From Local Invasion to Metastatic Cancer

Involvement of Distant Sites Through the Lymphovascular System
1. Auflage 2009
ISBN: 978-1-60327-087-8
Verlag: Humana Press
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 666 Seiten

In human solid tumors, nodal status is the most important prognostic indicator for patient outcome. Recent developments in the sentinel lymph node concept have resulted in new procedures to define the first draining node as the primary gateway through which the cancer will spread. In From Local Invasion to Metastatic Cancer: Involvement of Distant Sites Through the Lymphovascular System, a panel of international authorities takes an in-depth look at the role of the lymphovascular system in the spread of cancer. The authors summarize the findings of the Second International Symposium on Cancer Metastasis: Basis for Rational Therapy summit. Specifically, the book presents important developments in the biology and clinical understanding of cancer metastasis, describes the relationship between tumor microenvironment and proliferation, and defines the process of lymphangiogenesis and angiogenesis with special reference to cancer metastasis. From Local Invasion to Metastatic Cancer: Involvement of Distant Sites Through the Lymphovascular System provides oncologists, radiologists, and cancer researchers the necessary information to study and develop new strategies to curb the process of metastasis.

Autoren/Hrsg.

Inhaltsverzeichnis

1;FROM LOCAL INVASION TO METASTATIC CANCER;1
1.1;Acknowledgements;5
1.2;Foreword;6
1.3;Preface;7
1.4;Contents;8
1.5;Contributors;12
1.6;Color Plates;18
1.7;I INNOVATION AND EXPERIENCE;26
1.7.1;Frontiers of Cancer Research: The Metastasis Challenge;27
1.7.1.1;1.1. Predicting Metastasis;28
1.7.1.2;1.2. Origins of Metastatic Potential;29
1.7.1.2.1;1.2.1. Cancer Stem Cell Theory of Metastasis;31
1.7.1.2.2;1.2.2. Germline Metastatic Potential;31
1.7.1.3;1.3. Target Genes;32
1.7.1.4;1.4. Future Directions;33
1.7.1.5;References;34
1.7.2;Vascular Endothelial Growth Factor: Basic Biology and Clinical Applications;35
1.7.2.1;1. Introduction;35
1.7.2.2;2. History of VEGF;36
1.7.2.3;3. Biological Effects of VEGF-A;36
1.7.2.4;4. VEGF-A Isoforms;37
1.7.2.5;5. VEGF Receptors;37
1.7.2.6;6. Role of VEGF-A in Tumor Angiogenesis;38
1.7.2.6.1;6.1. Clinical Trials in Cancer Patients with VEGF Inhibitors;38
1.7.2.7;7. Role of VEGF-A in Intraocular Neovascular Syndromes;39
1.7.2.7.1;7.1. Clinical Studies of Anti-VEGF Therapy for Neovascular AMD: Pegaptanib and Ranibizumab;40
1.7.2.8;8. Perspectives;41
1.7.2.9;References;41
1.7.3;Proliferation and Cancer Metastasis from the Clinical Point of View;46
1.7.3.1;References;50
1.7.4;Gastrointestinal Cancer and the Lymphatic System: Patterns of Micrometastasis and Lymphatic Mapping with Clinical Outcome;51
1.7.4.1;4.1. Introduction;52
1.7.4.2;4.2. Current Status of SN Navigation Surgery in GI Cancer;53
1.7.4.2.1;4.2.1. Esophageal Cancer;53
1.7.4.2.2;4.2.2. Gastric Cancer;54
1.7.4.2.3;4.2.3. Colon Cancer;55
1.7.4.3;4.3. Identification of Micrometastases in SN;56
1.7.4.3.1;4.3.1. Esophageal Cancer;56
1.7.4.3.2;4.3.2. Gastric Cancer;56
1.7.4.3.3;4.3.3. Colon Cancer;58
1.7.4.4;4.4. Prognostic Impact of Micrometastases;59
1.7.4.4.1;4.4.1. Esophageal Cancer;59
1.7.4.4.2;4.4.2. Gastric Cancer;59
1.7.4.4.3;4.4.3. Colon Cancer;61
1.7.4.5;4.5. Clinical Significance of Circulating Tumor Cells and Bone Marrow;62
1.7.4.5.1;4.5.1. New Paradigm of Microscopic Disease;62
1.7.4.5.2;4.5.2. CTC in GI Cancer;63
1.7.4.5.2.1;4.5.2.1. Esophageal Cancer;63
1.7.4.6;4.6. Conclusion;63
1.7.4.7;References;64
1.7.5;Redefined Lymphatic Anatomy of the Breast with Clinical Implications;66
1.7.5.1;5.1. Introduction;67
1.7.5.2;5.2. Historical Review of the Breast Lymphatics;68
1.7.5.3;5.3. Materials and Methods;70
1.7.5.4;5.4. Superficial Lymphatic System;72
1.7.5.5;5.5. Perforating Lymphatic System;74
1.7.5.6;5.6. Clinical Implications for Sentinel Node Biopsy;75
1.7.5.7;5.7. Conclusions;75
1.7.5.8;References;76
1.7.6;Should Axillary Lymph Node Dissection be Done for Breast Cancer?;77
1.7.6.1;1. Introduction;77
1.7.6.2;2. Axillary Node Dissection in Patients with Invasive Breast Cancer: Pro by Douglas Reintgen;78
1.7.6.3;3. Axillary Node Dissection in Patients with Invasive Breast Cancer: By Dr. Blake Cody;81
1.7.6.4;References;84
1.8;II TUMOR MICROENVIRONMENT AND PROLIFERATION;87
1.8.1;Overview of Tumor Cells and the Microenvironment;88
1.8.1.1;1. Targeting Molecular Signals in the Tumor Cell Microenvironment;88
1.8.1.2;2. Convergence of Embryonic and Tumorigenic Pathways: Role in Tumor Progression;90
1.8.1.3;References;92
1.9;III LYMPHANGIOGENESIS AND ANGIOGENESIS;93
1.9.1;Heme/Lymphvasculogenesis, Hem/Lymphangiogenesis, Hem/Lymphangiotumorigenesis, and Tumor Hem/Lymphangiogenesis: Need for a Terminology Adjustment;94
1.9.1.1;1. Lymphologic Perspectives;95
1.9.1.2;2. Premolecular Era of (Hem)Angiogenesis and (Blood) Vascular Cell Biology;95
1.9.1.3;3. Premolecular Era of Lymphangiogenesis and Lymphatic Cell Biology;96
1.9.1.4;4. Proposal for Terminology Adjustment;98
1.9.1.5;5. Resurgence of Interest in Lymphangiogenesis in the Molecular Era of (Hem)Angiogenesis;99
1.9.1.6;6. Angiodysplasias, Hem/Lymphangiotumorigenesis, and Tumor Angiogenesis;103
1.9.1.7;7. Angiomodulation and Angioprotection;105
1.9.1.8;8. Unanswered Questions and Unquestioned Answers (Continued) (Fig. 8);106
1.9.1.9;9. Continuing Saga and Controversy About the Lymphatic System;107
1.9.1.10;References;107
1.9.2;Tumor Lymphangiogenesis: What We Know and Don’t Know;110
1.9.2.1;9.1. Introduction;111
1.9.2.2;9.2. Cancer Diagnosis and Prognosis: How Important is the Role of the Lymphatics?;111
1.9.2.3;9.3. Prolymphangiogenic Factors: What is their relevance in Tumor-Induced Lymphangiogenesis?;112
1.9.2.4;9.4. Signal Transduction Pathways that Mediate Lymphangiogenesis: Common Motifs?;114
1.9.2.5;9.5. Other Mechanisms that Actively Promote Tumor Entry into the Lymphatics: What is the Relative Importance of Tumor-Induced Lymphangiogenesis?;115
1.9.2.5.1;9.5.1. Chemokines;115
1.9.2.5.2;9.5.2. Vascular Mimicry;115
1.9.2.5.3;9.5.3. Lymph Node Lymphangiogenesis;116
1.9.2.6;9.6. Manipulation of Tumor-Associated Lymphatics: Therapeutic Applications?;117
1.9.2.7;9.7. Conclusions;118
1.9.2.8;References;118
1.10;IV DIAGNOSTIC IMAGING OF CANCER;122
1.10.1;Molecular Imaging of Cancer: Receptors, Angiogenesis, and Gene Expression;123
1.10.1.1;1. Angiogenesis;124
1.10.1.2;2. Receptor Expression in Prostate and Breast Cancer;125
1.10.1.3;3. Gene Expression Imaging;127
1.10.1.4;References;129
1.10.2;MRI and Ultrasound Imaging of Lymph Nodes;131
1.10.2.1;1. Introduction;131
1.10.2.2;2. Mechanism of Lymph Node Enhancement;132
1.10.2.3;3. Sentinel Node Detection;133
1.10.2.4;4. Recognition of Benign From Malignant Nodes;135
1.10.2.5;5. Conclusion;137
1.10.2.6;References;137
1.10.3;Molecular Imaging of the Sentinel Lymph Node via Lymphoseek;139
1.10.3.1;1. Introduction;140
1.10.3.2;2. Background;140
1.10.3.3;3. Optimal tracer;141
1.10.3.4;4. Lymphoseek;141
1.10.3.5;5. Preclinical Studies;142
1.10.3.6;6. Biodistribution and Toxicity;143
1.10.3.7;7. Phase I and Phase II Clinical Trials;146
1.10.3.8;8. Conclusion;148
1.10.3.9;References;148
1.10.4;Lymphatic Disorders in Patients with Cancer;150
1.10.4.1;13.1. Defining Lymphedema;151
1.10.4.2;13.2. Pathogenesis of Edema including Lymphedema;152
1.10.4.3;13.3. Broad Classification of Appendicular Lymphedema;153
1.10.4.4;13.4. Primary Lymphedema;153
1.10.4.5;13.5. Secondary Lymphedema;155
1.10.4.6;13.6. Lymphedema and Breast Cancer;157
1.10.4.7;13.7. Lymphedema after Sentinel Node Surgery for Breast Cancer;159
1.10.4.8;13.8. Lymphedema after Inguinal Node Surgery;160
1.10.4.9;13.9. Lymphedema and Genitourinary Cancer;161
1.10.4.10;13.10. Lymphedema and Sarcomas;163
1.10.4.11;13.11. Other Causes of Secondary Lymphedema;164
1.10.4.12;13.12. Diagnostic Imaging in Lymphedema;164
1.10.4.13;13.13. Lymphoscintigraphy;165
1.10.4.14;13.14. Summary and Conclusions;169
1.10.4.15;References;169
1.10.5;3D-CT Lymphography for Mapping Metastatic Breast Sentinel Node and Axillary Nodes;173
1.10.5.1;14.1. Introduction;174
1.10.5.1.1;14.1. Patients;175
1.10.5.1.2;14.1. 3D-CT LG;175
1.10.5.1.3;14.1. Surgical Methods;175
1.10.5.2;14.2. Lymph Flow from Tumor to SN (13);176
1.10.5.3;14.3. Lymph Flow from SN to Axillary Angle in Axilla (14);178
1.10.5.4;14.4. Metastatic Evaluation by 3D-CT LG;180
1.10.5.5;14.5. Endoscopic SNB Guided by 3D-CT LG;181
1.10.5.6;14.6. Conclusion;181
1.10.5.7;References;181
1.10.6;Molecular Imaging of Neuroendocrine Cancer by Fusion SPET/CT;183
1.10.6.1;15.1. Introduction;184
1.10.6.2;15.2. Material and Method;184
1.10.6.2.1;15.2.1. Patients;184
1.10.6.2.2;15.2.2. Imaging Protocol;184
1.10.6.2.3;15.2.3. Data Analysis;185
1.10.6.2.4;15.2.4. Statistical Analysis;185
1.10.6.3;15.3. Results;185
1.10.6.3.1;15.3.1. Image Quality;185
1.10.6.3.2;15.3.2. Equivocal Exams;186
1.10.6.3.3;15.3.3. Comparison Between SPET and SPET/CT;187
1.10.6.4;15.4. Discussion;187
1.10.6.5;15.5. Conclusion;188
1.10.6.6;References;188
1.10.7;Functional Molecular Imaging of Prostate Cancer Lymph Node Metastases: Adenovirus-Mediated Lymph Node Detection;190
1.10.7.1;16.1. Introduction;191
1.10.7.2;16.2. Debates on Lymph Node Sampling in Prostate Cancer;191
1.10.7.3;16.3. Noninvasive Imaging Approaches for Nodal Staging;192
1.10.7.4;16.4. Adenoviral Vector-Mediated Lymphangiography;193
1.10.7.5;16.5. Conclusions and Future Directions;197
1.10.7.6;References;199
1.11;V THERAPEUTIC TARGETING OF THE LYMPHOVASCULAR SYSTEM;202
1.11.1;Therapeutic Targeting of the Lymphovascular System in Cancer: Promise and Challenge;203
1.11.1.1;1. Introduction;204
1.11.1.2;2. Therapeutic Targetability of the Overall Metastatic Process;205
1.11.1.3;3. Clinical Significance of Lymph Node Metastasis;205
1.11.1.4;4. Impact of the ‘‘Marker’’ versus ‘‘Incubator’’ Controversy on Clinical Practice;206
1.11.1.5;5. Targeting Lymphangiogenesis as AntiMetastatic Cancer Therapy;207
1.11.1.6;6. Possible Clinical Utility of Antagonists of VEGFR-3 Signaling;208
1.11.1.7;References;210
1.11.2;Comparison of Liposomal and Aqueous Blue Dye in Visualization of Lymph Nodes Prior to Lymphadenectomy;212
1.11.2.1;1. Introduction;213
1.11.2.2;2. Material and Method;213
1.11.2.3;3. Results;214
1.11.2.4;4. Discussion;217
1.11.2.5;References;218
1.12;VI MOLECULAR MECHANISMS OF METASTASIS;220
1.12.1;The Role of Lymphangiogenesis in Regional Lymph Node Metastasis: Animal Models;221
1.12.1.1;1. Introduction;222
1.12.1.2;2. Animal Models of Lymphangiogenesis;223
1.12.1.2.1;2.1. Embryos;223
1.12.1.2.2;2.2. Skin Injury Models;223
1.12.1.2.3;2.3. Avian Chorioallantoic Membrane;223
1.12.1.2.4;2.4. Mouse Cornea;224
1.12.1.2.5;2.5. Mouse Tail;224
1.12.1.2.6;2.6. Regenerating Lizard Tail;224
1.12.1.2.7;2.7. Tadpoles;224
1.12.1.2.8;2.8. Zebrafish;225
1.12.1.2.9;2.9. Postnodal Lymphatic Vessels in Sheep;225
1.12.1.2.10;2.10. Transgenic Mouse Models;226
1.12.1.2.11;2.11. Peri- and/or Intratumoral Lymphangiogenesis;227
1.12.1.3;3. Animal Models that Demonstrated the Relationship Between Lymphangiogenesis and Lymph Node Metastasis;229
1.12.1.3.1;3.1. Lymphangiogenesis Associated with the Primary Tumor;229
1.12.1.3.2;3.2. Lymphangiogenesis Associated with the Sentinel Lymph Node;230
1.12.1.4;4. Summary;231
1.12.1.5;References;232
1.12.2;Sentinel Lymph Node Chemokine Microenvironment Modulated by Melanoma Metastasis;237
1.12.2.1;1. Introduction;238
1.12.2.2;2. Results;239
1.12.2.2.1;2.1. CXCL12 mRNA Expression in SLN;239
1.12.2.2.2;2.2. CCL21 mRNA Expression in SLN;241
1.12.2.2.3;2.3. CXCL12 and CCL21 mRNA Expression in Metastasis-Free SLN;241
1.12.2.2.4;2.4. IHC Analysis of Chemokine Expression in SLN;241
1.12.2.3;3. Discussion;242
1.12.2.4;References;244
1.12.3;Circulating and Disseminated Tumor Cells from Solid Tumors-Research and Clinical Aspects;246
1.12.3.1;1. Introduction;247
1.12.3.2;2. Bone Marrow as Common Homing Organ for Disseminating Tumor Cells;247
1.12.3.3;3. Clinical Studies on Disseminating Tumor Cells;247
1.12.3.4;4. Biological Characteristics of Disseminated and Circulating Tumor Cells;248
1.12.3.5;5. Conclusions;249
1.12.3.6;References;249
1.12.4;Head and Neck Cancer: An Example for the Role of Chemokine Receptors in Tumor Progression and Metastasis;251
1.12.4.1;1. Introduction;251
1.12.4.2;2. Chemokine Receptors;252
1.12.4.3;3. Chemokine Receptor Expression in Head and Neck Cancer;253
1.12.4.4;4. Chemokine Receptors Mediate Tumor Cell Migration, Invasion, and Survival;255
1.12.4.5;5. CCR7 Downstream Activation of Nuclear Factor-kappaB Completes the Autocrine Loop;257
1.12.4.6;6. Conclusion;258
1.12.4.7;References;258
1.12.5;Tumor and Lymph Node Lymphangiogenesis;263
1.12.5.1;1. Introduction;263
1.12.5.2;2. Tumor Lymphangiogenesis Promotes Lymph Node Metastasis;264
1.12.5.3;3. A New Concept of Tumor Metastasis: Lymph Node Lymphangiogenesis;265
1.12.5.4;4. Tumor Lymphangiogenesis and Metastasis in Human Cancers;265
1.12.5.5;5. Outlook;267
1.12.5.6;References;268
1.12.6;Treg, Chemokines, and Other Small Molecules: Role in Metastasis and Its Prevention;270
1.12.6.1;1. Introduction;271
1.12.6.2;2. Evolution of the Tumor-Infiltrating Lymphocyte Concept;271
1.12.6.3;3. Immunophenotyping and Subtyping TIL;272
1.12.6.4;4. Strategies to Augment Antimelanoma Immunity;274
1.12.6.5;5. Anti-CTLA-4 mAb Use in Melanoma Immunotherapy;275
1.12.6.6;6. Treg Depletion Strategies in the Immunotherapy of Melanoma;279
1.12.6.7;7. Additional Chemokine-Targeted Immunotherapy Strategies;279
1.12.6.8;8. Concluding Remarks;280
1.12.6.9;References;280
1.13;VII MOLECULAR TARGETED THERAPY AGAINST GROWTH FACTOR RECEPTORS,SIGNALING PATHWAYS AND ANGIOGENESIS AS THERAPEUTIC TARGETS;287
1.13.1;Molecular Targeting of Lymphangiogenesis and Tumor Metastasis;288
1.13.1.1;1. Introduction;289
1.13.1.2;2. Lymphangiogenic VEGF Receptors and Ligands;289
1.13.1.3;3. Angiopoietins and Tie Receptors;290
1.13.1.4;4. Chemokines, Chemokine Receptors, and other Cell-Homing Molecules;290
1.13.1.5;5. Matrix and Basement Membrane-Cell Interaction Proteins;291
1.13.1.6;6. Other Mediators of Lymphangiogenesis and Lymphatic Metastasis;291
1.13.1.7;7. Lymphangiogenesis and Tumor Metastasis;292
1.13.1.8;8. Strategies for Inhibition of Lymphangiogenesis and Tumor Metastasis;293
1.13.1.9;9. Antibodies Against VEGF Receptors and their Ligands;294
1.13.1.10;10. Soluble Receptors;294
1.13.1.11;11. Tyrosine Kinase Inhibitors;295
1.13.1.12;12. Other Therapeutic Agents Targeting VEGF-C/VEGFR-3 Signaling;295
1.13.1.13;13. Molecules Blocking Angiopoietins and Tie Receptors;295
1.13.1.14;14. Molecular Targeting of Chemokines and their Receptors;295
1.13.1.15;15. Targeting of Other Pathways;296
1.13.1.16;16. Future Prospects in Molecular Targeting of Lymphangiogenesis and Tumor Metastasis;296
1.13.1.17;References;296
1.13.2;Combined Targeting of EGFR and Angiogenesis in Aerodigestive Carcinomas;301
1.13.2.1;1. Introduction;301
1.13.2.2;2. EGFR and VEGF/VEGFR-Signaling Pathways;302
1.13.2.3;3. Strategies for EGFR and VEGF/VEGFR Inhibition;303
1.13.2.4;4. Clinical Experience with Dual Targeting of EGFR and VEGF/VEGFR;304
1.13.2.4.1;4.1. Nonsmall-Cell Lung Cancer;304
1.13.2.4.2;4.2. Squamous Cell Carcinoma of the Head and Neck;307
1.13.2.5;5. Conclusions and Future Perspectives;308
1.13.2.6;References;308
1.13.3;Targeting Signaling Pathways in Cancer Therapy;312
1.13.3.1;1. Introduction;313
1.13.3.2;2. Common Biological Targets;313
1.13.3.3;3. Monoclonal Antibodies and Small-Molecule Tkls;315
1.13.3.4;4. Small Molecules in Hepatocellular Cancer;317
1.13.3.4.1;4.1. Sorafenib;317
1.13.3.4.2;4.2. Sunitinib;318
1.13.3.4.3;4.3. EGFR Tyrosine Kinase Inhibitors;318
1.13.3.4.4;4.4. Conclusion;318
1.13.3.5;5. Small-Molecule Tkis in Nonsmall-Cell lung Cancer;319
1.13.3.6;6. Small Molecules in Breast Cancer;321
1.13.3.6.1;6.1. Gefitinib and Other EGFR-Specific TKIs;321
1.13.3.6.2;6.2. Lapatinib;321
1.13.3.7;7. Small Molecules in Colon Cancer;322
1.13.3.8;8. Conclusion;323
1.13.3.9;References;324
1.14;VIII IMPACT OF NODAL STATUS AND TUMOR BURDEN IN SENTINEL NODES ON THE CLINICAL OUTCOME ;330
1.14.1;Micrometastasis of Melanoma to Sentinel Lymph Nodes;331
1.14.1.1;28.1. Introduction;331
1.14.1.2;28.2. Significance of Micrometastasis in Melanoma SLNs;332
1.14.1.3;28.3. Further Definition of Micrometastasis in Melanoma SLNs;333
1.14.1.4;28.4. Data from Randomized Studies to Show the Significance of Micrometastasis in Melanoma SLNs;335
1.14.1.5;28.5. Recent Data on Micrometastasis in Melanoma SLNs from UCSF;336
1.14.1.6;28.6. New Paradigm of Metastasis for Melanoma Based on the SLN Data;336
1.14.1.7;28.7. Conclusion;337
1.14.1.8;References;337
1.14.2;Sentinel Lymph Node Micrometastases in Breast Cancer: Prognostic Relevance and Therapeutic Implications;340
1.14.2.1;29.1. Introduction;341
1.14.2.2;29.2. Accuracy of the SLN Procedure and Axillary Recurrence Rate After SLN Biopsy Alone;341
1.14.2.3;29.3. Detection Rate of SLN Micrometastases;342
1.14.2.4;29.4. Correlation of SLN and Non-SLN Metastases;342
1.14.2.5;29.5. Type of Non-SLN Metastases in Patients with SLN Micro-Metastases;343
1.14.2.6;29.6. Prognostic Significance of SLN Micrometastases;343
1.14.2.7;29.7. Conclusion;344
1.14.2.8;References;345
1.14.3;Micrometastasis of Genitourinary Cancer to Sentinel Lymph Nodes;347
1.14.3.1;30.1. Introduction;347
1.14.3.2;30.2. Penile Carcinoma;348
1.14.3.3;30.3. Prostate Gland;349
1.14.3.4;30.4. Bladder Carcinoma;350
1.14.3.5;30.5. Testicular Carcinoma;351
1.14.3.6;30.6. Renal Carcinoma;355
1.14.3.7;30.7. Conclusion;355
1.14.3.8;References;355
1.14.4;Sentinel Lymph Node Mapping in Colorectal Cancer;360
1.14.4.1;31.1. Introduction;361
1.14.4.2;31.2. Lymph Node Micrometastasis in Colon Cancer;361
1.14.4.3;31.3. Sentinel Lymph Node Mapping in Colorectal Cancer;363
1.14.4.3.1;31.3.1. Historical Review;363
1.14.4.3.2;31.3.2. Definition of a Sentinel Lymph Node;364
1.14.4.3.3;31.3.3. Technique of Sentinel Lymph Node Mapping in Colon Cancer;364
1.14.4.3.4;31.3.4. Technique of Sentinel Lymph Node Mapping in Rectal Cancer;366
1.14.4.3.5;31.3.5. Dyes Used in Sentinel Lymph Node Mapping in Colorectal Cancer;366
1.14.4.3.6;31.3.6. Ex Vivo Mapping;368
1.14.4.3.7;31.3.7. Laparoscopic Experience;368
1.14.4.3.8;31.3.8. Pathological Examination of SLNs;368
1.14.4.3.9;31.3.9. The Swiss Trial: The Amount of Dye is Related to the Size of the Tumor;369
1.14.4.3.10;31.3.10. Skip Metastasis;369
1.14.4.4;31.4. Multicenter Trials Evaluating Sentinel Lymph Node Mapping in Colorectal Cancer;370
1.14.4.5;31.5. Our Multicenter Trial Results;371
1.14.4.6;31.6. Colon Cancer;371
1.14.4.7;31.7. Rectal Cancer;372
1.14.4.8;31.8. Conclusion;374
1.14.4.9;References;375
1.14.5;Application of Cancer Biology in Cancer Staging and Predicting Clinical Outcome;379
1.14.5.1;References;385
1.15;IX IMMUNE RESPONSES IN THE DRAINING LYMPH NODES AGAINST CANCER:IMPLICATION FOR IMMUNOTHERAPY;387
1.15.1;Role of Lymph Nodes in Immunotherapy of Malignant Tumors;388
1.15.1.1;1. Introduction;388
1.15.1.2;2. Structure and Anatomy;389
1.15.1.3;3. Generation of Effector Cells for Adoptive Immunotherapy;389
1.15.1.4;4. Key Role of Antigen-Presenting Cells;391
1.15.1.5;5. Process of Dc -Tumor Cell Fusion;392
1.15.1.6;6. Sensitization by Fusion Cells;393
1.15.1.7;7. Future Directions;395
1.15.1.8;References;396
1.15.2;Tumor-Related Immune Modulation of the Regional Lymph Nodes;398
1.15.2.1;References;401
1.15.3;Reversal of Immune Suppression in Sentinel Lymph Nodes;404
1.15.3.1;35.1. Introduction;405
1.15.3.1.1;35.1. Historical Prospective;405
1.15.3.2;35.2. Role of the Immune System in SN;406
1.15.3.3;35.3. The Argument for Focused Analysis of SN;408
1.15.3.4;35.4. Immunohistochemistry Analysis of Sentinel and Non-Sentinel Lymph Nodes for Dendritic Cell Markers;409
1.15.3.5;35.5. Gene Expression of Dendritic Cell Markers of Activation from Sentinel and Non-Sentinel Lymph Nodes;410
1.15.3.6;35.6. Evaluate Gene Expression of TH-1- and TH-2-Related Cytokines from Sentinel and Nonsentinel Lymph Node Matches;412
1.15.3.7;35.7. Development of Real-Time Quantitative RT-PCR Analysis for Evaluation of Sentinel and Nonsentinel Lymph Node Matches;413
1.15.3.8;35.8. Evaluation of GM-CSF to Reverse the Phenotypic Changes to Sentinel Lymph Nodes;416
1.15.3.9;35.9. Significance of GM-CSF Data;417
1.15.3.10;References;417
1.15.4;Vaccine-Primed Lymph Node Cells in the Adoptive Immunotherapy of Cancer: Presence of Host Immune Suppression Induced by Established Cancer;421
1.15.4.1;1. Introduction;422
1.15.4.2;2. Tumor-Draining Lymph Node Cells: Animal Studies;422
1.15.4.3;3. Vaccine-Primed Lymph Node Cells: Clinical Studies;423
1.15.4.4;4. Immune Suppression of Tumor-Draining Lymph Node Effector Cells;424
1.15.4.5;5. Possible Mechanisms of Immune Suppression;426
1.15.4.6;6. Summary;427
1.15.4.7;References;427
1.16;X THE ROLE OF STEM CELLS IN CANCER METASTASIS;429
1.16.1;Cancer Stem Cells in Metastatic Melanoma;430
1.16.1.1;1. Cancer Stem Cells;430
1.16.1.2;2. Melanoma Stem Cells;432
1.16.1.3;3. Cancer Stem Cells in Metastasis;432
1.16.1.4;4. Therapeutic Implications of Melanoma Stem Cells;434
1.16.1.5;References;435
1.16.2;Implications of Cancer Stem Cells for Tumor Metastasis;437
1.16.2.1;38.1. Stem Cells: General Principles;438
1.16.2.2;38.2. Cancer Stem Cells: Definition and Identification;438
1.16.2.3;38.3. Cancer Stem Cells: Role in Tumor Metastasis;440
1.16.2.4;38.4. Conclusions;445
1.16.2.5;References;445
1.16.3;Prostate Cancer Stem Cells and Their Involvement in Metastasis;448
1.16.3.1;1. Introduction;449
1.16.3.2;2. Normal Prostate Stem/Progenitor Cells;449
1.16.3.3;3. CSCs: Resemblance to Normal SCs and Seeds of Tumor Development;450
1.16.3.4;4. Human Prostate CSCs: PCa-Initiating Cells;450
1.16.3.4.1;4.1. Surface Markers;451
1.16.3.4.2;4.2. Side Population Technique;451
1.16.3.4.3;4.3. Sphere-Formation Assays;451
1.16.3.5;5. CSCs and Metastasis;451
1.16.3.6;6. Potential Roles of CSCs in PCa Metastasis and Therapeutic Implications;452
1.16.3.7;References;453
1.17;XI GENOMIC SIGNATURES OF CANCER:BASIS FOR SELECTIVE ADJUVANT THERAPY;455
1.17.1;Estrogen Receptor-Positive Breast Cancer: Traditional Prognostics, Molecular Pathology: A New Breast Cancer Taxonomy and 21st Century Personalized Prognostic and Predictive Assays;456
1.17.1.1;40.1. Introduction;457
1.17.1.1.1;40.1.14. The Dawn of Molecular Pathology;457
1.17.1.1.2;40.1.14. Breast Carcinoma;457
1.17.1.2;40.2. Traditional Prognostic and Predictive Factors;457
1.17.1.2.1;40.2.1. Introduction;457
1.17.1.2.2;40.2.2. Tumor Stage: Axillary Lymph Nodes;458
1.17.1.2.3;40.2.3. Isolated Tumor Cells: pN0i+;458
1.17.1.2.4;40.2.4. AJCC Cancer Staging Manual;459
1.17.1.2.5;40.2.5. Micrometastases: pN1mi;459
1.17.1.2.6;40.2.6. Tumor Size;459
1.17.1.2.7;40.2.7. Tumor Grade;459
1.17.1.2.8;40.2.8. Histologic Subtypes;461
1.17.1.2.9;40.2.9. Hormone Receptors: An Introduction;461
1.17.1.2.9.1;40.2.9.1. The Estrogen and Progesterone Receptors;462
1.17.1.2.10;40.2.10. ER Negativity;462
1.17.1.2.10.1;40.2.10.1. Estrogen Receptor beta;462
1.17.1.2.10.2;40.2.10.2. Methods of Measuring Hormone Receptors;462
1.17.1.2.10.3;40.2.10.3. Methods of Measuring Hormone Receptors: the Ligand-Binding Method;463
1.17.1.2.10.4;40.2.10.4. Methods of Measuring Hormone Receptors: Immunohistochemistry;463
1.17.1.2.11;40.2.11. Protocol: Estrogen Receptor;463
1.17.1.2.12;40.2.12. Clinical Validation: Estrogen Receptor as a Continuous Variable;463
1.17.1.2.13;40.2.13. Clinical Validation: Progesterone Receptor;465
1.17.1.2.14;40.2.14. Endocrine Therapy;466
1.17.1.2.14.1;40.2.14.1. Tamoxifen-Resistance in ER+ Breast Cancer;466
1.17.1.2.14.2;40.2.14.2. Acquired Endocrine Resistance;466
1.17.1.2.14.3;40.2.14.3. Other Markers;466
1.17.1.3;40.3. Personalized Medicine: 21st Century Prognostic and Predictive Molecular Tools;467
1.17.1.3.1;40.3.1. Roadmap;467
1.17.1.3.2;40.3.2. Technology Introduction;467
1.17.1.3.2.1;40.3.2.1. Microarray Analysis: What Is It and Why Is It Valuable?;467
1.17.1.3.3;40.3.3. DNA Expression Microarrays: ‘‘Expression Arrays’’;468
1.17.1.3.3.1;40.3.3.1. Functional Genomics;468
1.17.1.3.4;40.3.4. Gene Arrays: Technical Comments (14);468
1.17.1.3.5;40.3.5. Gene Expression Arrays: Methodology;468
1.17.1.3.6;40.3.6. Comparative Genomic Hybridization: Methodology;469
1.17.1.3.7;40.3.7. Array CGH;470
1.17.1.3.8;40.3.8. Quantitative Real-Time Polymerase Chain Reaction;470
1.17.1.3.9;40.3.9. Introduction: 21st Century Prognostic and Predictive Factors;471
1.17.1.4;40.4. A New Breast Taxonomy: Molecular Subtypes Using Unsupervised Classification;471
1.17.1.4.1;40.4.1. Unsupervised Molecular Taxonomy of Breast: Luminal A/B, HER2, and Basal Subtypes of Breast Carcinoma;471
1.17.1.4.2;40.4.2. Confirmation of Taxonomy: Evaluation of Breast Cancer Data from van’t Veer et al.;472
1.17.1.4.3;40.4.3. Tumor Subtypes Are Associated with Significant Difference in Clinical Outcome;473
1.17.1.4.4;40.4.4. Breast Tumor Subtypes Represent Reproducible Distinct Biological Entities;474
1.17.1.4.5;40.4.5. Conclusion: New Breast Taxonomy;474
1.17.1.5;40.5. Genomic Classifiers: Prognostic and Predictive Signatures;475
1.17.1.5.1;40.5.1. Introduction;475
1.17.1.5.2;40.5.2. Classifier Development (54);475
1.17.1.6;40.6. The Mammoprint Breast Cancer Assay;476
1.17.1.6.1;40.6.1. Breast Cancer Classifier: van’t Veer et al. (59);476
1.17.1.6.2;40.6.2. Validation of the 70-Gene Classifier (60);478
1.17.1.6.3;40.6.3. Criticisms;479
1.17.1.7;40.7. Onco Type DXtrade;479
1.17.1.7.1;40.7.1. Introduction: Onco type DXtrade;479
1.17.1.7.2;40.7.2. Assay Design;479
1.17.1.7.3;40.7.3. Technical Feasibility Studies;480
1.17.1.7.4;40.7.4. Development Studies;480
1.17.1.7.5;40.7.5. Recurrence Score Calculation;480
1.17.1.7.6;40.7.6. Clinical Validation Studies;480
1.17.1.7.6.1;40.7.6.1. NSABP B-14: Introduction;480
1.17.1.7.7;40.7.7. Study Design;480
1.17.1.7.8;40.7.8. Methodology;481
1.17.1.7.9;40.7.9. Analysis;481
1.17.1.7.10;40.7.10. Results;481
1.17.1.7.11;40.7.11. Additional Validation Study: Kaiser Permanente Study;482
1.17.1.7.12;40.7.12. Prediction of Chemothrerapy Benefit: NSABP B-20;482
1.17.1.7.13;40.7.13. Results;482
1.17.1.7.14;40.7.14. Reclassification Versus Guidelines;483
1.17.1.8;40.8. Conclusion;483
1.17.1.9;References;484
1.17.2;Molecular Signatures in Melanoma Progression;487
1.17.2.1;41.1. Introduction;487
1.17.2.2;41.2. Biology Of Tumor Metastasis;488
1.17.2.3;41.3. Molecular Signatures: From Nevus To Melanoma;489
1.17.2.3.1;41.3.1. B-RAF Activating Mutation as a Precursor;489
1.17.2.3.2;41.3.2. Defining the Molecular Signatures in Melanoma Progression;489
1.17.2.3.2.1;41.3.2.1. Transition from RGP to VGP and Extending the Findings to Metastatic Melanoma;490
1.17.2.3.3;41.3.3. CDH3 and MMP-10;491
1.17.2.3.3.1;41.3.3.1. Distinguishing a Benign Nevus from a Primary Melanoma;493
1.17.2.3.4;41.3.4. Osteopontin as a Novel Molecular Prognostic Marker for Melanoma;494
1.17.2.3.4.1;41.3.4.1. Perform a Multiclass Analysis Comparing nevi, Primary, and Metastatic Lesions;495
1.17.2.3.5;41.3.5. Molecular Marker NCOA3 Overexpressed in Metastatic Melanoma;495
1.17.2.4;41.4. Molecular Markers And Sentinel Lymph Node Biopsy;496
1.17.2.5;41.5. Implications And Future Direction;496
1.17.2.6;References;497
1.18;XII PROMISING NEW TREATMENTS FOR SOLID TUMORS;500
1.18.1;Targeted Therapy for Breast Cancer: A Focus on HER2/neu and Antiangiogenic Therapy;501
1.18.1.1;1. Introduction;502
1.18.1.2;2. Targeting HER2/NEU;502
1.18.1.3;3. LAPATINIB;504
1.18.1.4;4. Novel HER2-Directed Therapy;505
1.18.1.5;5. Targeting HER2 and the Vascular Endothelial Growth Factor Receptor;506
1.18.1.6;6. Antiangiogenic Therapy;507
1.18.1.7;References;508
1.18.2;Advances in the Treatment of Colorectal Cancer: Targeting Receptors of Disease;510
1.18.2.1;1. Introduction;510
1.18.2.2;2. Angiogenesis;512
1.18.2.2.1;2.1. Bevacizumab;512
1.18.2.2.2;2.2. Sunitinib;513
1.18.2.3;3. Epidermal Growth Factor Receptor Pathway;513
1.18.2.3.1;3.1. Cetuximab;514
1.18.2.3.2;3.2. Panitumumab;514
1.18.2.3.3;3.3. Genetic Selection in Colorectal Cancer: KRAS Mutations and Efficacy of Anti-EGFR Therapy;515
1.18.2.4;4. Combined Targeting Of Angiogenesis And Egfr;516
1.18.2.5;5. Conclusion;516
1.18.2.6;References;517
1.18.3;Developments in the Management of Genitourinary Malignancies: Prostate Cancer and Renal Cell Carcinoma;520
1.18.3.1;1. Prostate Cancer;520
1.18.3.1.1;1.1. Secondary Hormonal Manipulations;520
1.18.3.1.2;1.2. MDV3100;522
1.18.3.1.3;1.3. Chemotherapy for Castration-Resistant Prostate Cancer;522
1.18.3.1.4;1.4. Epothilone Analogs: Ixabepilone;522
1.18.3.1.5;1.5. Chemotherapy Plus Angiogenesis Inhibition;523
1.18.3.1.6;1.6. VEGF Tyrosine Kinase Inhibition;523
1.18.3.1.7;1.7. Other Investigational Agents;523
1.18.3.1.7.1;1.7.1. Atrasentan;523
1.18.3.1.8;1.8. Immunotherapy;524
1.18.3.1.8.1;1.8.1. Sipuleucel-T;524
1.18.3.1.8.2;1.8.2. Cellular Vaccination;524
1.18.3.1.8.3;1.8.3. Anti-CTLA4 Therapy: Ipilimumab;525
1.18.3.1.9;1.9. Prostate Cancer: Conclusions;525
1.18.3.2;2. Renal Cell Carcinoma;525
1.18.3.2.1;2.1. Drug Targets in Renal Cell Carcinoma;526
1.18.3.2.1.1;2.1.1. VHL in Kidney Cancer;526
1.18.3.2.1.2;2.1.2. mTOR in Kidney Cancer;526
1.18.3.2.2;2.2. VEGF Pathway-Directed Angiogenesis Inhibitors;526
1.18.3.2.2.1;2.2.1. Bevacizumab;526
1.18.3.2.2.2;2.2.2. Sunitinib;527
1.18.3.2.2.3;2.2.3. Sorafenib;527
1.18.3.2.3;2.3. mTOR Inhibition;528
1.18.3.2.3.1;2.3.1. Temsirolimus (CCI-779);528
1.18.3.2.3.2;2.3.2. RAD001;529
1.18.3.2.4;2.4. Renal Cell Carcinoma-Conclusions;529
1.18.3.3;References;529
1.18.4;Advances in the Treatment of Lung Cancer;532
1.18.4.1;1. Nonsmall-Cell Lung Cancer;533
1.18.4.1.1;1.1. Early Disease;533
1.18.4.1.1.1;1.1.1. Radiation Therapy;533
1.18.4.1.1.2;1.1.2. Adjuvant Chemotherapy;533
1.18.4.1.2;1.2. Locally Advanced NSCLC;534
1.18.4.1.3;1.3. Advanced Disease;534
1.18.4.1.3.1;1.3.1. Cytotoxic Chemotherapy;534
1.18.4.1.4;1.4. Targeted Therapies;535
1.18.4.1.4.1;1.4.1. Epidermal Growth Factor Inhibitors;535
1.18.4.1.4.2;1.4.2. Angiogenesis Inhibitors;535
1.18.4.1.5;1.5. Predictive and Prognostic Molecular Markers;535
1.18.4.2;2. Small-Cell Lung Cancer;536
1.18.4.3;3. Conclusions;537
1.18.4.4;References;537
1.19;XIII RECENT ADVANCES IN THE TREATMENT OF MELANOMA;540
1.19.1;Pegylated Interferons in the Adjuvant Treatment of Melanoma;541
1.19.1.1;46.1. Introduction;541
1.19.1.2;46.2. Background and History of Interferons;542
1.19.1.3;46.3. Effects of Interferon-alpha;542
1.19.1.4;46.4. Pegylated Interferon-alpha Compared to Classic Interferon-alpha;542
1.19.1.5;46.5. Adjuvant Treatment with Interferon-alpha;544
1.19.1.6;46.6. Adjuvant Treatment with Pegylated Interferon-alpha;545
1.19.1.7;References;548
1.19.2;Sorafenib, a Multikinase Inhibitor: Results from Clinical Trials in Melanoma Patients;551
1.19.2.1;47.1. Introduction;552
1.19.2.2;47.2. Sorafenib: Mode of Action;552
1.19.2.3;47.3. Sorafenib: Clinical Trials in Various Cancers;553
1.19.2.4;47.4. Single-Agent Sorafenib: Clinical Trials in Melanoma;555
1.19.2.5;47.5. Sorafenib Plus Dacarbazine in Melanoma;555
1.19.2.6;47.6. Sorafenib Plus Temozolomide in Melanoma;555
1.19.2.7;47.7. Carboplatin, Paclitaxel with or without Sorafenib;556
1.19.2.8;47.8. Other Phase II Trials with Sorafenib;556
1.19.2.9;47.9. Sorafenib and Pegylated Interferon-alpha2b in Metastatic Melanoma;558
1.19.2.10;47.10. Conclusions;558
1.19.2.11;References;559
1.19.3;Targeting Immunological Synapse: New Horizons in Immunotherapy for Cancer;561
1.19.3.1;1. Immunological Synapse;562
1.19.3.2;2. Targeting Inhibitory Molecules;563
1.19.3.2.1;2.1. CTLA-4 (CD152);563
1.19.3.2.2;2.2. Programmed Death-1;565
1.19.3.3;3. Targeting Co-Stimulatory Molecules;566
1.19.3.3.1;3.1. CD28;566
1.19.3.3.2;3.2. 4-1BB;566
1.19.3.3.3;3.3. OX-40;566
1.19.3.4;4. Targeting APCS;567
1.19.3.4.1;4.1. CD40;567
1.19.3.5;5. Autoimmunity;568
1.19.3.6;6. Where do we come from? what are we? where are we Going?;569
1.19.3.7;References;571
1.19.4;Cutaneous Metastases of Melanoma: New Treatment Options;577
1.19.4.1;1. Introduction;578
1.19.4.2;2. Topical Treatment with 2-4 DNCB;578
1.19.4.3;3. Intratumoral IL-2 Treatment;579
1.19.4.3.1;3.1. Indication for intratumoral IL-2 treatment;579
1.19.4.3.2;3.2. Management of intratumoral IL-2 treatment;580
1.19.4.3.3;3.3. Tumor responses under intralesional IL-2 therapy;580
1.19.4.4;4. Topical Treatment with Imiquimod;581
1.19.4.5;5. Discussion;582
1.19.4.6;References;582
1.19.5;Neoadjuvant Approaches in Melanoma;585
1.19.5.1;1. Introduction;586
1.19.5.2;2. Immunity and Immunotherapy in Melanoma and Implications for Adjuvant and Neoadjuvant Therapy;586
1.19.5.3;3. Adjuvant High-Dose IFN-alpha2b for High-Risk Resected Melanoma;587
1.19.5.4;4. Neoadjuvant Treatment of Potentially Resectable Local-Regional Metastases of Cutaneous Melanoma;588
1.19.5.5;5. Neoadjuvant Concurrent Biochemotherapy in Melanoma Patients with Local-Regional Metastases;588
1.19.5.6;6. Neoadjuvant Treatment with High-Dose IFN-alpha2b for Patients with Regional Nodal Presentation or Recurrence as Stage IIIB-C Melanoma;589
1.19.5.7;7. Conclusion;590
1.19.5.8;References;590
1.19.6;Implications of Chemo/Biochemotherapy in the Treatment of Metastatic Melanoma;592
1.19.6.1;1. Introduction;592
1.19.6.2;2. Cytotoxic Chemotherapy;593
1.19.6.3;3. Immunotherapy;593
1.19.6.4;4. Biochemotherapy;593
1.19.6.5;5. Summary and Conclusions;594
1.19.6.6;References;594
1.20;XIV FUTURE PERSPECTIVES;595
1.20.1;Future Perspectives for Cancer Metastasis: Unanswered Questions and Unquestioned Answers;596
1.20.1.1;1. Introduction;596
1.20.1.2;2. Cancer Metastasis and the Lymphovascular System;597
1.20.1.3;3. Unanswered Questions and Unquestioned Answers;597
1.20.1.4;References;599
1.21;Index;600