 15.1.1 Pancreatic Intraepithelial Neoplasia (PanIN) 15.1.2 Acinar-Ductal Metaplasia (ADM) 15.1.3 Intraductal Papillary Mucinous Neoplasm (IPMN) 15.1.4 Histology of IPMN 15.1.5 Invasive Carcinomas in IPMN 15.1.6 Cytology of Cystic Lesions in the Pancreas 15.1.7 Pancreatic Intraductal Oncocytic Papillary Neoplasm (IOPN) 15.1.8 Intraductal Tubulopapillary Neoplasm (ITPN) 15.1.9 Mucinous Cystic Neoplasm (MCN) 15.2 Conclusions References Chapter 16: Cancer Cell Metabolism in Pancreatic Ductal Adenocarcinoma 16.1 Introduction 16.2 Normal and Cancer Cell Metabolism: The Warburg Effect 16.2.1 Energy Substrates and Glucose Homeostasis 16.2.2 PDAC Progression: Driver Mechanisms 16.3 Tumor Microenvironment in PDAC 16.3.1 Physical Changes Driving the Metabolic Switch 16.3.2 Immune Suppression 16.3.3 Metabolic Crosstalk 16.4 Treatment Challenges in PDAC with Respect to Metabolism 16.5 Conclusion References Chapter 17: The Cachexia Syndrome in Pancreatic Cancer 17.1 Introduction 17.2 Weight Loss and Body Composition 17.3 Adipose Tissue and Myosteatosis 17.4 Systemic Inflammation 17.5 Malabsorption and Altered Protein Metabolism 17.6 Anorexia 17.7 Future Perspectives and Treatment Options 17.7.1 Early Identification 17.7.2 Dynamic Investigation 17.7.3 Pre- and Post-treatment Assessments 17.7.4 Inputs from Translational Research 17.7.5 A Multimodal Approach 17.7.6 Drugs Targeting Cachexia Mechanisms 17.8 Conclusion References Chapter 18: Role of Stroma in Pancreatic Cancer 18.1 Introduction 18.2 Definition of the Stroma 18.3 Effect of Stroma on Treatment 18.4 Effect of Treatment on Stroma 18.5 Stroma as a Source of Biomarkers 18.6 Stroma as a Specific Treatment Target 18.7 Conclusions References Chapter 19: Role of the Microbiome in Pancreatic Cancer 19.1 Introduction 19.2 Bacterial Commensalism in the Human Host 19.3 Advances in Microbiome Research 19.3.1 Microbiota-Immune Cross-Talk 19.4 Microbiota and Cancer 19.5 Gut Microbiome Link to Cancer Immunotherapy Response 19.6 The Microbiome and Pancreatic Cancer 19.6.1 Preclinical Studies in Pancreatic Cancer 19.7 Clinical Studies 19.8 Conclusion References Chapter 20: Immuno-Oncology in Pancreatic Cancer 20.1 Introduction 20.2 Impediment to Immunotherapy in PDAC 20.2.1 Stroma 20.2.2 T-Cells 20.2.3 Immune Checkpoints 20.2.4 Myeloid Cells 20.2.5 B-Cells 20.3 Current Immunotherapeutic Approaches 20.3.1 Combining Immune Checkpoint Inhibitors with Untargeted Therapies 20.3.1.1 Chemotherapy 20.3.1.2 Radiotherapy 20.3.2 Combining Immune Checkpoint Inhibitors with Targeted Therapies 20.3.2.1 Sequencing of Chemotherapy and Immunotherapies 20.4 Other Immunotherapeutic Approaches 20.4.1 Targeting Tumour Antigens in PDAC 20.4.2 Tumour Associated Antigens as Targets for PDAC Immunotherapy 20.4.3 Vaccine Immunotherapy Strategies for PDAC 20.4.4 Augmenting T-Cell Responses: CAR-T-Cells 20.4.5 Selecting Patients with PDAC for Onco-Immunology Strategies 20.4.6 Influence of Microbiota on Onco-Immunology 20.4.7 Optimising Onco-Immunology Integration in PDAC 20.5 Conclusions References Chapter 21: Molecular Subtyping of Pancreatic Cancer 21.1 Introduction 21.2 Subtyping Pancreatic Cancer from Gene Expression 21.2.1 The Squamous (or Basal) Sub-Type 21.2.2 Classical Subtype 21.2.3 The Immunogenic Subtype 21.3 Consensus Towards Molecular Subtyping of Pancreatic Cancer 21.4 Evolution of Molecular Subtypes 21.5 Is There a Role for Molecular Subtyping in Surgery for Pancreatic Cancer? 21.6 Conclusions References Chapter 22: The Role of Epigenetics in Pancreatic Ductal Adenocarcinoma 22.1 Introduction 22.2 General Aspects of Epigenetics 22.2.1 Epigenetic Regulators 22.2.2 Technical Platforms for Epigenetic Mapping 22.2.3 Life-Time Exposure to Nutrients, Toxins and Behavioral Traits 22.2.4 Epigenetics and the Hallmarks of Cancer 22.2.5 Epigenetic Mechanisms in Carcinogenesis 22.3 Epigenetics in Pancreatic Ductal Adenocarcinoma 22.3.1 Epigenetics and the Development of PDAC 22.3.2 Epigenetics and the Metastatic Process in PDAC 22.3.3 Epigenetics and the Molecular Subtypes of PDAC 22.3.4 Epigenetic Mechanisms Shaping the Tumor Microenvironment 22.4 Epigenetics and the Role of Novel Therapies in PDAC 22.5 Epigenetics and Biomarkers for Early Detection of PDAC 22.6 Conclusion References Part V: Diagnosis, Imaging and Staging Chapter 23: Early Diagnosis of Sporadic Pancreatic Cancer 23.1 Introduction 23.2 Population at Risk 23.3 Conventional Imaging 23.3.1 Screening of High-Risk Individuals 23.3.2 Visible Precursor Lesions 23.4 Metabolic Changes and Use of Metabolomics Targets in PDAC 23.5 Biomarkers for Early Detection of PDAC 23.5.1 Available Panels and Criteria for Early Detection of PDAC 23.6 Further Developments and Novel Technology 23.6.1 Pancreatic Juice and Cyst Fluids 23.6.2 Saliva and Salivary Markers 23.6.3 Urine-Test and Urinary Markers 23.6.4 Imaging Tools and Radiomics 23.6.5 Biosensors 23.6.6 Liquid Biopsies and Circulating Biomarkers 23.7 Conclusion References Chapter 24: Clinical Presentation and Symptoms in Pancreatic Cancer 24.1 Introduction 24.2 Frequency of Different Symptoms 24.3 Jaundice 24.4 Pancreatic Cancer in New-Onset Versus Long-Standing Diabetes Mellitus 24.5 Maldigestion and Steatorrhea 24.6 Acute and Chronic Pancreatitis or Isolated Pancreatic Duct Stenosis 24.7 Venous Thromboembolism 24.8 Paraneoplastic Syndromes and Associated Conditions with Pancreatic Cancer 24.9 Clinical Algorithms to Identify Patients at High Risk of Pancreatic Cancer 24.10 Conclusion References Chapter 25: TNM Staging for Pancreatic Adenocarcinoma 25.1 Introduction 25.2 The TNM Staging System 25.2.1 TNM Descriptors 25.2.2 Changes in the Eighth Edition 25.2.3 Prognostic Factors 25.3 Validation of the Eighth Edition 25.4 Controversies in Clinical Practice 25.4.1 The “R” Status 25.4.2 Staging after Neoadjuvant Treatment 25.4.3 Cancers within the Cells of the Pancreatic Duct 25.4.4 Current and Future Biomarkers References Chapter 26: Computed Tomography for Diagnosis and Staging in Pancreatic Cancer 26.1 Introduction 26.2 TNM Staging and Assessment of Resectability 26.3 Indications for Imaging Studies 26.4 Standardized CT-Pancreas Protocol 26.5 Diagnosing the Pancreatic Tumor 26.5.1 Direct Signs 26.5.2 Indirect Signs 26.5.2.1 Pancreatic Duct Dilation 26.5.2.2 Parenchymal Atrophy 26.5.2.3 Retention Pseudocyst 26.5.2.4 Bile Duct Dilation 26.5.3 Diagnostic Performance 26.6 Staging Workup 26.6.1 Vascular Spread 26.6.2 Venous Spread 26.6.3 Arterial Spread 26.6.4 Retroportal Pancreatic Lamina 26.6.5 Perineural and Periduodenal Spread 26.6.6 Lymph Node Involvement 26.7 Evaluation of Distant Spread 26.8 Conclusion References Chapter 27: MR/MRCP for Diagnosis and Staging 27.1 Introduction 27.2 MRI Protocol for Pancreatic Cancer Evaluation 27.3 Typical Pancreatic Cancer Imaging Features 27.3.1 Primary Signs 27.3.2 Secondary Signs 27.4 Differential Diagnosis 27.5 Role of MRI in Pancreatic Cancer Imaging 27.5.1 Role of MRI in Local Staging 27.5.2 Role of MRI in Extra-Pancreatic Spread Evaluation 27.6 Conclusion References Chapter 28: EUS Evaluation of Pancreatic Cystic Lesions 28.1 Background 28.2 Classification of PCLs 28.3 Diagnostic Evaluation 28.3.1 EUS Imaging Characteristics of PCLs 28.3.2 EUS-Guided FNA 28.3.3 Cystic Fluid Analysis 28.3.4 Molecular Biomarkers in Pancreatic Cystic Fluid 28.3.5 EUS-Guided Microbiopsy of the Pancreatic Cystic Wall 28.3.6 Needle-Based Confocal Laser Endomicroscopy (nCLE) 28.4 Work-Up of PCLs and Current Guidelines 28.5 Surveillance of PCLs 28.6 EUS-Guided Cyst Ablation Therapy 28.7 Summary References Chapter 29: Imaging After Neoadjuvant Therapy 29.1 Introduction 29.2 Impact of Histopathologic Response Patterns on Imaging 29.3 Imaging Response Assessment with RECIST1.1 (Clinical Stage) 29.4 Imaging Assessment of Resectability 29.4.1 Clinical Impact of Patient Selection Based on Imaging 29.4.2 Neoadjuvant Therapy and R0 Resection in Study Settings 29.4.3 Tested Predictors for Resectability and Survival After Neoadjuvant Therapy 29.4.3.1 Regression of Vessel Contact 29.4.3.2 Size and Resectability 29.4.3.3 Tumour Enhancement 29.4.4 Study Characteristics of Imaging Predictor Assessment 29.5 Texture Analysis: Big Data Analysis in Imaging 29.5.1 Background 29.5.2 Application to Neoadjuvant Treatment of PDAC 29.6 Functional Imaging: Diffusion-Weighted MRI for Monitoring Response 29.6.1 Current Application and Results 29.6.2 Tumour Heterogeneity, Definition of the Region of Interest and Future Developments 29.7 Conclusion References Chapter 30: The Role of CA 19-9 in Pancreatic Adenocarcinoma 30.1 Introduction 30.1.1 Measuring CA 19-9 in Serum 30.1.2 Malignancy 30.1.2.1 Benign Disease 30.1.3 When Is CA 19-9 Not Detected? 30.2 Role of CA 19-9 in Pancreatic Adenocarcinoma 30.2.1 Screening 30.2.2 Diagnosis of PDAC or Precursors 30.2.2.1 Intraductal Papillary Mucinous Neoplasm of the Pancreas (IPMN) 30.2.2.2 Pancreatic Adenocarcinoma 30.3 Prognostic Assessment 30.3.1 Resectability Assessment 30.3.2 Assessment of Treatment Response 30.3.2.1 After Neoadjuvant Treatment 30.3.2.2 After Surgical Resection 30.3.3 Role of CA 19-9 in Metastatic Pancreatic Cancer 30.4 Conclusions References Chapter 31: Biomarkers in Pancreatic Cancer 31.1 Introduction 31.2 The Biomarker Definition 31.3 Technologies for Biomarker Discovery 31.4 Diagnostic Biomarkers 31.4.1 CA 19-9 31.4.2 THBS2 31.4.3 MIC-1 31.4.4 Stromal Markers 31.4.5 Biomarker Signatures 31.4.6 Combination of Circulating Tumor DNA and Protein Biomarkers 31.4.7 Circulating Nucleosomes 31.4.8 microRNAs 31.4.9 Exosomes 31.5 Prognostic Biomarkers 31.5.1 CA 19-9 31.5.2 VEGF 31.5.3 SMAD4 31.5.4 SPARC 31.5.5 S100 Proteins 31.5.6 PD-L1 31.5.7 microRNAs 31.5.8 Circulating Tumor Cells 31.5.9 Molecular Subtypes 31.6 Predictive Biomarkers 31.6.1 Gemcitabine Markers 31.6.2 FOLFIRINOX Markers 31.6.3 Nab-paclitaxel Markers 31.6.4 Erlotinib 31.6.5 Markers for PARP Inhibitors 31.6.6 Markers for Stromal-Targeting Treatment 31.6.7 Immunotherapy Markers 31.6.8 Directing Treatment by Molecular Subtype 31.7 Phases of Biomarker Development 31.8 Study Design Considerations 31.8.1 Sample Integrity 31.8.2 Data Analysis Including Machine Learning 31.9 Conclusion References Chapter 32: Difficult Diagnosis and Differentials to a Solid Pancreatic Tumour 32.1 Introduction 32.2 Diagnostic Work-Up 32.3 Differential Diagnoses of a Pancreatic Tumour 32.4 Autoimmune Pancreatitis 32.5 Acute Focal Pancreatitis 32.6 Groove Pancreatitis 32.7 Chronic Pancreatitis 32.8 Other Solid Malignant Tumours 32.9 Benign Solid Tumours and Mimickers 32.10 Diagnostic Traps 32.11 Conclusions References Chapter 33: The Multidisciplinary Team Conference 33.1 History of the Multidisciplinary Team Conference 33.2 Purpose of the Multidisciplinary Team Conference 33.3 Participants at the Multidisciplinary Team Conference 33.4 The Decision-Making Process and Group Dynamics 33.5 Efficiency of the Multidisciplinary Team Conference 33.6 Pancreatic Cancer Staging and Assessment of Resectability 33.7 Impact of Multidisciplinary Team Conferences 33.8 Perspectives of Multidisciplinary Team Conferences 33.9 The Multidisciplinary Team Conference in Education and Patient Involvement 33.10 Future Research References Chapter 34: Gross Evaluation and Histopathology 34.1 Introduction 34.2 Macroscopic Examination 34.2.1 Colour-Coded Inking 34.2.2 Specimen Dissection 34.2.3 Tissue Sampling 34.3 Microscopic Examination 34.3.1 Pancreatic Ductal Adenocarcinoma and Subtypes 34.3.2 TN-staging 34.3.3 Additional Descriptors 34.3.4 Margin Assessment and R-status 34.4 Neoadjuvant Treatment 34.5 Preoperative Diagnostics References Chapter 35: Rare Tumors of the Pancreas 35.1 Introduction 35.2 Rare Epithelial Neoplasms of the Pancreas 35.2.1 Potentially Malignant 35.2.1.1 Solid Pseudopapillary Neoplasm (SPN) 35.2.2 Malignant 35.2.2.1 Pancreatoblastoma 35.2.2.2 Acinar Cell Carcinoma 35.2.2.3 Acinar Cell Cystadenocarcinoma 35.3 Rare Non-epithelial Neoplasms in of the Pancreas 35.3.1 Benign 35.3.1.1 Haemangioma 35.3.1.2 Lymphangioma 35.3.2 Potentially Malignant 35.3.2.1 PEComa 35.3.2.2 Teratoma 35.3.2.3 Gastrointestinal Stromal Tumor (GIST) 35.3.2.4 Solitary Fibrous Tumor (SFT) 35.3.3 Malignant 35.3.3.1 Sarcomas 35.4 Rare Tumor-Like Lesions of the Pancreas 35.4.1 Acinar Cystic Transformation 35.4.2 Lymphoepithelial Cyst 35.4.3 Dysontogenetic Cyst 35.4.4 Parasitic Cyst 35.4.5 Pseudolymphoma References Chapter 36: PET in Pancreatic Cancer 36.1 Introduction 36.2 Positron Emission Tomography 36.3 Pancreatic Cancer 36.3.1 Equivocal Cross-Sectional Imaging 36.4 Preoperative Staging 36.4.1 Characterization of Lymph Nodes 36.4.2 Depiction of Metastases 36.4.3 Depiction of Tumour Recurrence and Monitoring Response to Therapy 36.5 Differential Diagnosis 36.5.1 Pancreatic Neuroendocrine Tumors 36.5.2 Pancreatic Lymphoma 36.5.3 Metastases 36.6 Cystic Neoplasms 36.7 Limitations 36.8 Conclusion References Part VI: Perioperative Care Chapter 37: Prehabilitation for Pancreatic Cancer Surgery 37.1 Introduction 37.2 Defining a Prehabilitation Programme 37.3 Potential Benefits of Prehabilitation 37.3.1 Measuring Outcomes in Prehabilitation 37.4 Prehabilitation Implemented for Pancreatic Surgery 37.5 Perioperative Rehabilitation 37.6 Specific Factors Associated with Pancreatic Surgery to Consider for Prehabilitation 37.6.1 Nutrition and Pancreatic Surgery 37.6.2 Prehabilitation Tailored to Patients Undergoing Pancreatic Surgery 37.6.3 Preoperative Exercise and Pancreatic Surgery 37.6.4 Timing of Prehabilitation in Pancreatic Surgery 37.7 Areas for Future Research 37.8 Conclusions References Chapter 38: Enhanced Recovery Principles in Pancreatic Cancer Surgery 38.1 Introduction 38.2 Preoperative Biliary Drainage 38.3 Preoperative Nutrition 38.4 Perioperative Oral Immunonutrition 38.5 Antithrombotic Prophylaxis 38.6 Postoperative Artificial Nutrition 38.7 Minimal Invasive Surgery 38.8 Conclusion References Chapter 39: The Elderly Patient with Pancreatic Cancer: Trends and Medical Oncology 39.1 Introduction 39.2 An Aging European Population 39.3 Definition of ‘the Elderly’ 39.4 Pancreatic Cancer 39.5 Metastatic Pancreatic Cancer 39.5.1 Elderly Patients and Gemcitabine-Based Chemotherapy 39.5.2 Elderly Patients and Contemporary Chemotherapy Regimens 39.6 Adjuvant Treatment for (Borderline) Resectable Pancreatic Cancer 39.7 Second Line Treatment 39.8 Guidelines for Chemotherapy Treatment in Elderly Patients 39.9 Comprehensive Geriatric Assessment 39.10 Decision-Making: The Elderly Patients’ Perspective 39.11 Conclusion 39.12 Appendix: Recommendations in International Clinical Practice Guidelines on Chemotherapy According to Age and Performance Status References Chapter 40: Surgery/Interventions in the Elderly Patient with Pancreatic Cancer 40.1 Introduction 40.2 Geriatric Considerations 40.2.1 Comprehensive Geriatric Assessment 40.2.2 Geriatric Screening Tools 40.2.3 Prehabilitation 40.3 Surgery 40.3.1 Short-Term Outcomes 40.3.2 Oncologic Outcomes 40.3.3 Patient-Centered and Geriatric-Relevant Outcomes 40.3.4 Prognostic Factors for Surgical Outcomes 40.3.5 Summary of the Surgical Literature 40.4 Peri-Operative Systemic Treatment 40.4.1 Adjuvant Systemic Treatment 40.4.2 Neoadjuvant Systemic Treatment 40.4.3 Chemotherapy as an Alternative to Surgery 40.5 Radiotherapy 40.5.1 Adjuvant Concurrent Chemoradiation 40.5.2 Stereotactic Body Radiation Therapy Without Surgery 40.5.3 Radiotherapy for Symptom Control 40.6 Integrating an Approach to Pancreatic Cancer in Older Adults 40.7 Conclusions References Chapter 41: Preoperative Management of Jaundice 41.1 Introduction 41.2 Historical Perspective 41.3 Aetiology of Obstructive Jaundice in Pancreatic Cancer 41.3.1 Clinical Features 41.4 Consequences of Obstructive Jaundice 41.5 Techniques of Preoperative Biliary Drainage (Table 41.1 [33, 34]) 41.6 Obstructive Jaundice in Pancreatic Head Cancer: To Drain or Not to Drain! 41.6.1 Indications for Preoperative Biliary Drainage 41.6.1.1 Cholangitis 41.6.1.2 Neoadjuvant Chemotherapy 41.6.1.3 Delays in Surgery 41.6.1.4 Elevated Bilirubin 41.7 Optimal Timing of Surgery Post-biliary Drainage 41.8 Complications of Preoperative Biliary Drainage 41.8.1 Effect on Perioperative Morbidity and Mortality 41.8.2 Effect on Bactibilia 41.8.3 Effect on Overall Survival 41.8.4 Complications Specific to ERCP and Stenting 41.8.4.1 Stent-Related Problems 41.8.4.2 Cholangitis 41.8.4.3 Pancreatitis 41.8.5 Complications Specific to PTBD 41.9 The Role of Antibiotics with Preoperative Biliary Drainage? References Chapter 42: Nutritional Support and Therapy Before and After Pancreatic Surgery 42.1 Introduction 42.2 Preoperative Evaluation of the Nutritional Status, Malnutrition Risk and Anthropometry 42.3 Indications to Pre-operative Nutritional Support 42.4 The Effect of the Gastrointestinal Reconstruction Technique on Gastric Emptying, Resumption of Oral Feeding, and Long-Term Nutritional Status 42.5 Safety and Efficacy of Early Oral Feeding 42.6 When to Place a Feeding Tube During Surgery 42.7 Optimal Route for Post-operative Artificial Nutritional Therapy 42.8 Techniques for Placement of an Enteral Feeding Tube 42.9 Evaluation of Exocrine Pancreatic Function (EPI) 42.10 Pancreatic Enzyme Replacement Therapy (PERT) 42.11 Conclusion References Chapter 43: Management of Pancreatic Exocrine Insufficiency 43.1 Introduction 43.1.1 Pathophysiology of Exocrine Insufficiency 43.2 Diagnosis of Pancreatic Exocrine Insufficiency in Pancreatic Cancer 43.2.1 Secretin-Pancreozymin Test 43.2.2 Faecal Fat Quantification 43.2.3 Breath Tests 43.3 Consequences of PEI in Adults with Pancreatic Cancer 43.4 Nutritional Evaluation 43.5 Quality of Life 43.6 Pancreatic Exocrine Replacement Therapy (PERT) in Pancreatic Cancer 43.6.1 Use of Replacement Therapy in Practice 43.6.2 Adjuncts to Treatment 43.7 Treatment of PEI and of Unresolved Symptoms of PEI When on PERT 43.7.1 After Pancreatic Head Surgery 43.8 Conclusion References Chapter 44: Chemotherapy for Advanced Pancreatic Cancer: Available Drugs, Mechanisms and Toxicity 44.1 Introduction 44.2 Chemotherapies 44.2.1 Fluoropyrimidines 44.2.2 Gemcitabine 44.2.3 Platinum Chemotherapies 44.2.4 Nab-Paclitaxel 44.2.5 Irinotecan and Liposomal Irinotecan 44.3 Non-chemotherapy Agents 44.3.1 Erlotinib 44.3.2 Olaparib 44.4 First Line Palliative Systemic Anti-cancer Regimens 44.4.1 Gemcitabine 44.4.2 Gemcitabine and Capecitabine 44.4.3 Gemcitabine and Nab-Paclitaxel 44.4.4 Other Lesser-Used Gemcitabine Combinations 44.4.5 FOLFIRINOX 44.5 Second Line Palliative Systemic Anti-cancer Regimens 44.5.1 Oxaliplatin and 5-FU 44.5.2 Liposomal Irinotecan and 5-FU 44.5.3 Maintenance Olaparib 44.6 Conclusion References Chapter 45: Neoadjuvant Therapy in Upfront Resectable Pancreatic Cancer 45.1 Introduction 45.2 Progress in Adjuvant Treatment 45.3 Neoadjuvant Approach 45.4 Current Evidence for a Neoadjuvant Approach 45.4.1 Observational Studies 45.4.2 Randomized Trials 45.4.3 Current Controversy and Debate 45.5 Potential Advantages with a Neoadjuvant Approach 45.5.1 Compliance to Chemotherapy 45.5.2 Managing Micrometastatic Disease 45.5.3 Test of Biology: Allow Emergence of Occult Metastatic Disease 45.5.4 Test of Performance Status Before Major Surgery 45.5.5 Decrease Surgical Complexity 45.5.6 Improve Resection Margin and Lymph Node Status 45.6 Potential Disadvantages with a Neoadjuvant Approach 45.6.1 Complications Related to Invasive Procedures 45.6.2 Low Rate of Complete or Significant Radiological or Pathologic Response 45.6.3 Therapeutic Toxicity 45.6.4 Progression During Neoadjuvant Therapy 45.7 Conclusions References Chapter 46: Neoadjuvant and Adjuvant Radiotherapy in Operable Pancreatic Cancer 46.1 Introduction 46.2 Neoadjuvant Radiotherapy in Borderline Resectable and Resectable Pancreatic Cancer 46.3 Adjuvant Radiotherapy in Resected Pancreatic Cancer 46.4 Future Directions 46.4.1 Utilizing Technological Advances to Improve Radiotherapy Delivery 46.4.2 Targeted Therapy and Immunotherapy in Combination with Radiotherapy 46.5 Conclusion References Chapter 47: Preoperative Therapy in Patients with Borderline Resectable and Locally Advanced Pancreatic Cancer 47.1 Locally Advanced and Borderline Resectable Pancreatic Cancer 47.2 Staging and Diagnosis 47.2.1 Imaging 47.2.2 Diagnosis 47.2.3 CA19-9 47.2.4 Baseline Conditions 47.2.5 Diagnostic Laparoscopy 47.3 Choice of Preoperative Treatment 47.3.1 Types of Chemotherapy 47.3.2 Side Effects 47.4 Response and Restaging After Induction Chemotherapy 47.4.1 Radiographic Response 47.4.2 Biochemical Response 47.4.3 Histopathologic Response 47.5 Outcomes 47.5.1 Borderline Resectable Pancreatic Cancer 47.5.2 Locally Advanced Pancreatic Cancer 47.6 Ablation Following Induction Chemotherapy 47.7 Conclusion References Chapter 48: The Evolution of Adjuvant Trials in Pancreatic Cancer 48.1 Introduction 48.2 Adjuvant Therapy Trials in Pancreatic Cancer 48.3 Adjuvant Chemoradiotherapy Trials in Pancreatic Cancer 48.4 Local/Distant Recurrence 48.5 Prognostic Factors 48.6 Conclusion References Part VII: Surgery Chapter 52: The Role of Laparoscopic Staging in Pancreatic Cancer 52.1 Introduction 52.2 Staging in Pancreatic Cancer 52.3 Controversies in Laparoscopic Staging 52.4 Indications for Laparoscopic Staging 52.5 Surgical Technique of Laparoscopic Staging 52.5.1 Positioning and Trocar Placement 52.5.2 Intrabdominal Examination 52.5.3 Laparoscopic Ultrasonography 52.6 Conclusion References Chapter 53: Standard Pancreatoduodenectomy for Resectable Pancreatic Cancer 53.1 Introduction 53.2 The Procedure 53.3 Exploratory Phase 53.3.1 Mobilization of Duodenum 53.3.2 Identification of the SMV 53.3.3 Dissection in Hepatoduodenal Ligament 53.4 Resection Phase 53.4.1 Transsection of the Duodenum and Pancreas 53.4.2 Division of the Mesopancreas 53.4.3 Standard lymphadenectomy 53.5 Reconstruction Phase 53.5.1 Pancreato-Enteric Anastomosis 53.5.2 Duct-to-Mucosa Pancreato-Jejunal Anastomosis 53.5.3 Dunking Procedure Pancreato-Jejunal Anastomosis (Invagination Technique) 53.5.4 Bilioenteric Anastomosis 53.5.5 Reconstruction of Gastrointestinal Continuity 53.6 Conclusions References Chapter 54: Pancreatoduodenectomy with Portal Vein Resection 54.1 Introduction 54.2 Historical Background 54.3 Oncological Considerations 54.4 Preoperative Work-Up and Imaging 54.5 Classifications 54.6 Types of Venous Reconstruction 54.6.1 Vein Reconstruction with Interposition Graft (Type 4) 54.7 Surgical Technique: Use of Left Renal Vein as Interposition Graft 54.8 Postoperative Treatment and Specific Complications 54.8.1 Anticoagulation and Extended Post-operative Thromboprophylaxis 54.8.2 Left-Sided Portal Hypertension 54.9 Clinical and Oncological Outcomes 54.