Else Adrenocortical Carcinoma

Basic Science and Clinical Concepts
1. Auflage 2010
ISBN: 978-0-387-77236-3
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 546 Seiten

We anticipate the book to be a definitive text on the subject that explores all aspects of the study of adrenal cancer and the treatment of patients with the disease. Chapters will cover epidemiology, pathogenesis, genetics, cancer stem cells, historic and emerging therapies, mouse models of adrenal cancer, new developments in tumor profiling, worldwide collaborative groups and tumor registries together with resources for the practitioner and community of adrenal cancer scientists. We do not wish this book to compete with the other larger books in the Endocrine and Endocrine Surgery literature. In addition, it is not expected to cover benign adrenal diseases that have been covered in detail in other venues. We envision this book to be a very specialized and exhaustive text on basic, translational and clinical aspects of adrenal cancer.

Autoren/Hrsg.

Else, Tobias

Inhaltsverzeichnis

1;Preface;5
2;Contents;7
3;Contributors;10
4;Part I History of Adrenocortical Carcinoma Research and Clinical Care;15
4.1;1 The History of Adrenocortical Carcinoma Treatment A Medical Perspective;16
4.1.1;References;21
4.2;2 The History of Adrenocortical Carcinoma Treatment A Surgical Perspective;22
4.2.1;References;31
5;Part II Epidemiology, Presentation and Diagnosis;33
5.1;3 Epidemiology of Adrenocortical Carcinoma;34
5.1.1;3.1 Incidence of Adrenocortical Carcinoma;34
5.1.2;3.2 Risk Factors for Adrenocortical Carcinoma;35
5.1.3;3.3 Stage at Presentation;36
5.1.4;3.4 Prognosis of Adrenocortical Carcinoma;37
5.1.5;3.5 Associated Malignancies;38
5.1.6;References;38
5.2;4 Clinical Presentation and Initial Diagnosis;41
5.2.1;4.1 Clinical Presentation;41
5.2.1.1;4.1.1 Hormone Excess;41
5.2.1.2;4.1.2 Loco-Regional Manifestations;44
5.2.1.3;4.1.3 Unspecific Symptoms -- Metastatic Disease;45
5.2.1.4;4.1.4 Incidentally Detected Adrenocortical Carcinoma;46
5.2.2;4.2 Laboratory Work-Up;46
5.2.3;4.3 Imaging at Presentation;49
5.2.4;4.4 Fine-Needle Aspiration/Cut Biopsy;51
5.2.5;References;53
5.3;5 Diagnostic Approach to Incidentaloma;58
5.3.1;5.1 Does the Adrenal Lesion Exhibit a Biologically Benign or Malignant Behavior?;59
5.3.1.1;5.1.1 Evidence from Epidemiological Studies -- Adrenocortical Tumors;59
5.3.1.2;5.1.2 Evidence from Epidemiological Studies -- Pheochromocytomas;60
5.3.1.3;5.1.3 Evidence from Epidemiological Studies -- Metastasis;60
5.3.1.4;5.1.4 Evidence from Epidemiological Studies -- Other Adrenal Lesions;61
5.3.1.5;5.1.5 Evidence from Imaging Studies;61
5.3.1.6;5.1.6 Evidence from Biopsy Studies;62
5.3.2;5.2 Is the Adrenal Lesion a Source of Autonomous Hormone Hypersecretion?;63
5.3.2.1;5.2.1 Evidence from Epidemiological Studies;63
5.3.2.2;5.2.2 Hormone Excess;64
5.3.2.2.1;5.2.2.1 Hypercortisolism;64
5.3.2.2.2;5.2.2.2 Hyperaldosteronism;65
5.3.2.2.3;5.2.2.3 Pheochromocytoma;66
5.3.2.2.4;5.2.2.4 Hyperandrogenemia;66
5.3.2.2.5;5.2.2.5 Other Endocrine Functions;66
5.3.3;5.3 Is Surgical Removal Necessary or Is an Observational Policy a Safe and Reasonable Approach?;67
5.3.4;References;68
6;Part III Imaging;74
6.1;6 Computed Tomography/Magnetic Resonance Imaging of Adrenocortical Carcinoma;75
6.1.1;6.1 Clinical Utility of CT and MRI;77
6.1.2;6.2 Pheochromocytoma;78
6.1.3;6.3 The Incidentally Discovered Adrenal Mass (Incidentaloma);78
6.1.4;6.4 Myelolipoma;79
6.1.5;6.5 Cyst;80
6.1.6;6.6 Hemorrhage;80
6.1.7;6.7 Adrenocortical Adenoma;81
6.1.8;6.8 Adrenocortical Carcinoma;82
6.1.9;6.9 Metastasis;84
6.1.10;6.10 Differential Diagnosis: Adrenocortical Adenoma or Metastasis?;85
6.1.11;6.11 Differential Diagnosis: Adrenocortical Adenoma or Carcinoma?;89
6.1.12;6.12 Imaging and Staging of Adrenocortical Carcinoma;90
6.1.13;References;90
6.2;7 Functional Imaging of Adrenocortical Carcinoma;93
6.2.1;7.1 [18F]-FDG-PET-CT in Adrenocortical Carcinoma;93
6.2.2;7.2 Molecular Imaging with Specific Adrenocortical Tracers;97
6.2.2.1;7.2.1 Norcholesterol Scintigraphy;98
6.2.2.2;7.2.2 Enzyme Inhibitors;100
6.2.2.3;7.2.3 Metomidate;100
6.2.2.4;7.2.4 [18F]-Fluoro-etomidate;104
6.2.2.5;7.2.5 [123I /131I]-Iodo-metomidate;104
6.2.3;References;106
7;Part IV Pathology;112
7.1;8 Classical Histopathology and Immunohistochemistry;113
7.1.1;8.1 Gross Findings;113
7.1.2;8.2 Histopathology;115
7.1.3;8.3 Scoring Systems;118
7.1.4;8.4 Immunocytochemistry;122
7.1.5;8.5 Ultrastructure;124
7.1.6;8.6 Grading;125
7.1.7;8.7 Staging;126
7.1.8;8.8 Differential Diagnosis;127
7.1.9;References;129
7.2;9 Cellular and Molecular Pathology of Adrenocortical Carcinoma;133
7.2.1;9.1 Clonality;134
7.2.2;9.2 Genomic and Genetic Abnormalities;135
7.2.2.1;9.2.1 Ploidy and DNA Content of Adrenocortical Tumors;135
7.2.2.2;9.2.2 Genomic Aberrations in Adrenocortical Carcinoma: Analysis by Comparative Genomic Hybridization (CGH);136
7.2.2.3;9.2.3 LOH and Mutation Analysis of Genomic Loci and Genes;138
7.2.3;9.3 The RAS-Associated Signaling Networks in Adrenocortical Carcinoma;143
7.2.4;9.4 Angiogenesis in Adrenocortical Carcinoma;145
7.2.5;9.5 Peptide Hormones and Cytokines in Adrenocortical Carcinoma;146
7.2.6;9.6 Contributions of Physiological Regulators of the HPA-Axis, ACTH, and Steroid Hormones to Adrenocortical Tumorigenesis;148
7.2.7;9.7 Timing of the Occurrence of Tumorigenesis-Related Changes;149
7.2.8;References;151
8;Part V Genetic and Molecular Aspects;157
8.1;10 Overview of Genetic Syndromes Associated with Adrenocortical Cancer;158
8.1.1;10.1 Syndromes Associated with Adrenocortical Cancer;165
8.1.1.1;10.1.1 The Overgrowth Syndromes: BWS and IHH;165
8.1.1.2;10.1.2 Li--Fraumeni Syndrome;169
8.1.1.3;10.1.3 Familial Adenomatous Polyposis;169
8.1.1.4;10.1.4 Multiple Endocrine Neoplasia Type 1;170
8.1.1.5;10.1.5 Neurofibromatosis Type 1;172
8.1.2;10.2 Screening for Germline Mutations in Adrenocortical Cancer Patients;172
8.1.3;10.3 Screening and Surveillance of Patients with Hereditary Syndromes Predisposing to Adrenocortical Cancer;173
8.1.4;References;174
8.2;11 Li-Fraumeni Syndrome;178
8.2.1;11.1 Clinical Definition of LFS;178
8.2.2;11.2 Cancer Risk Patterns in LFS Families;180
8.2.3;11.3 The TP53 Tumor Suppressor;180
8.2.4;11.4 TP53 Gene Inactivation;182
8.2.5;11.5 TP53 and the LFS;183
8.2.6;11.6 The Role of Other Genes in LFS;184
8.2.7;11.7 Modifier Genes in LFS;184
8.2.8;11.8 The Unique Brazilian LFS-TP53Codon 337 Mutation Phenotype;185
8.2.9;11.9 Functional Models of Germline TP53 Mutations;186
8.2.10;11.10 Mouse Models of LFS;187
8.2.11;11.11 Medical and Ethical Considerations;190
8.2.12;References;192
8.3;12 TP53 Molecular Genetics;197
8.3.1;12.1 The Pre-eminent Tumor Suppressor;197
8.3.2;12.2 Transcription Is Key;198
8.3.3;12.3 The TP53 Signaling Pathway: Loops Within Loops;199
8.3.4;12.4 Acquired and Inherited TP53 Mutations;201
8.3.5;12.5 TP53 Mutations in Childhood and Adult Adrenocortical Tumors;201
8.3.6;12.6 Low-Penetrance Mutant TP53 Alleles;202
8.3.7;12.7 Genetic Modifiers;204
8.3.8;12.8 Concluding Thoughts;205
8.3.9;References;206
8.4;13 Telomeres and Telomerase in Adrenocortical Carcinoma;210
8.4.1;13.1 The End-Replication Problem and Telomerase;211
8.4.2;13.2 Telomeres;213
8.4.3;13.3 Telomere-Based Model of Carcinogenesis;216
8.4.4;13.4 Telomerase in Experimental Adrenocortical Carcinoma;218
8.4.5;13.5 Human Syndromes with Defects in Telomere Physiology;220
8.4.6;13.6 Telomerase and Adrenocortical Carcinoma;221
8.4.7;13.7 Telomeres and Adrenocortical Carcinoma;221
8.4.8;References;224
8.5;14 Beckwith--Wiedemann Syndrome;229
8.5.1;14.1 Diagnosis;229
8.5.2;14.2 Clinical Features;230
8.5.3;14.3 Genetics;232
8.5.4;14.4 Cancer;233
8.5.5;References;235
8.6;15 The Insulin-Like Growth Factor System in Adrenocortical Growth Control and Carcinogenesis;237
8.6.1;15.1 The IGF System;237
8.6.2;15.2 The Role of the IGF System in the Normal Adult Adrenal Gland;238
8.6.2.1;15.2.1 Insulin-Like Growth Factors;238
8.6.2.2;15.2.2 IGF Receptors;240
8.6.2.3;15.2.3 IGF-Binding Proteins;240
8.6.3;15.3 Specific Role of the IGF System in Adrenocortical Tumorigenesis;242
8.6.3.1;15.3.1 IGF1;242
8.6.3.2;15.3.2 IGF2;245
8.6.4;15.4 IGF Receptors;249
8.6.4.1;15.4.1 The IGF1R;249
8.6.4.2;15.4.2 The IGF2/Mannose-6-Phosphate (IGF2R)-Receptor;251
8.6.5;15.5 IGFBPs;252
8.6.6;15.6 Summary and Conclusion;255
8.6.7;References;257
8.7;16 WNT/-Catenin Signaling in Adrenocortical Carcinoma;265
8.7.1;16.1 The WNT/-Catenin Signaling Pathway;266
8.7.1.1;16.1.1 Molecular Mechanisms of the Canonical WNT/-Catenin Signaling Pathway;266
8.7.1.2;16.1.2 Components of the WNT/-Catenin Signaling Pathway;267
8.7.1.2.1;16.1.2.1 Initiation of the WNT/-Catenin Signaling Pathway at the Cell Membrane;267
8.7.1.2.2;16.1.2.2 WNT/-Catenin Signaling Events in the Cytoplasm;268
8.7.1.2.3;16.1.2.3 Nuclear Components of the WNT/-Catenin Signaling Pathway;270
8.7.1.3;16.1.3 The WNT/-Catenin Signaling Pathway Target Genes;271
8.7.2;16.2 The WNT/-Catenin Signaling Pathway in Familial Adenomatous Polyposis Coli;271
8.7.3;16.3 The WNT/-Catenin Signaling Pathway in the Adrenal Cortex and in Adrenocortical Tumors;271
8.7.3.1;16.3.1 Adrenal Cortex Development;271
8.7.3.2;16.3.2 Adrenocortical Diseases;272
8.7.4;16.4 The WNT Signaling Pathway in Adrenocortical Carcinoma;276
8.7.4.1;16.4.1 Activation of the WNT/ -Catenin Pathway and -Catenin Mutations;276
8.7.4.2;16.4.2 Role of -Catenin Activation in Adrenocortical Tumor Development;276
8.7.4.3;16.4.3 Alternatives to CTNNB1 Mutation for WNT/-Catenin Pathway Activation in Adrenocortical Carcinoma;277
8.7.4.3.1;16.4.3.1 WTX, AXIN1, AXIN2, or GSK3;278
8.7.4.3.2;16.4.3.2 APC;278
8.7.5;16.5 The WNT/-Catenin Signaling Pathway: A Potential Target for Cancer Treatment;278
8.7.6;16.6 Conclusion;279
8.7.7;References;279
9;Part VI Models of Adrenocortical Cancer;285
9.1;17 Adrenocortical Stem and Progenitor Cells: Implications for Cancer;286
9.1.1;17.1 Adrenocortical Tumors;288
9.1.2;17.2 Normal Adrenal Adult Stem Cells;289
9.1.2.1;17.2.1 Adrenal Development and Structure;289
9.1.2.2;17.2.2 Where Do the Adrenal Adult Stem Cells Reside?;290
9.1.2.3;17.2.3 Establishment of the Stem Cell Niche;291
9.1.2.3.1;17.2.3.1 Adrenal Precursor Cells in Fetal Zone;292
9.1.2.3.2;17.2.3.2 Stem/Progenitor Cells in Adrenal Capsule;292
9.1.3;17.3 What Factors Regulate Adrenal Adult Stem and Progenitor Cells?;294
9.1.3.1;17.3.1 Dax1;294
9.1.3.2;17.3.2 Shh;295
9.1.3.3;17.3.3 Wnt/-Catenin;295
9.1.3.4;17.3.4 IGF2;296
9.1.3.5;17.3.5 Telomerase;296
9.1.4;17.4 How Do Normal Adrenal Cells Become Cancer Cells/or How Is Adrenocortical Carcinoma Initiated?;296
9.1.4.1;17.4.1 Wnt/-Catenin;297
9.1.4.2;17.4.2 IGF2;298
9.1.4.3;17.4.3 Pod1;299
9.1.4.4;17.4.4 p53/Telomerase;299
9.1.5;17.5 How Is Adrenocortical Carcinoma Maintained: Cancer Stem Cell or Stochastic Model?;300
9.1.6;17.6 Summary;301
9.1.7;References;302
9.2;18 Adrenocortical Cell Lines;306
9.2.1;18.1 Human Adrenocortical Cell Lines;308
9.2.1.1;18.1.1 The NCI-H295, NCI-H295R, and NCI-H295A Adrenocortical Carcinoma Cell Lines;308
9.2.1.1.1;18.1.1.1 Origin and Development;308
9.2.1.1.2;18.1.1.2 Cell Line Growth and Characterization;310
9.2.1.1.3;18.1.1.3 Expression of Hormone Receptors and Hormonal Responsiveness;311
9.2.1.1.4;18.1.1.4 Steroidogenesis;312
9.2.1.1.5;18.1.1.5 Steroidogenic Enzyme Expression;313
9.2.1.1.6;18.1.1.6 NCI-H295 Cell Line As Adrenal Cancer Therapy Tool;313
9.2.1.2;18.1.2 Human Adrenocortical Carcinoma, Clone 15 (HAC15) Cell Line, and Related Clones;314
9.2.1.3;18.1.3 Pediatric Adrenocortical Adenoma Derived Cell Line;315
9.2.1.3.1;18.1.3.1 Origin and Development;315
9.2.1.3.2;18.1.3.2 Growth and Steroidogenesis;315
9.2.1.4;18.1.4 The SW13 Human Adrenal Carcinoma Derived Cell Line;315
9.2.1.5;18.1.5 The ACT-1 Human Adrenal Carcinoma Derived Cell Line;315
9.2.1.6;18.1.6 The RL-251 Human Adrenal Carcinoma Derived Cell Line;316
9.2.1.7;18.1.7 Human Adrenal Cell Lines from Viral Oncogenes;316
9.2.2;18.2 Rodent Adrenocortical Cell Lines;317
9.2.2.1;18.2.1 The Y1 Adrenal Cell Line;317
9.2.2.2;18.2.2 Experimentally Induced Rodent Adrenal Cell Lines;318
9.2.3;18.3 Bovine Adrenocortical Cell Lines;319
9.2.4;18.4 Summary;319
9.2.5;References;320
9.3;19 Mouse Models of Adrenal Tumorigenesis;326
9.3.1;19.1 Mouse Models with Spontaneous or Induced Adrenal Tumor Growth;327
9.3.2;19.2 Mouse Models Utilizing Transplanted Adrenal Tumor Cells;329
9.3.3;19.3 Genetically Modified Mouse Models with an Adrenal Tumor Phenotype;334
9.3.4;19.4 Mouse Models with Transgenic Expression of an Oncogene-Inducing Adrenal Tumor;334
9.3.5;19.5 Mouse Models with Targeted Deletions Inducing Adrenal Tumors;336
9.3.6;References;337
10;Part VII Therapies;342
10.1;20 Overview of Treatment Options for Adrenocortical Carcinoma;343
10.1.1;20.1 Adjuvant Treatment;344
10.1.2;20.2 Treatment of Metastatic Disease;344
10.1.3;20.3 Medical Treatment of Adrenocortical Carcinoma Steroidogenic Hormone Excess;346
10.1.4;20.4 Emerging Therapies;346
10.1.5;References;347
10.2;21 Chemotherapy;350
10.2.1;21.1 Single-Agent Chemotherapy;351
10.2.2;21.2 Combination Chemotherapy;353
10.2.3;21.3 Chemotherapy Plus Mitotane;356
10.2.4;21.4 Chemotherapy Plus Target Therapy;360
10.2.5;21.5 The FIRM-ACT Study;361
10.2.6;21.6 Prognostic and Predictive Factors of Response to Chemotherapy in Advanced Patients;362
10.2.7;21.7 Conclusion;364
10.2.8;References;364
10.3;22 Mitotane;368
10.3.1;22.1 Pharmacokinetics;368
10.3.2;22.2 Historical Background;369
10.3.3;22.3 Mitotane in Advanced Adrenocortical Carcinoma;370
10.3.4;22.4 Toxicity and Dosage;372
10.3.5;22.5 Mitotane in Adjuvant Setting;374
10.3.6;References;378
10.4;23 Pharmacotherapy for Hormone Excess in AdrenocorticalCarcinoma;381
10.4.1;23.1 Adrenal Steroid Biosynthesis;381
10.4.1.1;23.1.1 Basics of Adrenal Steroidogenesis and Zonation;381
10.4.1.2;23.1.2 Steroidogenic Enzymes;383
10.4.1.3;23.1.3 Steroidogenic Pathways in the Adrenal Gland;385
10.4.1.4;23.1.4 Acute and Chronic Regulation of Adrenal Steroidogenesis and Dysregulation in Adrenocortical Carcinoma;386
10.4.2;23.2 Approach to the Adrenocortical Carcinoma Patient;387
10.4.2.1;23.2.1 Clinical Manifestations of Adrenal Steroid Excess;387
10.4.2.2;23.2.2 Therapeutic Strategies;388
10.4.3;23.3 Specific Treatments;389
10.4.3.1;23.3.1 Mineralocorticoid Excess;389
10.4.3.1.1;23.3.1.1 Inhibitors of Mineralocorticoid Synthesis;389
10.4.3.1.2;23.3.1.2 Mineralocorticoid Receptor Antagonists;390
10.4.3.1.3;23.3.1.3 Nonspecific Treatment of Hypertension and Hypokalemia;391
10.4.3.2;23.3.2 Glucocorticoid Excess;391
10.4.3.2.1;23.3.2.1 Inhibitors of Glucocorticoid Synthesis;392
10.4.3.2.2;23.3.2.2 Glucocorticoid Receptor Antagonists;394
10.4.3.2.3;23.3.2.3 Nonspecific Treatment of Cardiovascular and Metabolic Consequences;394
10.4.3.3;23.3.3 Androgen Excess;394
10.4.3.3.1;23.3.3.1 Inhibitors of Androgen Synthesis;395
10.4.3.3.2;23.3.3.2 Androgen Receptor Antagonists;395
10.4.3.3.3;23.3.3.3 Nonspecific Treatment of Androgen Excess;396
10.4.3.4;23.3.4 Treatment of Estrogen Excess;396
10.4.4;23.4 Conclusions;397
10.4.5;References;397
10.5;24 Surgery for Adrenocortical Carcinoma;401
10.5.1;24.1 Surgical Adrenal Anatomy;402
10.5.1.1;24.1.1 Arterial Supply;403
10.5.1.2;24.1.2 Venous Drainage;404
10.5.1.3;24.1.3 Lymphatics;404
10.5.1.4;24.1.4 Adjacent Structures;404
10.5.2;24.2 Perioperative Considerations;406
10.5.2.1;24.2.1 Preoperative;406
10.5.2.2;24.2.2 Intraoperative;408
10.5.2.3;24.2.3 Postoperative;409
10.5.3;24.3 Role of Surgery;409
10.5.3.1;24.3.1 Primary Therapy -- Curative Intent;409
10.5.3.2;24.3.2 Recurrences;410
10.5.3.3;24.3.3 Palliation: Hormonal Control and Tumor Debulking;411
10.5.4;24.4 Surgical Approaches to the Adrenal Glands;412
10.5.4.1;24.4.1 Anterior Transabdominal -- Open;412
10.5.4.2;24.4.2 Thoracoabdominal;413
10.5.4.3;24.4.3 Approaches to Difficult Resections;414
10.5.4.3.1;24.4.3.1 Vascular Control and Resection;416
10.5.4.4;24.4.4 Laparoscopic Surgery for Primary Adrenal Malignancy;418
10.5.5;24.5 Surgical Complications;420
10.5.6;24.6 Conclusion;421
10.5.7;References;421
10.6;25 Radiation Therapy for Adrenocortical Carcinoma;424
10.6.1;25.1 Current Surgical and Adjuvant Management;425
10.6.2;25.2 Radiotherapy for Adrenocortical Carcinoma;428
10.6.3;25.3 Case Studies;431
10.6.3.1;25.3.1 Case #1. Adjuvant Radiotherapy;431
10.6.3.2;25.3.2 Case #2. Adjuvant Radiotherapy After Resection of a Local Recurrence;433
10.6.3.3;25.3.3 Case #3. Palliation of a Bulky Liver Metastasis;434
10.6.4;25.4 Summary;435
10.6.5;References;435
10.7;26 Follow-Up and Monitoring of Adrenocortical Carcinoma;439
10.7.1;26.1 General Modalities for Follow-Up;440
10.7.2;26.2 History;440
10.7.3;26.3 Physical Examination;440
10.7.4;26.4 Laboratory Evaluation;441
10.7.5;26.5 Imaging;442
10.7.5.1;26.5.1 Symptom-Specific/Sign-Specific Imaging;443
10.7.5.2;26.5.2 Cross-Sectional Imaging;443
10.7.5.3;26.5.3 Functional Imaging;444
10.7.6;26.6 Risk-Based Follow-Up Strategies;445
10.7.6.1;26.6.1 Low-Risk Localized Disease/Complete Resection;446
10.7.6.2;26.6.2 High-Risk Disease/Complete Resection;446
10.7.6.3;26.6.3 Unresectable Localized or Metastatic Disease;447
10.7.7;26.7 Risk Modifiers and Follow-Up Strategies;447
10.7.8;26.8 Conclusion;448
10.7.9;References;448
11;Part VIII Unique Cohorts and Future Perspectives;450
11.1;27 Aldosterone-Producing Adrenocortical Carcinoma;451
11.1.1;27.1 Epidemiology;451
11.1.2;27.2 Clinical and Hormonal Features;452
11.1.3;27.3 Pathology;454
11.1.4;27.4 Imaging Characteristics;455
11.1.5;27.5 Prognosis;455
11.1.6;27.6 Treatment;456
11.1.7;References;458
11.2;28 Adrenocortical Cancer in Children;460
11.2.1;28.1 Epidemiology of Adrenocortical Cancer;460
11.2.2;28.2 Biology of Adrenocortical Carcinoma;461
11.2.3;28.3 Clinical Characteristics of Pediatric Adrenocortical Carcinoma;464
11.2.4;28.4 Diagnosis of Adrenocortical Carcinoma;465
11.2.5;28.5 Prognostic Factors;466
11.2.6;28.6 Treatment of Pediatric Adrencortical Carcinoma;468
11.2.7;28.7 A Collaborative Research Initiative for Childhood Adrenocortical Carcinoma;470
11.2.8;References;471
11.3;29 Genome-Wide Studies in Adrenocortical Neoplasia;475
11.3.1;29.1 Introduction and the Potential of Genomic Studies;475
11.3.2;29.2 Genome-Wide Gene Expression Studies;475
11.3.3;29.3 Array-Based Comparative Genomic Hybridization;480
11.3.4;29.4 MicroRNA Profiling;481
11.3.5;29.5 Molecular Profiling and Its Potential Impact on Adrenal Pathology and Management of Patients with Adrenal Cancer;481
11.3.5.1;29.5.1 Diagnosis;481
11.3.5.2;29.5.2 Prognosis;482
11.3.5.3;29.5.3 Prediction;482
11.3.6;29.6 Conclusion;482
11.3.7;References;482
11.4;30 New Strategies for the Treatment of Adrenocortical Carcinoma;484
11.4.1;30.1 Therapy Targeted Towards Altered Signaling Pathways in Adrenocortical Carcinoma Cells;484
11.4.1.1;30.1.1 Identification of Potential Signaling Targets;484
11.4.1.1.1;30.1.1.1 Target Identification from the Study of Genetic Syndromes;485
11.4.1.1.2;30.1.1.2 Targets Identified from Gene Expression Analysis;488
11.4.1.2;30.1.2 Targeting the IGF2-IGF1R Pathway;488
11.4.1.2.1;30.1.2.1 Small Molecule TKIs;488
11.4.1.2.2;30.1.2.2 Anti-IGF1R Antibodies;489
11.4.1.3;30.1.3 Targeting the FGF Receptor;489
11.4.1.4;30.1.4 Targeting the EGF Receptor;490
11.4.1.5;30.1.5 Multi-kinase Inhibition Strategies;490
11.4.1.6;30.1.6 Targeting the Wnt Signaling Pathway;490
11.4.2;30.2 Enhancing the Effectiveness of Cytotoxic Chemotherapy;491
11.4.3;30.3 Proapoptoic Strategies;491
11.4.4;30.4 Novel Strategies;492
11.4.4.1;30.4.1 Targeting Tumor Vasculature;492
11.4.4.2;30.4.2 Targeting the Microenvironment;494
11.4.4.2.1;30.4.2.1 Fibroblasts of the Microenvironment;495
11.4.4.2.2;30.4.2.2 Immune Cells of the Microenvironment;496
11.4.4.2.3;30.4.2.3 Proteolytic Enzymes in the Microenvironment;496
11.4.4.3;30.4.3 Therapy Aimed at Metastasis Suppression;497
11.4.5;30.5 Delivery of Newer Modes of Therapy;498
11.4.6;30.6 Summary and Future Directions;499
11.4.7;References;500
12;Part IX Adrenal Cancer Networks and Registries;505
12.1;31 The Dutch Adrenal Network;506
12.1.1;31.1 The Dutch Adrenal Network;506
12.1.2;31.2 The Dutch Adrenal Registry;507
12.1.3;31.3 Results;507
12.1.4;31.4 Future Goals;508
12.1.5;31.5 Conclusion;508
12.2;32 The ENS@T Initiative ;509
12.2.1;32.1 The History: From National Networks to ENS@T;509
12.2.2;32.2 Increasing the Patient Number;510
12.2.3;32.3 Increasing Technical and Methodological Exchange;511
12.2.4;32.4 The Idea of Exchange;512
12.2.4.1;32.4.1 Harmonization;512
12.2.4.2;32.4.2 Material;512
12.2.4.3;32.4.3 Science;512
12.2.5;32.5 Examples of Research Advancements;513
12.2.6;32.6 Organizing the Network;515
12.2.6.1;32.6.1 The Steering Committee;515
12.2.6.2;32.6.2 The Working Groups;515
12.2.6.3;32.6.3 ENS@T Website;516
12.2.7;32.7 Financing the Network;516
12.2.8;32.8 Perspectives;516
12.2.8.1;32.8.1 Integrational and Disseminative Effects of a European Network;517
12.2.9;References;518
13;Index;520