The Pancreas E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 3432

Veröffentlichungsjahr: 2018

Beschreibung

This brand new updated edition of the most comprehensive reference book on pancreatic disease details the very latest knowledge on genetics and molecular biological background in terms of anatomy, physiology, pathology, and pathophysiology for all known disorders. Included for the first time, are two brand new sections on the key areas of Autoimmune Pancreatitis and Benign Cystic Neoplasms. In addition, this edition is filled with over 500 high-quality illustrations, line drawings, and radiographs that provide a step-by-step approach to all endoscopic techniques and surgical procedures. Each of these images can be downloaded via an online image bank for use in scientific presentations. Every existing chapter in The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery, 3rd Edition has been thoroughly revised and updated to include the many changes in clinical practice since publication of the current edition. The book includes new guidelines for non-surgical and surgical treatment; new molecular biologic pathways to support clinical decision making in targeted treatment of pancreatic cancer; new minimally invasive surgical approaches for pancreatic diseases; and the latest knowledge of neuroendocrine tumors and periampullary tumors. * The most encyclopedic book on the pancreas--providing outstanding and clear guidance for the practicing clinician * Covers every known pancreatic disorder in detail including its anatomy, physiology, pathology, pathophysiology, diagnosis, and management * Completely updated with brand new chapters * Over 500 downloadable illustrations * An editor and author team of high international repute who present global best-practice The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery, 3rd Edition is an important book for gastroenterologists and gastrointestinal surgeons worldwide.

Leseprobe

Table of Contents

Cover

Title Page

Contributors

Preface

Abbreviations

About the Companion Website

Section 1: Anatomy of the Pancreas

1 Development of the Pancreas and Related Structures

Anatomy of the Pancreas

Organogenesis in the Region of the Pancreas

Early Pancreatic Development

Differentiation of Pancreas Cell Types

Transcriptional Mechanisms Underlying Pancreatic Cell Fate Decision

Development and Disease

Acknowledgment

References

2 Anatomy, Histology, and Fine Structure of the Pancreas

Introduction

Gross Anatomy

Histology and Ultrastructure

Endocrine Pancreas

Acknowledgments

References

3 Congenital and Inherited Anomalies of the Pancreas

Introduction

Primary Malformations

Isolated Congenital Disorders of Pancreatic Endocrine Function

Other Hereditary Disorders with Variable Pancreatic Involvement and Metabolic Diseases Affecting the Pancreas

Inherited Metabolic Disorders Affecting the Pancreas

References

Section 2: Physiology and Pathophysiology of Pancreatic Functions

4 Physiology of Acinar Cell Secretion

Introduction

Composition of Pancreatic Acinar Juice

Acinar Fluid and Enzyme Secretion

Ca Signaling

Organelles Important for Ca Homeostasis

Mechanisms of Ca Signal Generation

Ca Entry and Exit

Ca‐Mediated Control of Enzyme Secretion

Ca‐Mediated Control of Fluid Secretion

Dangers of Ca Signaling

References

5 Physiology of Duct Cell Secretion

Introduction

Sequential Secretion by Acinar and Duct Cells

Regulation of Ductal Secretion

The Ca and cAMP Pathways Synergize to Activate Ductal Secretion

Ductal Secretion‐Associated Pancreatic Diseases

Acknowledgment

References

6 Pathophysiology of Experimental Pancreatitis

Introduction

Models of Acute Pancreatitis

Phases of Acute Pancreatitis

Early Intra‐Acinar Events in Acute Pancreatitis

Conclusion

References

7 Physiology and Pathophysiology of Function of Sphincter of Oddi

Introduction

Anatomy and Morphology

Innervation

Physiology

Motility of the Sphincter of Oddi

Sphincter of Oddi Motility Studies in Animals

Sphincter of Oddi Motility in Humans

Pathophysiology of the Sphincter of Oddi Dysfunction (SOD)

Conclusion

References

8 Neurohormonal and Hormonal Control of Pancreatic Secretion

Introduction

Stimulation of Pancreatic Secretion

Inhibition of Pancreatic Secretion

Feedback Regulation of Pancreatic Secretion

Conclusion

References

9 Regulation of Pancreatic Protein Synthesis and Growth

Introduction

Regulation of Protein Synthesis

Regulation of Pancreatic Growth

References

10 Fibrogenesis in the Pancreas: The Role of Stellate Cells

Introduction

Pancreatic Stellate Sells (PSC)

Acute Pancreatitis

Chronic Pancreatitis

Pancreatic Cancer

Conclusion

References

11 Fibrogenesis of the Pancreas: The Role of Macrophages

Introduction

Macrophages

Origin and Characteristics of Pancreatic Macrophages

Role of Macrophages in Chronic Pancreatitis‐Associated Fibrosis

Role of Macrophages in Pancreatic Cancer‐Associated Fibrosis

Conclusion

References

12 Insulo–Acinar Relationship

Introduction

Structural Relationships Between Pancreatic Islets and Exocrine Pancreas

Insulo‐Acinar Portal System

Regulation of Pancreatic Exocrine Secretion by Islet Hormones

Pancreatic Exocrine Function and Diabetes Mellitus

References

Section 3: Acute Pancreatitis

13 Epidemiology and Etiology of Alcohol‐Induced Pancreatitis

Introduction

Epidemiology

Pathogenesis

Summary

Acknowledgment

References

14 Epidemiology and Etiology of Acute Biliary Pancreatitis

Introduction

Etiology of Gallstone Pancreatitis

Epidemiology of Biliary Acute Pancreatitis

References

15 Genetic Factors in Acute Pancreatitis

Introduction

Genetic Susceptibility Factors

Multiple Genetic Defects and Susceptibility

Progression to Chronic Pancreatitis

Future Directions

References

16 The Role of the Intestine and Mesenteric Lymph in the Development of Systemic Inflammation and MODS in Severe Acute Pancreatitis

Introduction

Role of the Intestine and Mesenteric Lymph in Multiple Organ Dysfunction Syndrome

Role of the Intestine in Severe Acute Pancreatitis

Altered Gut–Lymph Composition in Acute Pancreatitis

Gut–Lymph Toxicity in Acute Pancreatitis

Translating the Gut–Lymph Concept to Clinical Treatments for Acute Pancreatitis

Conclusion

References

17 The Role of Neurogenic Inflammation in Pancreatitis

References

18 Molecular, Biochemical, and Metabolic Abnormalities in Acute Pancreatitis

Introduction

Molecular and Biochemical Abnormalities

Metabolic and Systemic Abnormalities

Electrocardiographic Abnormalities in Acute Pancreatitis

References

19 Histopathology of Acute Pancreatitis

Introduction

Definition

Histopathologic Patterns of Tissue Necrosis

Acute Pancreatitis with Type 1 Necrosis Pattern

Acute Pancreatitis with Type 2 Necrosis Pattern

Acute Pancreatitis with Type 3 Necrosis Pattern

Histopathology Related to Etiologic Factors and Pathophysiologic Mechanisms

Unsolved Questions

References

20 Clinical Classification Systems of Acute Pancreatitis

Introduction

Reasons for Classifying the Severity of Acute Pancreatitis

New Classification Systems

Validation and Comparison of Classification Systems

Future of Classification Systems

Conclusions

References

21 Clinical Assessment and Biochemical Markers to Objectify Severity and Prognosis

Introduction

Historical Perspectives: Approaches to Severity Assessment

Dynamics of Organ Failure

Multiparameter Scoring Systems

Laboratory Variables

Overview

References

22 Acute Pancreatitis Associated With Congenital Anomalies

Introduction

Pancreas Divisum

Anomalous Pancreaticobiliary Ductal Union

Choledochal Cyst/Choledochocele

Annular Pancreas

Ectopic Pancreatic Tissue

Enteric Duplication Cysts

Conclusions

References

23 Acute Pancreatitis in Children

Introduction

Incidence

Etiology

Pathophysiology

Investigations

Diagnosis

Imaging

Management

Outcomes

Acute Recurrent Pancreatitis

References

24 Acute Pancreatitis Associated With Metabolic Disorders, Infectious Diseases, or Drugs

Introduction

Metabolic Diseases

Infectious Diseases

Drug‐Related Diseases

References

25 Radiologic Diagnosis and Staging of Severe Acute Pancreatitis

Introduction

Classification of Acute Pancreatitis

Radiographic Diagnosis of Severe Acute Pancreatitis

Diagnosis of Local Complications of Acute Pancreatitis

Radiologic Staging of Severe Acute Pancreatitis

Limitations and Pitfalls of Radiological Diagnosis of Acute Pancreatitis

References

Clinical Course and Medical Treatment of Acute Pancreatitis

26 Conservative Therapy of Acute Pancreatitis

Introduction

Fluid Resuscitation

Enteral and Parenteral Nutrition

Conclusions

References

27 ICU Treatment of Severe Acute Pancreatitis

Introduction

Pre‐ICU Management

Special Considerations

Indications for ICU Admission

ICU Treatment of Severe Acute Pancreatitis

Early ICU Management (0–48 Hours from Onset of Pain)

Management of Metabolic Derangements

Late ICU Management (>48 Hours After the Onset of Pain)

Management of Infectious Risks

Transition Planning

References

28 Use of Antibiotics in Severe Acute Pancreatitis

Introduction

Infectious Complications

Spectrum of Bacteria

Rationales for Antibiotics inAcute Pancreatitis

Clinical Studies with Antibiotics

Indications for Antibiotic Treatment

Limitations of Antibiotic Treatment

References

Interventional and Surgical Management of Acute Pancreatitis

29 Indications for Interventional and Surgical Treatment of Necrotizing Pancreatitis

Introduction

Interventions for Pancreatic Necrosis: Historical Perspective

Indications and Timing of Intervention

Pancreatic Necrosis with Infection

Symptomatic Pancreatic Necrosis/Walled‐Off Necrosis

Surgical and Interventional Procedures

Surgical Debridement

Percutaneous Catheter Drainage

Direct Endoscopic Necrosectomy

References

30 Management of Infected Pancreatic Necroses

Pancreatic Necrosis

Mechanical Intervention

Transmural Drainage

Results of Endoscopic Therapy of Pancreatic Necrosis

Adverse Events of Endoscopic Therapy of Pancreatic Necrosis

References

31 Minimally Invasive Debridement and Lavage of Necrotizing Pancreatitis

Introduction

Technique

Techniques for Complex Collections

Early Complications

Postoperative Course

Outcome

References

32 Open Surgical Debridement in Necrotizing Pancreatitis

Introduction

General Technique of Open Surgical Debridement

Continuous Closed Lavage

Debridement and Open Packing/Staged Laparotomy

Debridement and Closed Packing

Open Cystogastrostomy for Walled‐Off Pancreatic Necrosis

Conclusion

References

33 Endoscopic Treatment of Biliary Acute Pancreatitis

Pathogenesis of Acute Biliary Pancreatitis

Diagnosis

Indication of Endoscopic Treatment

Techniques

Outcomes and Timing of Endoscopic Interventions

Cholecystectomy After Endoscopic Treatment

References

34 Strategies for the Treatment of Pancreatic Pseudocysts and Walled‐Off Necrosis After Acute Pancreatitis

Introduction

Indications for Endoscopic Treatment

Endoscopic Drainage vs. Necrosectomy: Choosing the Right Patient

Preventing Recurrence by Treating Disconnected Duct Syndrome

References

35 Strategies for the Treatment of Pancreatic Pseudocysts and Walled‐Off Necrosis After Acute Pancreatitis

Introduction

Definition of Pancreatic Pseudocyst and Walled‐Off Necrosis

Indications for Surgical Intervention

Timing of Interventions and Optimal Interventional Strategy for Walled'Off Necrosis

Surgical Intervention for PPC

References

36 Management of Fluid Collection in Acute Pancreatitis

Introduction

Definitions

Imaging of Acute Fluid Collections

Conservative Treatment of Pancreatitis and Pancreatic Fluid Collections

Conclusion

References

37 Management of Pancreatic Fistula in Acute Pancreatitis

Introduction

Pathogenesis and Classification

Diagnosis

Management of External Fistulas

Management of Internal Fistulas

Conclusions

References

Long-Term Outcome After Treatment of Acute Pancreatitis

38 Long‐Term Outcome After Acute Pancreatitis

Introduction

Risk Factors

Endocrine Pancreatic Dysfunction

Exocrine Dysfunction

Recurrent Pancreatitis and Chronic Pancreatitis

Quality of Life and Pain

Incisional Hernia

Pancreatic Cancer and Pancreas‐Related Death

Imaging Findings

Postpancreatitis Care and Follow‐Up Visits

Conclusions

References

Section 4: Chronic Pancreatitis

39 Molecular Understanding of Chronic Pancreatitis

Introduction

Risk Factors in Chronic Pancreatitis

Sentinel Acute Pancreatic Event Model

Epigenetics as a Modifying Factor in Chronic Pancreatitis

Environmental Exposures as Modifying Factors in Chronic Pancreatitis

Genetic Influences in Chronic Pancreatitis

Inflammatory Response in Chronic Pancreatitis

Fibrogenesis in Chronic Pancreatitis

Conclusions

References

40 Epidemiology and Pathophysiology of Alcoholic Chronic Pancreatitis

Introduction

Epidemiology of Alcoholic Chronic Pancreatitis

Pathophysiology

Co‐Predisposing Factors for the Development of Alcoholic Chronic Pancreatitis

References

41 Pain Mechanisms in Chronic Pancreatitis

Introduction

Extrapancreatic Pain

Pancreatic Pain

Neural Remodeling

Conclusions

References

42 Natural History of Recurrent Acute and Chronic Pancreatitis

Introduction

Natural History After First Attack of Acute Pancreatitis

Natural History of Chronic Pancreatitis

Conclusion

References

43 Chronic Pancreatitis with Inflammatory Mass of the Pancreatic Head

Introduction

Incidence

Symptoms, Pathophysiology, and Clinical Problems

Clinical Workup and Differential Diagnosis

Treatment

Conclusions

References

44 Early Chronic Pancreatitis

Introduction

Diagnosis of Early Chronic Pancreatitis

References

45 Hereditary Chronic Pancreatitis

Clinical and Genetic Definitions

Epidemiology

Clinical Presentation

Management

Molecular Genetics

Genetic Testing and Counseling

References

46 Epidemiology and Pathophysiology of Tropical Chronic Pancreatitis

Introduction

Pathophysiology

Natural History of the Disease

Conclusion

References

47 Cystic Fibrosis (CFTR)‐Associated Pancreatic Disease

Introduction

Pathophysiology—Genotype and Phenotype Correlations

Clinical Manifestations

Diagnosis

Therapy

References

48 Clinical and Laboratory Diagnosis of Chronic Pancreatitis

Introduction

Clinical Presentation

Etiology

Pain

Malabsorption and Weight Loss

Endocrine Insufficiency

Jaundice

Laboratory Diagnosis

Conclusion

References

49 Evidence of Contrast‐Enhanced CT and MRI/MRCP

Introduction

Diagnosis of Chronic Pancreatitis

Differential Diagnosis of Mass‐Forming Chronic Pancreatitis and Pancreatic Cancer

CT and MRI for Autoimmune Pancreatitis

CT and MRI for Groove Pancreatitis

Complications of Chronic Pancreatitis

References

50 Chronic Pancreatitis:

Introduction

Descriptive Findings

Measuring the Strength of the Pancreatitis–Pancreatic Cancer Association

Discussion

References

Conservative Treatment of Chronic Pancreatitis

51 Pain Management in Chronic Pancreatitis

Introduction

Neuropathologic Theory

The Plumbing Theory

Pain Measurement

Treatment Options for Patients with Chronic Pancreatitis

Timing

Conclusions

References

52 Medical Treatment of Chronic Pancreatitis: Pancreatic Digestive Enzymes: Lipases, Proteases

Introduction

Management of Exocrine Pancreatic Insufficiency

Emerging Therapies

References

53 Nutritional Support of Chronic Pancreatitis

Introduction

Undernutrition

Nutrient Deficiency

Micronutrient Supplementation

Osteoporosis and Bone Health

Dietary Intervention

Enteral and Parenteral Nutrition

Combined Pancreatic Exocrine and Endocrine Deficiency

Structured Nutritional Assessment

References

54 Medical Therapy for Chronic Pancreatitis:

Introduction

Pain and Oxidative Stress

Clinical Studies of Antioxidants for Pain

Conclusions

References

Strategies for Endoscopic and Surgical Treatment of Chronic Pancreatitis

55 Evidence of Endoscopic and Interventional Treatment of Chronic Pancreatitis and Pseudocysts

Indications for Interventional Endoscopic or Surgical Therapy

Treatment of Pancreatic Cysts

Therapy of Pancreatic Duct Stenoses and Ductal Stones

Endoscopic Treatment of Bile Duct Obstruction

References

56 Indications and Goals of Surgical Treatment

Introduction

Surgical Drainage of the Pancreatic Duct

Surgical Resection of the Pancreas

Surgical Management of Biliary Obstruction

References

57 Pancreatic Duct Drainage Procedure

Introduction

Indication for Surgery

Drainage Procedures

Conclusion

References

58 Duodenum‐Preserving Pancreatic Head Resection

Introduction

Are Duct Stenting and Endoscopic Interventions an Alternative to Surgery?

Who Benefits from Surgical Treatment?

Kausch–Whipple Resection or Hemipancreatectomy—Still Standard Treatment for Chronic Pancreatitis?

Indications and Rationale for Duodenum‐Preserving Pancreatic Head Resection

Surgical Technique of DPPHR for Chronic Pancreatitis

Early Postoperative Course

Long‐Term Outcome After DPPHR

The Frey Procedure—an Alternative Surgical Approach for all Patients with Chronic Pancreatitis?

Summary

References

59 Major Pancreatic Resection

Overview

Major Pancreatic Resection

Pancreatoduodenectomy

Distal Pancreatectomy

Total Pancreatectomy

References

60 Laparoscopic Surgery

Introduction

Resection Procedures

Drainage Procedures

Combination Procedures (Resection and Drainage)

Patient Selection

Conclusion

References

Management of Diabetes and Long-Term Outcome of Chronic Pancreatitis

61 Chronic Pancreatitis

Introduction

Outcomes of Interventional and Surgical Therapy for Pancreatic Pseudocysts

Outcome of Pain Management in Chronic Pancreatitis

Outcome of Therapeutic Options for Biliary and Pancreatic Ductal Stenoses

Conclusion

References

62 Management of Pancreatic Diabetes Secondary to Chronic Pancreatitis

Introduction

Definition and Prevalence of Pancreatic Diabetes

Incidence of Diabetes in Chronic Pancreatitis

Risk Factors for Pancreatic Diabetes in Chronic Pancreatitis

Pathogenesis of Pancreatic Diabetes

Diagnosis of Type 3c Diabetes

Clinical Characteristics of Pancreatic Diabetes

Complications of Pancreatic Diabetes

Therapy of Pancreatic Diabetes

Prognosis of Pancreatic Diabetes

References

Section 5: Autoimmune Pancreatitis

63 Epidemiology of Autoimmune Pancreatitis

Introduction

Nationwide Survey of Autoimmune Pancreatitis in Japan

First International Survey of Autoimmune Pancreatitis

Second International Survey of Autoimmune Pancreatitis

Third International Survey of Autoimmune Pancreatitis

Conclusions

References

64 Pathogenesis of Autoimmune Pancreatitis

Introduction

Type 1 Autoimmune Pancreatitis

Type 2 Autoimmune Pancreatitis

References

65 Histology of Autoimmune Pancreatitis

Introduction

Type 1 Autoimmune Pancreatitis

Pancreatic Cancer and Autoimmune Pancreatitis

Type 2 Autoimmune Pancreatitis

Unclassified Autoimmune Pancreatitis

Conclusions

References

66 Clinical Manifestation of Type 1 Autoimmune Pancreatitis

Type 1 and Type 2 Autoimmune Pancreatitis

International Consensus Diagnostic Criteria (ICDC) for Autoimmune Pancreatitis

Clinical Features of Type 1 Autoimmune Pancreatitis

IgG4‐Related Disease (IgG4‐RD)

References

67 Clinical Manifestations of Type 2 Autoimmune Pancreatitis

Introduction

Search Criteria

Historical Perspective

Terminology

Epidemiology

Demographics

Disease Associations

Clinical Symptoms and Signs

Diagnosis

Differential Diagnosis

Treatment

Disease Relapse

Clinical Course and Outcome

Summary

References

68 Laboratory Diagnosis of Autoimmune Pancreatitis

Introduction

Serum Markers

Markers of Autoimmunity

Other Markers

Conclusion

References

69 What is the Evidence Measuring Immune Markers

Introduction

Evidence of the Utility of Markers in Autoimmune Pancreatitis Diagnosis

Evidence of the Utility of Markers in Differentiating Autoimmune Pancreatitis from Mimicking Conditions

Evidence of the Utility of Markers in Predicting Relapse

Acknowledgments

References

70 Imaging Diagnosis of Autoimmune Pancreatitis

Introduction

Pancreatic Parenchyma Imaging

Pancreatic Duct Imaging

Acknowledgment

References

71 Medical Management of Autoimmune Pancreatitis

Introduction

Management of Autoimmune Pancreatitis: An Overview

Definitions

Management of Initial Presentation

Management of Relapse

Follow‐Up and Management of Disease‐Related Sequelae

Risk of Pancreatic Malignancy

Management of Medication Side‐Effects

Management of Idiopathic Duct‐Centric Pancreatitis

Conclusion

References

Long-Term Outcome of Management of Autoimmune Pancreatitis

72 Long‐Term Outcome After Treatment of Autoimmune Pancreatitis

Introduction

Disease Relapse after Steroids and Treatment

Loss of Pancreatic Function and Evolution Toward Chronic Pancreatitis

Risk for Pancreatic and Extrapancreatic Cancer

References

Section 6: Neoplastic Tumors of the Exocrine Tissue: Benign Cystic Neoplasms of the Pancreas

73 Epidemiology of Cystic Neoplasms of the Pancreas

Introduction

Pancreatic Cyst Lesions

Pancreatic Cystic Neoplasms

References

74 Histologic Classification and Staging of Cystic Neoplasms

Introduction

Serous Cystic Neoplasms

Mucinous Cystic Neoplasm

Intraductal Papillary Mucinous Neoplasm

Solid Pseudopapillary Neoplasm

Acinar Cell Cystadenoma

Mature Cystic Teratoma

References

75 Molecular Mechanisms of Cystic Neoplasia

Introduction

Serous Cystic Neoplasm

Intraductal Papillary Mucinous Neoplasm

Mucinous Cystic Neoplasm

Solid‐Pseudopapillary Neoplasm

Other Cystic Neoplasms of the Pancreas

Clinical Applications

Implications for Families

Conclusions

References

76 Clinical Presentation of Cystic Neoplasms

Introduction

Classification

General Clinical Presentation of Pancreatic Cysts

Clinical Presentation and Characteristics of Serous Cystic Neoplasms

Clinical Presentation and Characteristics of Mucinous Cystic Neoplasms

Clinical Presentation and Characteristics of Intraductal Papillary Mucous Neoplasms

Clinical Presentation and Characteristics of Solid‐Pseudopapillary Neoplasms

Clinical Presentation and Characteristics of Cystic Pancreatic Neuroendocrine Neoplasms

References

77 Evaluation of Cystic Lesions Using EUS, MRI, and CT

Introduction

Low‐Risk Pancreatic Cysts

Pancreatic Cysts with Malignant Potential

Future Technology

Acknowledgment

References

78 Cytologic Evaluation of Cystic Neoplasms

Introduction

Cytology of Neoplastic Cysts

Summary

References

79 Natural History of Cystic Neoplasms: IPMN, MCN, SCN, and SPN

Introduction

Intraductal Papillary Mucinous Neoplasms

Mucinous Cystic Neoplasms

Serous Cystic Neoplasms

Solid‐Pseudopapillary Neoplasm

References

80 Surveillance or Surgical Treatment in Asymptomatic Cystic Neoplasms

Introduction

Rationale for Surveillance or Surgery in Asymptomatic Cystic Neoplasms

Treatment Guidelines for Asymptomatic Cystic Neoplasms

Quality of Life, Surgery Versus Surveillance

Cost‐Effectiveness of Each Approach

References

Local and Standard Surgical Treatment of Cystic Neoplasms

81 Duodenum‐Preserving Partial or Total Pancreatic Head Resection

Background

Classical Pancreatoduodenectomy or Local Extirpation for Cystic Neoplasms of the Pancreatic Head?

Rationale for Local Pancreatic Head Resection

Duodenum‐Preserving Total Pancreatic Head Resection With or Without Segmental Resection of the Peripapillary Duodenum and the Intrapancreatic Common Bile Duct

Conclusion

Acknowledgment

References

82 Pancreatic Middle Segment Resection

Introduction

Indications

Contraindications

Technique

Results

Conclusions

References

83 The Indications For and Limitations of Tumor Enucleation

Introduction

Indications

Contraindications

Surgical Technique

Postoperative Management

Complications

Outcomes

Contraindications

Cyst Ablation

Conclusions

References

84 Standard Surgical Management of IPMN, MCN, SPN, and SCN Lesions:

Introduction

Pancreatic Cystic Neoplasm Subtypes, Surgical Indications, and Operative Intervention

Pancreatectomy

Conclusion

References

85 Surgical Treatment of Cystic Neoplasms

Introduction

Specific Surgical Considerations and Procedures

Future Perspectives

References

86 Management of Recurrence of Cystic Neoplasms

Introduction

Fate of the Pancreatic Remnant

Predictors of Recurrence

Low‐Risk Lesions Left Behind in Remnant

Postoperative Surveillance Strategy

Conclusions

References

Long-Term Outcome of Management of Cystic Neoplasms

87 Long‐Term Outcome After Observation and Surgical Treatment: What is the Evidence?

Introduction

Serous Cystic Neoplasms

Mucinous Cystic Neoplasms

Intraductal Papillary Mucinous Neoplasms

Solid Pseudopapillary Neoplasms

Final Remarks

References

Section 7: Neoplastic Tumors of Exocrine Tissue: Pancreatic Cancer

88 Epidemiology of Pancreatic Cancer

Incidence, Mortality Trends, Survival Prognosis

Cigarette Smoking

Diabetes

Body Mass Index

Alcohol

Pancreatitis

Dietary Factors

Gastrointestinal Microbiome

Allergy

Family History

Conclusions

References

89 Smoking, a Risk for Pancreatic Cancer

Introduction

Experimental Data Regarding Smoking: A Risk Factor for Pancreatic Cancer

Clinical Data Supporting the Experimental Findings

Summary

References

90 Molecular Understanding of Development of Ductal Pancreatic Cancer

Introduction

Genetic Alterations: The Four Mountains

Genetic Alterations: The Hills

Chromosome Instability

Microsatellite Instability

Mitochondrial Gene Mutations

Expression Changes

Precursor Lesions

Neoplasms with Acinar Differentiation

Clinical Applications

Summary and Conclusions

References

91 Familial Pancreatic Cancer

Introduction

Familial Pancreatic Cancer

Pathology of Familial Pancreatic Cancer

Common Genetic Variants

Summary

References

92 Pathology of Exocrine Pancreatic Tumors

Introduction

Ductal Adenocarcinoma

Cystic Neoplasms

Acinar Cell Lesions

Conclusions

References

93 Pancreatic Cancer

Introduction

Pancreatic Intraepithelial Neoplasia

Intraductal Papillary Mucinous Neoplasm

Intraductal Tubulopapillary Neoplasm

Mucinous Cystic Neoplasms

Acknowledgments

References

94 Clinical History and Risk Factors of Pancreatic Cancer

Introduction

Clinical History of Pancreatic Cancer

Risk Factors for Pancreatic Cancer

Conclusion

References

95 Pancreatic Cancer Within the Uncinate Process

Embryology of the Pancreas

Radiologic Characteristics

Clinical Characteristics of the Uncinate Process Pancreatic Cancer (UPDAC)

References

96 The Role of EUS in the Diagnosis and Differential Diagnosis of Neoplastic Lesions

Introduction

Characteristics of Endoscopic Ultrasound

New Screening Modality Comprising Contrast EUS and Elastography

EUS‐FNA for Solid Pancreatic Lesions (Figs 96.2 and 96.3)

Diagnostic Yield and Safety of EUS‐FNA for Solid Pancreatic Lesions

Factors Affecting EUS‐FNA Procedures

References

97 Radiologic Diagnosis of Pancreatic Cancer: CT, MRI

Introduction

Multidetector Computed Tomography

Magnetic Resonance Imaging

Conclusion

References

98 Screening of Patients with Hereditary Pancreatic Cancer

Pancreatic Cancer Risk and Pancreatic Screening

At What Age Should Pancreatic Screening Begin and End?

Pancreatic Screening Tests

Lesions Identified by Pancreatic Screening

Pancreatic Pathology not Detected by Current Screening Tests

Surveillance

Surgery for Lesions Identified by Pancreatic Screening

Developing Better Pancreatic Screening Tests

Evaluating the Long‐Term Outcomes of Patients who Undergo Pancreatic Screening

Summary

Acknowledgments

References

99 The Role of  PET in Diagnosis of Pancreatic Cancer and Cancer Recurrence

Introduction

The Role of  PET and  PET‐CT in Primary Tumor Diagnostic of Pancreatic Carcinoma

The Role of PET and PET‐CT in Oncologic Staging of Pancreatic Carcinoma

Therapy Control and Diagnostics of Malignant Pancreatic Tumor Recurrence by PET and PET‐CT

Potential Value of PET‐MRI in Patients with Pancreatic Cancer

Conclusion

References

100 Tumor Markers in Pancreatic Malignancies

Conventional Tumor Markers for Pancreatic Cancer

Other Markers for Pancreatic Malignancies

Novel Markers for Pancreatic Cancer

References

101 The Role of Laparoscopy and Peritoneal Cytology in the Management of Pancreatic Cancer

Introduction

Laparoscopy

Peritoneal Cytology

References

102 Clinical Assessment and Staging of Advanced Pancreatic Cancer

Introduction

Clinical Presentation

Evaluation for Pancreatic Cancer

Staging for Advanced Pancreatic Cancer

Conclusion

References

Surgical Treatment of Pancreatic Cancer

103 Pancreatic Cancer

Introduction

Clinical Criteria for Resection

Surgical Criteria for Resection

Surgery for Pancreatic Cancer

Local Invasion

Extrapancreatic Nerve Plexus Invasion

Vascular Invasion

Lymph Node Metastases

Peritoneal Metastases

Liver Metastases

Other Distant Metastases

Effect of Clinical Volume

References

104 Pancreaticoduodenectomy for Pancreatic Cancer, Short‐ and Long‐Term Outcomes After Kausch–Whipple and Pylorus‐Preserving Resection

Introduction

Short‐Term Outcome

Long‐Term Outcome

Future Trends

References

105 Left Pancreatectomy for Body and Tail Cancer

Introduction

Tumor Staging and Resection Eligibility

Surgical Technique

Minimally Invasive Left Pancreatectomy

Postoperative Considerations

Conclusions

References

106 Total Pancreatectomy

Total Pancreatectomy

Elective Total Pancreatectomy and Salvage Completion Pancreatectomy

Perioperative Outcomes After Total Pancreatectomy

Long‐Term Outcomes After Total Pancreatectomy

Indications for Total Pancreatectomy

Limitations of Total Pancreatectomy

References

107 Laparoscopic and Robotic Resection for Pancreatic Cancer

Introduction

Patient Selection and Indications for the MIS Approach to Pancreaticoduodenectomy

Laparoscopic Pancreaticoduodenectomy

Robotic Pancreaticoduodenectomy

Indications for the MIS Approach to the Distal Pancreatectomy

Laparoscopic Distal Pancreatectomy

Robot‐Assisted Distal Pancreatectomy

Adopting the MIS Pancreatectomy: The Learning Curve

Conclusion

References

108 Extended Radical Surgery for Pancreatic Cancer

Introduction

Surgical Procedures and Outcomes

Postoperative Outcome of Extended Surgical Approaches

References

109 Palliative Pancreatoduodenectomy

Introduction

Definition of Palliative Resection

Review of the Literature

Management of Preoperatively Under‐Staged Patients

Conclusions

References

110 Bypass Surgery for Advanced Pancreatic Cancer

Introduction

Background

Symptoms

Endoscopic or Interventional Biliary Decompression

Surgical Bypass: Techniques

Endoscopic Versus Surgical Bypass

Gastric Decompression

Surgical Technique

Comparison of Surgical Gastric Decompression with Nonsurgical Management

Our Approach

References

Nonsurgical Palliation of Pancreatic Cancer

111 Endoscopic and Interventional Palliation of Pancreatic Cancer

Introduction

Biliary Obstruction

Malignant Gastric Outlet Obstruction

Pain Management Derived from Cancer

Anticancer Therapy

Miscellaneous

Acknowledgment

References

Medical Treatment of Pancreatic Cancer

112 Neoadjuvant Treatment of Pancreatic Cancer

Introduction

Neoadjuvant Therapy for Resectable Pancreatic Cancer

Emerging Recognition of Borderline Resectable Pancreatic Cancer

Downstaging Borderline Resectable Disease with Neoadjuvant Therapy

Challenges of Neoadjuvant Therapy in Borderline Resectable and Locally Advanced Pancreatic Cancer

Future Directions

Summary

References

113 Adjuvant Chemotherapy in Pancreatic Cancer

Introduction

Rationale for Adjuvant Therapy

Adjuvant Chemoradiotherapy

Future Directions in Adjuvant Therapy

Timing and Duration of Adjuvant Therapy

Conclusions

References

114 Immunotherapy for Pancreatic Cancer

Introduction

Immunology of Pancreatic Cancer

Therapeutic Vaccines

Non‐Vaccine Immunomodulators Used in Pancreatic Cancer

Targeting Tumor‐Associated Macrophages

Combination Immunotherapy

Conclusion

References

115 Targeted Therapies for Pancreatic Cancer

Introduction

Genomic Landscape of PDAC

Molecular Subtypes Reveal Therapeutic Vulnerabilities

Targeting RAS

MEK/ERK Inhibition

Epidermal Growth Factor Receptor Inhibition

Insulin Growth Factor‐1 Receptor

Pancreatic Stroma

Enabling Targeted Therapies in Pancreatic Cancer

Summary

References

116 Palliative Chemotherapy for Advanced Pancreatic Cancer

The Clinical Burden of Advanced Pancreatic Cancer

The Management of Advanced Pancreatic Carcinoma

References

117 Management of Pain in Pancreatic Cancer

Anatomy and Physiology of Pancreas Cancer Pain

Pharmacologic Pain Management

Chemical Ablation of the Splanchnic Nerves or Celiac Plexus

Surgical Options for Treatment of Pancreatic Cancer

References

118 Role of Radio and Proton Beam Therapy for Pancreatic Cancer

Introduction

Radiation in the Adjuvant Setting

Radiation in Borderline Resectable and Locally Advanced Disease

Proton Beam Therapy

Future Directions

References

119 Management of Cancer Recurrence

Introduction

Incidence, Timing, and Pattern of Recurrence

Surveillance After Resection for Pancreatic Cancer

Treatment of Systemic Recurrence of Pancreatic Cancer

Treatment of Isolated Local Recurrence of Pancreatic Cancer

Rationale for “Local” Therapy Options

Chemoradiation for Isolated Local Recurrence

Re‐resection for Isolated Local Recurrence

Selection of Patients for Local Therapy

Conclusions

References

Long-Term Outcome After Treatment of Pancreatic Cancer

120 Survival and Late Morbidity After Resection of Pancreatic Cancer

Introduction

Survival after Resection for Pancreatic Cancer

Prognostic Risk Factors

Long‐Term Morbidity

Conclusions

References

Section 8: Neoplastic Tumors of the Endocrine Pancreas

121 Epidemiology and Classification of Neuroendocrine Tumors of the Pancreas

Introduction

Epidemiology of Pancreatic Neuroendocrine Tumors (Table 121.1)

Classification

Conclusions

References

122 Pathology of Neuroendocrine Neoplasms

WHO Classification and TNM Classification

Macroscopy

Microscopy

Cytology

Immunohistochemistry and Differential Diagnosis

References

123 Molecular Genetics of Neuroendocrine Tumors

Introduction

Genetics of Sporadic PanNET

Pathways Altered in PanNETs

High‐Grade Neuroendocrine Carcinomas

Comparison of the PanNET Genetic Landscape with Other Pancreatic Neoplasias

Familial Syndromes

Epigenetics

Clinical Implications

Conclusions

References

124 Clinical Manifestation of Endocrine Tumors of the Pancreas

Introduction

Epidemiology of PanNET

Clinical Symptoms of PanNET

Diagnosis of PanNET

References

125 Evidence of Hormonal, Laboratory, Biochemical, and Instrumental Diagnostics of Neuroendocrine Tumors of the Pancreas

Introduction

Serum‐Based Laboratory Investigations

Instrumental and Invasive Investigations

Imaging

Conclusions

References

126 Pancreatic Neuroendocrine Tumors in Multiple Neoplasia Syndromes

Introduction

Epidemiology

Genetics

Diagnosis

Clinical Presentation

Surgical Treatment

Medical Treatment

Prognosis

References

127 Nonfunctioning Pancreatic Neuroendocrine Tumors

Definition

Pathology

Mechanism of Tumorigenicity

Clinical Findings

Symptoms

Diagnosis

Surgical Treatment for Localized Lesions

Multidisciplinary Treatment for Metastatic Lesions

References

128 Medical and Nucleotide Treatment of Neuroendocrine Tumors of the Pancreas

Introduction

Nonsurgical Treatment of the Secretory Syndromes

Nonsurgical Treatment Directed Against Tumor Growth

Conclusions

References

129 Interventional Radiology in the Treatment of Pancreatic Neuroendocrine Tumors

Type of Interventional Radiology Treatment

TAE/TACE

RFA

References

Surgical Management of Endocrine Tumors of the Pancreas

130 Surgical Treatment of Endocrine Tumors

Introduction

Observation Versus Surgery for Small Sporadic, Benign‐Appearing, Nonfunctioning Pancreatic Neuroendocrine Tumors

Preoperative Imaging and Assessment of Proliferative Tumor Activity

Surgical Technique of Enucleation

Short‐ and Long‐Term Outcomes After Enucleation

Outcome After Laparoscopic Enucleation

References

131 Local Treatment of Endocrine Tumors

Background

Surveillance or Treatment of Neuroendocrine Tumors of the Pancreas?

Indication for Surgical Treatment of PanNETs

Parenchyma‐Sparing Local Resection of Neuroendocrine Tumors of the Pancreatic Head

Duodenum‐Preserving Total or Partial Pancreatic Head Resection

Pancreatic Middle‐Segment Resection

Conclusion

Acknowledgment

References

132 Surgical Treatment of Endocrine Tumors

Introduction

Clinical Workup of Advanced PanNET for Major Oncologic Resection

Surgical Approach to Locally Advanced Nonfunctioning PanNET Without Clinical Evidence of Distant Metastases

Locally Advanced Nonfunctioning PanNET with Clinical Evidence of Distant Metastases

References

133 Management of Insulinoma

Introduction

Clinical Features of Insulinomas

Diagnosis of Insulinomas

Localization of Insulinomas

Treatment of Insulinomas

References

134 Evidence of Medical and Surgical Treatment of Gastrinoma

Treatment Strategy

Tumor Localization

Surgery

Treatment of Hepatic Metastases

Systemic Chemotherapy

References

135 Rare Neuroendocrine Tumors of the Pancreas

Introduction

Clinical Features

Prognosis and Survival

Diagnosis

Tumor Localization

Surgical Treatment

Medical Treatment

References

136 Treatment of Neuroendocrine Tumors of the Pancreas and Biliary Tract

Introduction

Neuroendocrine Tumors of the Pancreas

Neuroendocrine Tumors of the Duodenum

Neuroendocrine Tumors of the Liver

Neuroendocrine Tumors of the Extrahepatic Biliary Tract

Neuroendocrine Tumors of the Gallbladder

References

Long-Term Outcome After Treatment of Neuroendocrine Tumors of the Pancreas

137 Long‐Term Outcome After Treatment of Endocrine Tumors

Introduction

Risk Stratification of Pancreatic Endocrine Tumors

Surgical Considerations for Pancreatic Endocrine Tumors

Conclusion

References

Section 9: Periampullary Cancers and Tumors Other Than Pancreatic Cancer

138 Periampullary Cancer

Introduction

Clinical Presentation

Diagnostic Evaluation

Determination of Extent of Resection

Summary

References

139 Histology and Genetics of Cancer of the Papilla, Distal Common Bile Duct, and Duodenum

Carcinoma of Papilla (Ampulla of Vater)

Distal Common Bile Duct Carcinoma

Nonampullary Duodenal Carcinoma

Pathologic Staging of Cancers of this Region

Neuroendocrine Neoplasms and Related Tumors

Pseudotumors that Commonly Mimic Cancer

Secondary Tumors

References

140 Adenoma and Adenocarcinoma of the Ampulla of Vater

Introduction

Epidemiology and Biologic Behavior

Pathology and Pathogenesis

Clinical Features

Diagnosis and Staging of Ampullary Malignancy

Management and Treatment

Posttreatment Surveillance

Long‐Term Results of Surgical Resection

References

141 Endoscopic Treatment of Adenomas of the Ampulla of Vater: Techniques, Results, Benefits, and Limitations

Introduction

Endoscopic Papillectomy

Preprocedural Evaluation

Techniques

Clinical Results

Complications

Postprocedural Surveillance

Conclusions

References

142 Surgical Treatment of Adenoma and Cancer of Papilla of Vater

Introduction

Molecular Pathology of Ampullary Cancer

Endoscopic and Surgical Treatment of Large Adenomas and Carcinoma of the Ampulla of Vater

Ampullectomy for Large Adenomas and Low‐Risk Ampullary Cancer

Pancreatoduodenectomy for Advanced Ampullary Cancer

Survival After Ampullectomy and Pancreatoduodenectomy

Conclusion

Acknowledgment

References

143 Surgical Treatment of Duodenal Cancer

References

144 Surgical Treatment of Distal Cholangiocarcinoma

Introduction

Pyloric Ring Preservation

Lymph Node Dissection

Skeletonization of the Hepatoduodenal Ligament and Dissection of Pancreatic Head Neural Plexus

Bile Duct Cut Margin

Surgery‐Related Complications

Summary

References

145 Adjuvant and Palliative Chemotherapy of Periampullary Cancers

Introduction

Distal Cholangiocarcinoma

Duodenal Adenocarcinoma

Ampullary Carcinoma

Conclusion

References

Long-Term Survival After Tumor Resection

146 Long‐Term Survival After Resection of Periampullary Cancer

Introduction

Distal Bile Duct Cancer

Ampullary Region Cancer

Duodenal Cancer

References

Section 10: Transplantation of the Pancreas

147 Transplantation of Pancreatic Islets

Introduction

Manufacturing, Release Testing, and Infusion of Allogeneic Human Islets

Selection of Islet Allotransplant Recipients

Outcomes of Islet Allotransplantation in T1D

Adverse Effects of Islet Transplantation and Immunosuppression

Outcomes of Islet Autotransplantation in Chronic Pancreatitis

Research Priorities in Islet Transplantation

Conclusions

Acknowledgments

References

148 Transplantation of the Pancreas

Introduction

Epidemiology and Sequelae of Insulin‐Dependent Diabetes Mellitus

Historical Aspects

Indications for Pancreas Transplantation

Preoperative Workup and Cardiac Risk Assessment

Donor Selection and Donor Pancreatectomy

Donor Operation

Deceased Cardiac Death Donors (DCD)

Preservation

Technical Aspects of the Recipient Operation

Current Status and Results of Pancreas Transplantation in the United States

Conclusion

References

Index

End User License Agreement

List of Tables

Chapter 03

Table 3.1 Isolated deficiency of pancreatic enzymes.

Table 3.2 Inherited metabolic diseases with increased risk of pancreatitis

Chapter 07

Table 7.1 Effects of various bioactive agents on the sphincter of Oddi.

Table 7.2 Pressures recorded from the sphincter of Oddi of normal subjects.

Table 7.3 Rome III compulsory diagnostic criteria for sphincter of Oddi disorders.

Table 7.4 Modified Milwaukee Classification for biliary and pancreatic sphincter of Oddi dysfunction.

Chapter 10

Table 10.1 Characteristics of quiescent and activated PSC phenotypes.

Table 10.2 Pancreatic stellate cell activating factors.

Table 10.3 Pancreatic stellate cells: signaling pathways.

Chapter 13

Table 13.1 Individual susceptibility to alcoholic pancreatitis.

Chapter 14

Table 14.1 Landmarks in the understanding of the relationship between the biliary tree and acute pancreatitis.

Table 14.2 Accuracy of three separate systems in predicting gallstones as the cause of acute pancreatitis.

Chapter 15

Table 15.1 Genetic factors involved in the pathogenesis of acute pancreatitis.

Chapter 19

Table 19.1 Correlation of the most important criteria of the Atlanta classification 2012 with the main histopathologic features of conventional acute pancreatitis.

Chapter 20

Table 20.1 The reasons for classification systems in acute pancreatitis.

Table 20.2 New classifications for the severity of acute pancreatitis.

Table 20.3 Key differences between the two classification systems.

Table 20.4 Studies that have compared the determinant‐based classification (DBC) and revised Atlanta classification (RAC) systems from the same dataset.

Table 20.5 Modified determinant‐based classification (DBC) system for patients admitted to intensive care with organ failure [16].

Chapter 21

Table 21.1 Definition of three grades of severity in acute pancreatitis according to the revised Atlanta classification 2012 [3].

Table 21.2 Relevant multiparameter scoring systems and laboratory markers for severity stratification and prediction of specific complications in acute pancreatitis.

Chapter 23

Table 23.1 Series looking at the incidence of acute pancreatitis. Studies reporting increase in number of cases of acute pancreatitis diagnosed in children over time.

Table 23.2 Potential etiologies of acute pancreatitis. The differential list is extensive. A clinician must consider the particular patient’s history of present illness, past medical history, and family history in considering the potential trigger of an attack of acute pancreatitis [2,5,10,11,14–16,20–27].

Table 23.3 Summary of pediatric acute pancreatitis series detailing etiology in 1757 children.

Table 23.4 Mortality data in pediatric acute pancreatitis series [3–5,10,12–17,79].

Chapter 24

Table 24.1 Infectious agents associated with acute pancreatitis.

Chapter 25

Table 25.1 Diagnostic criteria of pancreatic necrosis and their accuracy.

Table 25.2 Diagnosis of local complications on imaging.

Table 25.3 Modified CT severity index.

Chapter 26

Table 26.1 Important human studies of fluid resuscitation in acute pancreatitis.

Chapter 28

Table 28.1 Complications of severe acute pancreatitis with the potential risk of bacterial infection, according to the current revised Atlanta Classification [4].

Table 28.2 Development of the bacterial spectrum of infected pancreatic necrosis during the past 30 years. Selected strains from different studies. Note the increase in the incidence of enterococci and fungi.

Table 28.3 Studies on antibiotic prophylaxis in severe acute pancreatitis. Note that only a few had adequate scientific power for meaningful conclusions.

Chapter 32

Table 32.1 Continuous closed lavage.

Table 32.2 Open packing staged laparotomy.

Table 32.3 Debridement and closed packing.

Chapter 38

Table 38.1 Patterns of long‐term sequelae after acute pancreatitis.

Table 38.2 Risk factors for long‐term complications of acute pancreatitis.

Chapter 42

Table 42.1 Summary of recent studies examining rates and risk factors for readmission after a first attack of acute pancreatitis.

Table 42.2 Summary of recent studies examining the rate and risk factors for development of recurrent acute pancreatitis (RAP) after a first attack of acute pancreatitis.

Table 42.3 Summary of recent studies examining the incidence and risk factors for development of chronic pancreatitis after an attack of acute pancreatitis.

Chapter 45

Table 45.1 Genes associated with pancreatitis.

Table 45.2 Genotype–phenotype correlations and multiorgan syndromes.

Chapter 46

Table 46.1 Gene mutations involved in the pathogenesis of tropical chronic pancreatitis.

Chapter 47

Table 47.1 Effects of

CFTR

mutations on chronic pancreatitis risk.

Chapter 49

Table 49.1 CT and MRI/MRCP findings of chronic pancreatitis.

Chapter 51

Table 51.1 Izbicki pain score.

Table 51.2 Examples of analgesic medication for chronic pancreatitis.

Chapter 52

Table 52.1 Predominant human pancreatic proteases.

Table 52.2 Predominant human pancreatic lipases.

Table 52.3 Recommended pancreatic enzyme dose.

Chapter 55

Table 55.1 Summary of transmural endoscopic pseudocyst/walled‐off pancreatic necrosis drainage, including studies of: traumatic pancreatic pseudocysts [31], pancreatic abscess [32,33], “acute pseudocysts” [34], “infected pseudocysts” [35], “symptomatic peripancreatic fluid collections” [36,37]. Two studies compared ultrasound‐guided versus conventional transmural drainage of pseudocysts in a prospective randomized trial [38,39].

Chapter 56

Table 56.1 Authors’ choice of operation for chronic pancreatitis based on pancreatic morphology typically present.

Chapter 58

Table 58.1 Chronic pancreatitis—frequency of local complications.

Table 58.2 Early postoperative results after duodenum‐preserving subtotal pancreatic head resection in 603 patients.

Table 58.3 Long‐term endocrine and exocrine pancreatic functions after DPPHR for chronic pancreatitis.

Table 58.4 Endocrine function and pain after DPPHR for chronic pancreatitis—results of long‐term follow‐up.

Table 58.5 DPPHR versus pancreatoduodenectomy for chronic pancreatitis—results of a meta‐analysis 2008 [44].

Chapter 59

Table 59.1 Indications and contraindications for surgical resection in chronic pancreatitis.

Table 59.2 Results of pancreatoduodenectomy for chronic pancreatitis.

Table 59.3 Trends in treatments prior to pancreatoduodenectomy from 1976 to 1997 versus 1998–2013.

Table 59.4 Trends in postoperative complications from 1976 to 1997 and 1998–2013.

Table 59.5 Long‐term results (15 years) following pancreatoduodenectomy for chronic pancreatitis.

Chapter 60

Table 60.1 Clinical outcomes following laparoscopic treatment for chronic pancreatitis.

Chapter 62

Table 62.1 Islet cell hormonal response to mixed‐nutrient meal testing.

Chapter 63

Table 63.1 Clinical, radiologic, and serologic features of nonhistologically confirmed AIP patients in the second international survey.

Table 63.2 Initial treatment strategies and relapse in type 1 and type 2 AIP patients in the third international survey.

Chapter 65

Table 65.1 Histopathologic differences between type 1 and type 2 autoimmune pancreatitis

Chapter 66

Table 66.1 Level 1 and level 2 criteria for type 1 AIP.

Table 66.2 Level 1 and level 2 criteria for type 2 AIP.

Table 66.3 Diagnosis of definitive and probable type 1 and type 2 AIP, and AIP‐NOS.

Table 66.4 Comparison of clinical features of Type 1 and Type 2 AIP in eight recent reports.

Chapter 67

Table 67.1 Terminology used to describe type 2 AIP

Chapter 68

Table 68.1 Disease‐specific autoantibodies and immunoglobulins in autoimmune pancreatitis

Chapter 72

Table 72.1 Frequency of relapse in patients suffering from AIP.

Table 72.2 Frequency of relapse in patients suffering from AIP divided in those treated with steroids and who underwent surgery.

Table 72.3 Frequency of pancreatic exocrine and endocrine insufficiency in patients suffering from AIP.

Chapter 74

Table 74.1 Classification of cystic lesions of the pancreas.

Chapter 75

Table 75.1 Identification of cyst type can be problematic.

Table 75.2 Types of cysts with their major genetic alterations.

Chapter 76

Table 76.1 Characteristics of pancreatic cystic lesions

Chapter 78

Table 78.1 Clinical, imaging, and cyst fluid characteristics of primary neoplastic cysts of the pancreas.

Chapter 81

Table 81.1 Short‐ and long‐term metabolic and functional sequelae after pancreatoduodenectomy.

Table 81.2 Indication for DPPHR for benign cystic neoplasms of the pancreatic head.

Table 81.3 Findings after local, parenchyma‐sparing duodenum‐preserving total or partial pancreatic head resection for cystic neoplasms of the pancreatic head.

Chapter 83

Table 83.1 Indications for pancreatic cyst enucleation.

Table 83.2 Contraindications to pancreatic cyst enucleation.

Table 83.3 Pancreatic cyst enucleation case‐control/case series studies from 2007–current. Contemporary case‐control and case series studies from the last decade are displayed. Outcomes of case‐control studies show both the rate of occurrence and an arrow indicating comparison of cyst enucleation to formal resection.

Table 83.4 Risk factors for pancreatic fistula following cyst enucleation.

Chapter 86

Table 86.1 Studies reporting recurrence rates after resection of benign IPMN.

Chapter 90

Table 90.1 “Mountains” of pancreatic tumorigenesis

Table 90.2 Well‐defined “hills” of pancreatic tumorigenesis

Table 90.3 Precursors to ductal adenocarcinoma

Chapter 93

Table 93.1 Nomenclature of the entities, now known as tubular‐predominant, gastric‐type IPMN and ITPN and previously considered as (different grades of) the same entity

Chapter 94

Table 94.1 Clinical symptoms of pancreatic carcinoma.

Table 94.2 Risk factors for pancreatic adenocarcinoma.

Chapter 95

Table 95.1 Clinicopathologic findings of patients with UPDAC: an overview of the reported series.

Table 95.2 Comparison of clinicopathologic findings of uncinate process (UPDAC) and non‐uncinate process cancer (non‐UPDAC) [8].

Chapter 96

Table 96.1 Advantages and disadvantages of EUS imaging modalities.

Chapter 98

Table 98.1 Pancreatic cancer screening guidelines [2].

Chapter 102

Table 102.1 Summary of AJCC Staging, 7th edition, with correlation to overall survival.

Table 102.2 Surgical staging system of NCCN and MD Anderson.

Chapter 103

Table 103.1 Criteria defining resectability status.

Chapter 104

Table 104.1 Definition of resectability of pancreatic cancer.

Table 104.2 Trends of the three most common postoperative morbidities after Whipple for pancreatic cancer.

Chapter 105

Table 105.1 Resectability criteria for pancreatic body and tail cancer.

Chapter 106

Table 106.1 Perioperative mortality and morbidity rates after an elective total pancreatectomy reported in the main literature.

Table 106.2 Long‐term outcomes after total pancreatectomy reported in the main literature.

Chapter 107

Table 107.1 Case series of laparoscopic and robotic pancreaticoduodenectomies.

Table 107.2 Comparative effective analyses of laparoscopic to open pancreaticoduodenectomies.

Table 107.3 Comparative analyses of robotic to open pancreaticoduodenectomies.

Table 107.4 Case series of laparoscopic and robotic distal pancreatectomies

Chapter 110

Table 110.1 Selected studies on endoscopic biliary stenting.

Chapter 111

Table 111.1 Typical technique of nonsurgical biliary decompression.

Chapter 113

Table 113.1 Summary of major trials of adjuvant therapy for pancreatic cancer.

Table 113.2 Comparison of patient populations in JASPAC‐01, CONKO‐01, and ESPAC‐4 trials.

Chapter 118

Table 118.1 Summary of prospective studies evaluating the role of proton beam therapy in pancreatic cancer.

Chapter 119

Table 119.1 Incidence, timing and pattern of recurrence after potentially curative resection for pancreatic cancer in selected RCTs on adjuvant therapy.

Table 119.2 Treatment options for recurrent pancreatic cancer.

Table 119.3(a) Retrospective series of chemoradiation for local recurrence of pancreatic cancer.

Table 119.3(b) Retrospective series of re‐resection for local recurrence of pancreatic cancer.

Chapter 120

Table 120.1 Five‐ and 10‐year survival rates for patient with pancreatic cancer after surgical resection.

Table 120.2 Gastrectomy‐associated complications for patients post‐pancreatoduodenectomy.

Table 120.3 Prevalence of pancreatogenic diabetes mellitus after pancreatectomy.

Table 120.4 Prevalence of post‐pancreatectomy pancreatic exocrine insufficiency.

Chapter 121

Table 121.1 Incidence of pancreatic neuroendocrine tumors in selected autopsy series after the 1970s.

Table 121.2 Functional pancreatic neuroendocrine tumors.

Table 121.3 Pancreatic neuroendocrine tumors associated with hereditary syndromes.

Table 121.4 WHO classification of pancreatic neuroendocrine tumors (2004).

Table 121.5 ENETS 2006 grading proposal for pancreatic neuroendocrine tumors.

Table 121.6 WHO 2010 classification and grading of pancreatic neuroendocrine tumors.

Table 121.7 TNM classification and disease staging for endocrine tumors of the pancreas (ENETS 2006).

Table 121.8 TNM classification and disease staging for endocrine tumors of the pancreas (UICC/AJCC/WHO 2010).

Chapter 122

Table 122.1 WHO 2017 classification of pancreatic neuroendocrine neoplasms [1].

Table 122.2 Two TNM classification of pancreatic neuroendocrine neoplasms listed in the 8th edition of Union for International Cancer Control (UICC) TNM classification for malignant tumors. The two different TNM classifications, one for well‐differentiated tumor (NET G1, G2, G3), the other is for poorly differentiated neuroendocrine carcinoma and other pancreatic neoplasms [8].

Chapter 123

Table 123.1 Comparison of commonly mutated genes and their prevalence in PanNET and other pancreatic neoplasms.

Chapter 124

Table 124.1 Symptomatic gastroenteropancreatic neuroendocrine tumors.

Chapter 125

Table 125.1 Investigation of pancreatic neuroendocrine tumors (see text for details).

Chapter 126

Table 126.1 Suggested program of combined clinical, biochemical, and radiologic screening and follow‐up.

Chapter 127

Table 127.1 Summary of diagnosis and treatment principles for nonfunctioning pancreatic neuroendocrine tumors.

Chapter 128

Table 128.1 Treatment of PanNET according to their secretory component.

Table 128.2 Factors that need to be considered in order to select the most appropriate treatment among the currently available nonsurgical treatments for PanNET.

Table 128.3 Comparison of the findings of Phase III trials of molecular‐targeted therapies.

Chapter 130

Table 130.1 Indications for enucleation of PanNET.

Chapter 131

Table 131.1 Surveillance or local, parenchyma‐sparing pancreatic resection of benign PanNETs and low‐risk NECs.

Table 131.2 Local surgical treatment of neuroendocrine pancreatic tumors and other neoplasms: frequency of extirpation procedures DPPHR and pancreatic middle segment resection (PMSR) for PanNETs.

Table 131.3 Local surgical treatment of neuroendocrine and cystic neoplasms of the pancreas: frequency of surgery‐related complications after DPPHR and PMSR.

Chapter 133

Table 133.1 Clinical symptoms and frequencies in patients with insulinoma.

Table 133.2 Fasting test instructions.

Chapter 135

Table 135.1 Rare pancreatic neuroendocrine tumors.

Chapter 138

Table 138.1 Relative frequencies of resected periampullary cancers.

Chapter 140

Table 140.1 TNM and American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) Staging Systems for Ampullary Cancer.

Table 140.2 Stage‐based approach to endoscopic and surgical management of ampullary malignancy.

Chapter 142

Table 142.1 Correlation between frequency of lymph node metastasis to invasion depth and size of tumor in ampullary cancer.

Table 142.2 Postoperative outcome after resection of neoplasm/cancer of the ampulla of Vater.

Table 142.3 Long‐term survival of cancer of ampulla of Vater after Kausch–Whipple type pancreatoduodenectomy.

Chapter 143

Table 143.1 Survival of duodenal cancer.

Chapter 144

Table 144.1 Clinical factors that have an impact on survival.

Table 144.2 Long‐term survival after resection of distal cholangiocarcinoma.

Chapter 145

Table 145.1 Studies of adjuvant treatments in resected periampullary cancers.

Table 145.2 Studies of palliative treatments in locally advanced and metastatic periampullary cancers.

Chapter 146

Table 146.1 Published series of survivals after surgical resection of distal bile duct cancer.

Table 146.2 Published series of prognostic factors after surgical resection of distal bile duct cancer.

Table 146.3 Published series of survivals after surgical resection of ampullary region cancer.

Table 146.4 Published series of prognostic factors after surgical resection of ampullary region cancer.

Table 146.5 Published series of survivals after surgical resection of duodenal cancer.

Table 146.6 Published series of prognostic factors after surgical resection of duodenal cancer.

List of Illustrations

Chapter 01

Figure 1.1 Germ disks sectioned through the region of the primitive streak, showing gastrulation. (a) On days 14 and 15, the ingressing epiblast cells replace the hypoblast to form the definitive endoderm. (b) The epiblast that ingresses on day 16 migrates between the endoderm and epiblast layers to form the intraembryonic mesoderm.

Figure 1.2 Contributions of the dorsal and ventral pancreas to the definitive organ. The ventral pancreas becomes most of the head. The dorsal pancreas becomes the remainder of the head, plus the body and tail. The duct of the dorsal pancreas contributes a large part of the main pancreatic duct plus the accessory duct. The duct of the ventral pancreas becomes the part of the main duct nearest the duodenum.

Chapter 02

Figure 2.1 This pancreas, from the autopsy of a 47‐year‐old woman, measures 22.5 cm in length and has been dissected free of most surrounding fat. (a) Anterior view with the head at image left. (b) Posterior view. A thin layer of fat (translucent yellow) covers a portion of the head at image right. Note the thin neck region just to the left of the head. (c) Cut surface of a transection through the head of the pancreas showing the lobular pancreatic parenchyma.

Figure 2.2 A pancreas dissected to reveal the pancreatic ducts and common bile duct as it traverses the head of the pancreas, ending as it joins the main pancreatic duct near the ampulla of Vater. Interlobular branches of the main duct are depicted but smaller ducts (intralobular ducts and ductules) are not. Eponyms identify the anatomist, embryologist, or physician who is credited with first describing a structure. Wirsung and Santorini were such scientists.

Figure 2.3 Relationships of the pancreas to surrounding organs. This two‐dimensional drawing depicts structures that lie in several different planes; for example, the kidneys lie lateral to the spine and posterior to the pancreas. The superior mesenteric artery and vein lie anterior to the aorta and inferior vena cava.

Figure 2.4 Frontal CT scan in the plane of the head and body of the pancreas. The technology dictates that all structures shown lie in the same plane. The tail of the pancreas is not shown because it lies posterior to the depicted plane.

Figure 2.5 Diagram of the upper abdomen at the level of the pancreas based on a CT scan. Note that the plane of the image is angled upward on the left as indicated, upper image right. The vertebral column is unlabeled bottom center.

Figure 2.6 Axial CT scan of the upper abdomen at the level of the pancreas. This scan is oriented with the abdominal wall at the top and the spine and muscles of the back at the bottom as viewed from below. Key structures are labeled.

Figure 2.7 The arterial blood supply of the pancreas. Image (a) is visualized from the front and (b) is seen from the back.

Figure 2.8 Lymph nodes draining the pancreas. There is considerable individual variation in the location and size of lymph nodes, so this drawing is somewhat schematic. Both (a) and (b) are anterior views; (b) includes some nodes that lie posterior to the pancreas.

Figure 2.9 Nerves (yellow) serving the pancreas. The cross‐sectional image (a) emphasizes the location of the celiac ganglia of the autonomic system lateral to the aorta while (b) emphasizes the rich nerve plexus that connects these ganglia to the pancreas. SMA, superior mesenteric artery; PL, plexus.

Figure 2.10 Pancreatic lobular tissue with acinar cells, small duct, ductule, and small islet. This H&E‐stained section is largely composed of acini and acinar tubules cut in cross‐section or tangentially. A small intralobular duct (a) is shown image right and at its upper end it gives rise to a ductule (b) with virtually no connective tissue evident in its wall. Liquid content of the duct and ductule is homogeneous and pink (eosinophilic). Large, clear spaces are fat cells (c). A small vein (d) and artery (e) are at image right above center. A small islet is near the lower image right corner.

Figure 2.11 Pancreatic tissue with acinar, centroacinar, and ductal cells. The acinar cells are easily identified because of the darkly stained zymogen granules (ZG) and are larger than centroacinar and ductal cells. The basal portion (B) of the acinar cells lies next to the interstitial space that contains vessels (V), nerves, and connective tissue. Nuclei (N) with nucleoli (n) are in the basal portion of the acinar cells. The golgi (G) lies at the junction of the basal and apical (A) portions of the cell. Centroacinar cells (CAC) have pale cytoplasm with no secretory granules. A small ductule (D) extends from image right to below center. Mitochondria (m) are identified at the top of the field. This is a 1 μm thick section of plastic embedded tissue prepared for electron microscopy that was stained with toluidine blue.

Figure 2.12 Acinar cells with RER, mature, and immature zymogen granules. Two centroacinar cells are near the center. The acinar cell at 3 o’clock, image right, is binucleate. Numerous mitochondria are present in the acinar cells and lower centroacinar cell. There are several electron‐dense residual bodies in the acinar cells. It appears that two have been extruded into the interstitial space at the top of the image and others are being extruded into the acinar lumen near the center of the image.

Figure 2.13 Apical portions of several acinar cells border two luminal spaces, lower image right and upper image left. A centroacinar cell with numerous mitochondria borders the lumen, lower image right. Microvilli protrude into the lumens from the luminal aspect of the acinar and centroacinar cells. Zymogen granules are prominent in all acinar cells.

Figure 2.14 Serial cross‐sections of main pancreatic duct (a) (H&E stain) stained to demonstrate collagen (b) (trichrome stain), myofibroblasts (c) (immunoperoxidase stain to demonstrate smooth muscle actin, a marker for myofibroblasts), and smooth muscle (d) (immunoperoxidase stain to demonstrate desmin, a marker for smooth muscle). The lining epithelium has been lost, probably reflecting preoperative ERCP and stenting of the pancreatic duct. The patient underwent a Whipple procedure because of chronic pancreatitis. There are many myofibroblasts and fewer smooth muscle cells in the wall of the main duct.

Figure 2.15 Serial cross‐sections of a small intralobubular duct surrounded by acinar tissue from the same patient as in Fig. 2.14. (a) H&E stain. Note the origin of a ductule branching into acinar tissue at 7 o’clock. (b) Trichrome stain with blue‐staining collagen. There is fibrosis around acinar lobules (upper image left). (c) Immunoperoxidase stain with antibody to smooth muscle actin (SMA) to demonstrate the abundant myofibroblasts. (d) Immunoperoxidase stain with antibody to desmin to demonstrate smooth muscle cells. There is little staining.

Figure 2.16 Pancreas ductule (top center) branches (upper image right) to reach several acini or acinar tubules (upper image right and near the center). Blue zymogen granules are conspicuous in the acinar cells and the liquid content of the ductule is also dark blue. Ductal and centroacinar cells have pale cytoplasm. The presence of numerous round empty capillaries (arrows) in the interstitial spaces indicates that the pancreas was perfused with fixative. Toluidine blue stain, 1 μm thick plastic embedded tissue.

Figure 2.17 Pancreatic stellate cell (PSC) from a patient with acute pancreatitis. The PSC is near a macrophage (Ma), image right, and an acinar cell (Ac), image left. Fat droplets (F) and RER are conspicuous in the PSC cytoplasm below the nucleus (N). Original magnification 6000×.

Figure 2.18 A pancreatic stellate cell (PSC)

in situ

is surrounded by multiple acinar cells containing zymogen granules. Extensions of PSC cytoplasm between acinar cells are conspicuous, upper image right and lower image left. The dark, irregular cytoplasmic inclusions at the origin of the latter interstitial extension may represent lipid droplets—a characteristic of PSC.

Figure 2.19 Pancreatic lobules with acinar cells and four islets at 12, 3, 6–7, and 9 o’clock. The islets are paler than the surrounding acinar tissue. The upper and lower islets are small and the lateral islets are medium size. H&E stain.

Figure 2.20 Serial sections of a human islet immunostained using antibodies to insulin (a), glucagon (b), and somatostatin (c). The presence of the hormones is indicated by brown staining. The predominance of insulin secreting β cells is obvious. In (b) and (c), the location of α cells and δ cells is primarily at the border of groups of β cells.

Figure 2.21 Mouse islet stained to demonstrate pancreatic polypeptide (red) and insulin (green). Immunofluorescence using antibodies to insulin and neuropeptide Y (NPY) that cross‐reacts with PP.

Figure 2.22 Mouse islet with β‐cell cytoplasm containing insulin granules (image left), a δ cell with nucleus and less dense secretory granules (right of center), and α‐cell cytoplasm with glucagon granules (upper image right corner) and at the bottom margin near the center. In murine species, β‐cell granules have a wide halo surrounding the dense core. Acinar cell cytoplasm with zymogen granules, RER, and mitochondria is present (lower image right).

Figure 2.23 Human islet from transplant isolation with α, β, and δ cells labeled. The α‐cell granules are typically slightly larger than β‐cell granules; δ‐cell granules are typically less densely stained than the granules in α and β cells. The cytoplasm of several islet cells contains lipid—most notably in the central β cell where lipid bodies lie at 4 and 11–12 o’clock around the nucleus.

Chapter 03

Figure 3.1 ERCP of pancreas annulare in an adult. Note the ring‐shaped pancreatic duct encircling the duodenum.

Figure 3.2 Pancreas divisum on ERCP. Whereas the intra‐ and extrahepatic bile ducts are of regular size and proportions, the pancreatic duct is short and tender (already overfilled with contrast medium) and supplies only the head of the pancreas.

Figure 3.3 Ectopic pancreas 4 cm distant from the duodenal papilla under endoscopic vision and during endoscopic snare dissection (top images) and histologically (bottom panels, at bottom right cytokeratin staining). Note the complete absence of endocrine cells on histology, which corresponds to a type II ectopic pancreas according to Heinrich (1909), that is, composed only of exocrine cells.

Figure 3.4 Large cysts in the head and tail of the pancreas in a patient with chronic pancreatitis.

Figure 3.5 Fatty replacement of the entire pancreas (black central box on the abdominal CT) in Shwachman–Diamond syndrome.

Figure 3.6 Prominent aplasia of the nasal wings as a characteristic feature of Johanson–Blizzard syndrome.

Chapter 04

Figure 4.1 Fluid and enzyme secretion from acinar cells. (a) Acinar transport model illustrating the individual ion transport events that work together to produce an isotonic NaCl‐rich fluid. For graphical convenience, different aspects of the processes are shown in separate cells. In the top cell it is shown that ACh or CCK stimulation of their respective specific receptors on the basolateral membrane elicits a rise in the cytosolic Ca

2+

concentration ([Ca

2+

]

i

), which in turn activates Cl

+

channels in the apical (luminal) membrane and K

+

channels in the basolateral membrane (for graphical convenience all events in the basolateral membrane are shown only in the basal membrane). The middle cell illustrates transcellular Cl

−

transport. The Na

+

/K

+

/2Cl

−

cotransporter, the K

+

channel, and the Na

+

/K

+

pump are shown in the basal membrane and it is indicated that the net transport event is uptake of Cl

−

, whereas at the apical membrane Cl

−

exit into the lumen simply occurs through a Cl

−

channel. The lower cell illustrates the overall electrical circuit and explains the transepithelial electrical potential difference. The Na

+

/K

+

/2Cl

−

cotransporter is electrically neutral, so the only electrogenic event at the basolateral membrane is the transport of cations (K

+

and Na

+

) through the K

+

channel and Na

+

/K

+

pump (3Na

+

pumped out for 2K

+

taken in). This net outward (cation exit) current has to be matched by an inward (anion exit) current across the apical membrane and the completion of the circuit depends on the high conductance of the so‐called tight junctions (TJs). (b) Model drawing of acinar unit with small duct segment attached. The polarity of acinar cells is shown with the nucleus (N) surrounded by endoplasmic reticulum (ER) in the basal part and zymogen granules (ZG) in the apical part. (c) Fluid and amylase secretion from isolated perfused rat pancreas stimulated by the frog skin peptide cerulein (analog of CCK) and secretin.

Figure 4.2 Ca

2+

signaling and organelle distribution in the intact mouse pancreas. (a) Merged confocal images showing distribution of specific fluorescent markers for zymogen granules (ZG – red), nuclei (N – blue), and mitochondria (Mit – green). The optical slice goes through three cells (nuclei). The ZG are seen distributed around the lumen and are surrounded by mitochondria. Mitochondria are also located around the nuclei and close to the plasma membrane. (b) Confocal image of larger part of the pancreas showing many acinar units. One cell is highlighted by white dashed lines and in this cell apical (red) and basal (blue) regions of interest are signposted. The traces shown in (c) are from these two regions. (c) ACh‐elicited cytosolic Ca

2+

signals. At the low ACh concentration of 100 nM, repetitive Ca

2+

spikes are seen exclusively in the apical pole. When the ACh concentration is increased to 1 μM, there is a rise in [Ca

2+

]

i

in both the apical and basal regions. (d) Fluorescent images showing (upper row) a single local apical Ca

2+

spike (numbers refer to time points in (c)) and (lower row) the initial Ca

2+

wave generation following the increase in ACh concentration (numbers again refer to time points signposted in C).

Figure 4.3 Organelle distribution and Ca

2+

transport events in acinar cell. The main part of the figure shows a model cell with the distribution of organelles and Ca

2+

transport pathways signposted. Insert (in red frame) shows triple measurements of Ca

2+

‐activated Cl

−

current (

), mitochondrial Ca

2+

concentration ([Ca

2+

]

m

—measured by Rhod‐2 fluorescence—and concentration of NADH (autofluorescence). It is seen that ACh evokes a rapid rise in

, which is followed immediately by a rise in [Ca

2+

]

m

and after a small delay by an increase in the NADH concentration signifying activation of mitochondrial metabolism and therefore ATP production.

Figure 4.4 Ca

2+

transport and signaling events in acinar cell. (a) Events at the plasma membrane. Two receptor pathways are shown. CCK interaction with CCK1 receptors results in activation—via an unknown mechanism—of the cytosolic enzyme ADP‐ribosyl cyclase, which generates two separate messengers, namely cADPR and NAADP. ACh binding to muscarinic M3 receptors activates, via interaction with a classical trimeric G‐protein, phospholipase C (PLC) generating the messenger IP

3

(as well as diacyl glycerol—not shown in diagram). The absence of the Na

+

/Ca

2+

exchanger is highlighted. Ca

2+

extrusion by the plasma membrane Ca

2+

‐activated ATPase is shown. Ca

2+

entry occurs through store‐operated Ca

2+

channels (SOC). (b) Schematic illustration of Ca

2+

release from the ER through the IP

3

R elicited by IP

3

and through the RyR by NAADP or cADPR. Positive and negative Ca

2+

interactions between the two Ca

2+

release channels are also shown. (c) Confocal fluorescent images illustrating changes in organellar [Ca

2+

] following ACh stimulation. The left image shows the high resting [Ca

2+

] in the ER (mostly in the basal (left) part of the cell). After maximal ACh stimulation, [Ca

2+

] in the ER has been reduced markedly (shift from warm (red) to cold (green) color) and the perigranular mitochondrial belt is now clearly seen (yellow). This indicates that Ca

2+

lost from the ER has been taken up in part by the mitochondria. The third image shows the almost complete loss of Ca

2+

from the ER and the still elevated [Ca

2+

] in the perigranular mitochondria. (d) Confocal image showing the distribution of fluorescent thapsigargin (white), a very specific marker for the ER Ca

2+

pump. The optical slice goes through two cells (but only through one nucleus – N). It is seen that by far the highest ER Ca

2+

pump density is in the basolateral parts of the cell, but it is important to note that there are some light elements in the darker granular (secretory pole – SP) areas signifying ER elements with Ca

2+

pumps also in this part of the cell. (e) Schematic drawing of Ca

2+

, H

+

, and K

+

transports across the ZG membrane.

Figure 4.5 Acetylcholine (ACh)‐induced breakdown of phosphatidylinositol 4,5‐bisphosphate (PIP

2

) in the plasma membrane (PM) and generation of inositol 1,4,5‐trisphosphate (IP

3

) in the cytosol (cyt). The green fluorescent protein (GFP)‐linked PH domain of PLC

δ

1 binds with high affinity to both PIP

2

and IP

3

. (1) Before stimulation, the main GFP fluorescence is seen in the basolateral membrane, indicating the presence of PIP

2

at this site. (2) Generation of a substantial rise in [Ca

2+

]

i

by photolytic release of Ca

2+

into the cytosol from caged Ca

2+

does not cause any reduction in the PIP

2

concentration in the membrane. (3) ACh (1 μmol/L) causes a rise in [Ca

2+

]

i

of similar magnitude to that seen after Ca

2+

uncaging, but in this case there is loss of GFP fluorescence from the basolateral membrane, signifying loss of PIP

2

, and appearance of fluorescence in the cytosol indicating appearance of IP

3

.

Figure 4.6 IP

3

‐elicited local apical Ca

2+

spikes and exocytotic secretion. The main part of the figure shows the result from a patch clamp experiment with internal acinar cell perfusion. The trace shows the repetitive spikes of Ca

2+

‐dependent Cl

−

current elicited by intracellular IP

3

infusion (10 μM). The images below illustrate the configuration and the distribution of the elevated [Ca

2+

]

i

during the height of a spike. It is clearly seen that the Ca

2+

signal occurs in the apical granular pole. The insert (in red frame) shows correlation between a single apical Ca

2+

spike (during IP

3

infusion), recorded here as an increase in Cl

−

conductance (∆G), and the exocytotic response recorded as an increase in membrane capacitance (∆C). It is seen that the increase in Cl

−

conductance (a sensitive indicator of [Ca

2+

]

i

) slightly precedes the rise in capacitance and that the secretory response is completed just before [Ca

2+

]

i

returns to the inter‐spike level.

Figure 4.7 Overall Ca

2+

homeostasis: Ca

2+

entry and exit. The left part illustrates an experiment in which [Ca

2+

] is measured outside an isolated acinar cell by using a Ca

2+

‐sensitive fluorescent indicator linked to high molecular weight dextran, thereby limiting the indicator mobility. The morphology of the cell, with clear identification of the granular apical (Ap) pole is shown in (a). (b) to (i) are fluorescent images (taken at 3‐s intervals) showing the distribution of the extracellular [Ca

2+

] rise immediately following stimulation with ACh (10 μM). It is clear that the Ca

2+

extrusion from the cell occurs predominantly across the apical membrane. The right part of the figure illustrates the rise in [Ca

2+

] of mitochondria close to the basal plasma membrane during store‐operated Ca

2+

entry. Mitochondrial [Ca

2+

] ([Ca

2+

]

m

) was measured with a fluorescent probe and traces from three regions of interest (red, black, and green) are shown. The cell was initially poisoned with thapsigargin in the absence of external Ca

2+

to deplete the ER of Ca

2+

. During the time period indicated by the bar labelled 10 mM Ca

2+

, Ca

2+

was readmitted to the external solution and it is seen that there was a marked rise in [Ca

2+

]

m

particularly in the red region of interest, very close to the basal plasma membrane. The image marked with a red arrow shows the distribution of the elevated [Ca

2+

] at the time indicated by a similar red arrow above the fluorescence traces. Clearly the elevation of [Ca

2+

]

m