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Table of Contents
Title Page
Copyright Page
Section 1 Biological Basis of Childhood Cancer
1 Epidemiology of Childhood Cancer
Cancer Surveillance and Descriptive Epidemiology
Analytic Epidemiology
Summary and Future Considerations
2 Heredity and Childhood Cancer
Constitutional Chromosomal Abnormalities
Structural Chromosomal Abnormalities
Overgrowth Disorders and Imprinting Errors
Autosomal Dominant Disorders
Autosomal Recessive Disorders
Issue in Genetic Testing for the Pediatric Oncology Patient
3 Molecular and Genetic Basis of Childhood Cancer
General Nature of Cancer-Associated Genetic Aberrations
Comprehensive Analysis of the Cancer Genome
Germline Mutations
Somatically Acquired Chromosomal Aberrations and Mutation
Gross Chromosomal Rearrangements
Oncogenic Consequences of Gross Chromosomal Rearrangements-General Themes
Chromosomal Translocations Lead to Activation of Proto-Oncogenes and Generation of Oncogenic Fusion Genes
Chromosomal Deletion Leads to Inactivation of Tumor Suppressor Genes
Gene Amplification
Point Mutations Leading to Gene Activation or Inactivation
Comprehensive Genomic Studies of Pediatric Tumors
Mechanisms of Malignant Cell Transformation, Growth, and Clonal Expansion
Outlook for Molecularly Targeted Therapies
Summary
4 Biology of Childhood Cancer
Gene Regulation
Protein Regulation
Signal Transduction
Cell Proliferation
Programmed Cell Death
Cancer Metabolism
Metastasis and the Tumor Microenvironment
5 Tumor Immunology of Childhood Cancer
Overview of the Immune System
Modern Concepts of Immune Surveillance
T-Cell Recognition of Cancer
Innate Immune Cells and the Tumor Microenvironment
Immune Function in Cancer Patients
Immunotherapy of Cancer
Summary and Future Directions.
Section 2 Diagnosis and Evaluation of the Child with Cancer
6 Clinical Assessment and Differential Diagnosis of Suspected Childhood Cancer
Children at Risk
Time to Diagnosis
Differential Diagnosis
Establishing the Diagnosis
Summary
7 Pathology and Molecular Diagnosis of Leukemias and Lymphomas
Introduction
Ancillary Studies
Lymphoblastic Leukemia
Myeloid Neoplasms
Mature Lymphoid Neoplasms
Histiocytic Disorders
8 Diagnostic Pathology of Pediatric Solid and Central Nervous System Malignancies
Introduction
Brief Pathologic Classification of Pediatric Solid Tumors
Traditional Approaches to Childhood Solid Tumor Diagnosis
Molecular Genetic Evaluation of Childhood Cancer
Integrated Diagnostic Molecular Pathology of Pediatric Solid Tumors
The Holistic Cancer Genome
DNA
RNA
Emerging Technologies for Diagnosis
The Future of Pediatric Cancer Diagnosis
9 Imaging Studies in the Diagnosis of Childhood Cancer
Relative Merits of Available Imaging Procedures
General Concepts of Pediatric Tumor Imaging
Future Directions
Section 3 Principles of Multimodal Therapy
10 General Principles of Chemotherapy
Principles of Cancer Chemotherapy
Clinical Pharmacology of Anticancer Drugs
Alkylating Agents
Nonclassical Alkylating Agents
Antimetabolites
Purine Antimetabolites
Pyrimidine Antimetabolites
Topoisomerase Inhibitors
Tubulin Inhibitors
Miscellaneous Agents
Small-Molecule Pathway Inhibitors
Therapeutic Antibodies
Perspectives
11 General Principles of Cellular Immunotherapy
T Cells
Natural Killer Cells
γδ Thymus-Derived T Cells
Invariant Natural Killer T Cells
Strategies to Improve Adoptive Cellular Therapies
Conclusions
12 General Principles of Targeted Therapy
Introduction.
Basic Principles for the Clinical Development of Molecularly Targeted Agents
Therapies Targeted to Apoptosis Pathways
Targeting Extracellular Survival Signaling Pathways
Targeting Development, Differentiation, and Other Intracellular Processes
Targeting Angiogenesis
Conclusions
13 General Principles of Hematopoietic Stem Cell Transplantation
Autologous Transplantation-High-Dose Chemotherapy with Hematopoietic Stem Cell (Hsc) Rescue
Allogeneic Transplantation
Allogeneic Hematopoietic Stem Cell Transplantation Preparative Regimens
Transplantation for Leukemia
Transplantation for Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL)
Transplantation for Solid Tumors
Complications After Hematopoietic Stem Cell Transplantation
Late Effects After Hematopoietic Stem Cell Transplantation
Future Directions
14 General Principles of Radiation Oncology
Biologic Basis of Radiation Therapy
Physical Basis of Radiation Therapy
Interactions of Radiation Therapy and Chemotherapy
Radiation Effects on Normal Tissues
15 General Principles of Surgery
Preoperative Considerations for the Oncologist
Perioperative Considerations for the Oncologist
Minimally Invasive Surgery
Section 4 Management of Common Cancers of Childhood
16 Acute Lymphoblastic Leukemia
Epidemiology
Genetic Risk Factors
Environmental Risk Factors
Pathogenesis
Classification of Acute Lymphoblastic Leukemia
Molecular Genomics of Acute Lymphoblastic Leukemia
Pharmacogenetics
Clinical Presentation
Assessing Treatment Response
Prognostic Factors
Treatment
Treatment of Relapse
Late Effects of Treatment
Future Challenges
17A Acute Myeloid Leukemia and Myelodysplastic Syndromes
Historical Background and Definitions.
Epidemiology of Pediatric Acute Myeloid Leukemia and Myelodysplastic Syndrome
Biologic Basis of Acute Myeloid Leukemia and Myelodysplastic Syndrome: From Normal Progenitors to Leukemia
Methodologies for Classifying Myeloid Malignancies
Defining Subtypes: Evolution of Diagnostic Classification of Myeloid Malignancies
Clinical and Laboratory Presentation
Prognostic Factors and Implications of Risk Group Stratification on Treatment
Evolution of Risk Adapted Therapy
Unique Aml Subtypes and Settings
The Treatment of Relapsed or Refractory Acute Myeloid Leukemia
Survivorship
17B Myeloproliferative Neoplasms of Childhood
Chronic Myeloid Leukemia
Juvenile Myelomonocytic Leukemia
Polycythemia Vera and Essential Thrombocythemia
18 Hodgkin Lymphoma
Biologic Considerations
Epidemiology, Pathogenesis &
Pathology
Clinical Presentation
Treatment and Outcome
Nodular Lymphocyte Predominant Hodgkin Lymphoma
Approach to Patients with Primary Refractory Disease or Relapse of Hodgkin Lymphoma
Late Effects
Future Considerations
19 Malignant Non-Hodgkin Lymphomas in Children
Non-Hodgkin Lymphoma Overview
NHL Cellular Classifications: Specific Biologic and Clinical Considerations
Conclusions
Management Summary
20 Lymphoproliferative Disorders and Malignancies Related to Immunodeficiencies
Viral Pathogens and the Development of Malignancies
Epstein-Barr Virus and Malignancies
Human herpesvirus-8 and Malignancies in Immunodeficient Patients
Malignancies in Primary Immunodeficiencies
Secondary Immunodeficiency and Cancer
Malignancies in the Posttransplant Patient
Summary
21 Histiocytoses
Langerhans Cell Histiocytosis
Hemophagocytic Lymphohistiocytosis
Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)
Juvenile Xanthogranuloma.
Malignant Histiocytic Diseases
Summary
Management Summary
22A Gliomas, Ependymomas, and Other Nonembryonal Tumors of the Central Nervous System
Epidemiology
Inherited Syndromes Associated with Central Nervous System Tumors
Ionizing Radiation and Central Nervous System Tumors
Pathologic Classification of Central Nervous System Tumors
Clinical Presentation
Neuroimaging in Pediatric Central Nervous System Tumors: Current Status and Future Directions
Neurosurgery: Diagnosis and Treatment
Radiation Therapy
Principles of Chemotherapy
Ependymoma
Low-Grade Gliomas
Tumors of the Optic Pathway
Supratentorial High-Grade Gliomas
Brainstem Gliomas
Craniopharyngioma
Choroid Plexus Neoplasms
Intramedullary Spinal Cord Tumors
Sequelae of Treatment
22B Tumors of the Central Nervous System: Embryonal and Pineal Region Tumors
Embryonal Tumors
Medulloblastoma
Atypical Teratoid/Rhabdoid Tumor
Embryonal Tumors with Multilayered Rosettes
Other Rare Embryonal Tumors
Pineal Region Tumors
Germ Cell Tumors
23 Neuroblastoma
Epidemiology
Genetic Predisposition
Molecular Pathogenesis
Pathology
Clinical Presentation
Paraneoplastic Syndromes
Clinical and Laboratory Evaluation
Staging and Treatment Response
Prognostic Considerations
Principals of Initial Therapy
Late Effects
Future Considerations
24 Renal Tumors
Epidemiology
Genetics and Molecular Biology
Pathology
Clinical Presentation and Diagnostic Workup
Prognostic Factors
Treatment of Wilms Tumor
Clear Cell Sarcoma of the Kidney
Malignant Rhabdoid Tumor
Renal Cell Carcinoma
Congenital Mesoblastic Nephroma
25 Rhabdomyosarcoma
Epidemiology and Genetic Susceptibility
Molecular Biology
Animal Models
Pathology
Patterns of Spread and Clinical Presentation.
Methods of Diagnosis.
Copyright Page
Section 1 Biological Basis of Childhood Cancer
1 Epidemiology of Childhood Cancer
Cancer Surveillance and Descriptive Epidemiology
Analytic Epidemiology
Summary and Future Considerations
2 Heredity and Childhood Cancer
Constitutional Chromosomal Abnormalities
Structural Chromosomal Abnormalities
Overgrowth Disorders and Imprinting Errors
Autosomal Dominant Disorders
Autosomal Recessive Disorders
Issue in Genetic Testing for the Pediatric Oncology Patient
3 Molecular and Genetic Basis of Childhood Cancer
General Nature of Cancer-Associated Genetic Aberrations
Comprehensive Analysis of the Cancer Genome
Germline Mutations
Somatically Acquired Chromosomal Aberrations and Mutation
Gross Chromosomal Rearrangements
Oncogenic Consequences of Gross Chromosomal Rearrangements-General Themes
Chromosomal Translocations Lead to Activation of Proto-Oncogenes and Generation of Oncogenic Fusion Genes
Chromosomal Deletion Leads to Inactivation of Tumor Suppressor Genes
Gene Amplification
Point Mutations Leading to Gene Activation or Inactivation
Comprehensive Genomic Studies of Pediatric Tumors
Mechanisms of Malignant Cell Transformation, Growth, and Clonal Expansion
Outlook for Molecularly Targeted Therapies
Summary
4 Biology of Childhood Cancer
Gene Regulation
Protein Regulation
Signal Transduction
Cell Proliferation
Programmed Cell Death
Cancer Metabolism
Metastasis and the Tumor Microenvironment
5 Tumor Immunology of Childhood Cancer
Overview of the Immune System
Modern Concepts of Immune Surveillance
T-Cell Recognition of Cancer
Innate Immune Cells and the Tumor Microenvironment
Immune Function in Cancer Patients
Immunotherapy of Cancer
Summary and Future Directions.
Section 2 Diagnosis and Evaluation of the Child with Cancer
6 Clinical Assessment and Differential Diagnosis of Suspected Childhood Cancer
Children at Risk
Time to Diagnosis
Differential Diagnosis
Establishing the Diagnosis
Summary
7 Pathology and Molecular Diagnosis of Leukemias and Lymphomas
Introduction
Ancillary Studies
Lymphoblastic Leukemia
Myeloid Neoplasms
Mature Lymphoid Neoplasms
Histiocytic Disorders
8 Diagnostic Pathology of Pediatric Solid and Central Nervous System Malignancies
Introduction
Brief Pathologic Classification of Pediatric Solid Tumors
Traditional Approaches to Childhood Solid Tumor Diagnosis
Molecular Genetic Evaluation of Childhood Cancer
Integrated Diagnostic Molecular Pathology of Pediatric Solid Tumors
The Holistic Cancer Genome
DNA
RNA
Emerging Technologies for Diagnosis
The Future of Pediatric Cancer Diagnosis
9 Imaging Studies in the Diagnosis of Childhood Cancer
Relative Merits of Available Imaging Procedures
General Concepts of Pediatric Tumor Imaging
Future Directions
Section 3 Principles of Multimodal Therapy
10 General Principles of Chemotherapy
Principles of Cancer Chemotherapy
Clinical Pharmacology of Anticancer Drugs
Alkylating Agents
Nonclassical Alkylating Agents
Antimetabolites
Purine Antimetabolites
Pyrimidine Antimetabolites
Topoisomerase Inhibitors
Tubulin Inhibitors
Miscellaneous Agents
Small-Molecule Pathway Inhibitors
Therapeutic Antibodies
Perspectives
11 General Principles of Cellular Immunotherapy
T Cells
Natural Killer Cells
γδ Thymus-Derived T Cells
Invariant Natural Killer T Cells
Strategies to Improve Adoptive Cellular Therapies
Conclusions
12 General Principles of Targeted Therapy
Introduction.
Basic Principles for the Clinical Development of Molecularly Targeted Agents
Therapies Targeted to Apoptosis Pathways
Targeting Extracellular Survival Signaling Pathways
Targeting Development, Differentiation, and Other Intracellular Processes
Targeting Angiogenesis
Conclusions
13 General Principles of Hematopoietic Stem Cell Transplantation
Autologous Transplantation-High-Dose Chemotherapy with Hematopoietic Stem Cell (Hsc) Rescue
Allogeneic Transplantation
Allogeneic Hematopoietic Stem Cell Transplantation Preparative Regimens
Transplantation for Leukemia
Transplantation for Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL)
Transplantation for Solid Tumors
Complications After Hematopoietic Stem Cell Transplantation
Late Effects After Hematopoietic Stem Cell Transplantation
Future Directions
14 General Principles of Radiation Oncology
Biologic Basis of Radiation Therapy
Physical Basis of Radiation Therapy
Interactions of Radiation Therapy and Chemotherapy
Radiation Effects on Normal Tissues
15 General Principles of Surgery
Preoperative Considerations for the Oncologist
Perioperative Considerations for the Oncologist
Minimally Invasive Surgery
Section 4 Management of Common Cancers of Childhood
16 Acute Lymphoblastic Leukemia
Epidemiology
Genetic Risk Factors
Environmental Risk Factors
Pathogenesis
Classification of Acute Lymphoblastic Leukemia
Molecular Genomics of Acute Lymphoblastic Leukemia
Pharmacogenetics
Clinical Presentation
Assessing Treatment Response
Prognostic Factors
Treatment
Treatment of Relapse
Late Effects of Treatment
Future Challenges
17A Acute Myeloid Leukemia and Myelodysplastic Syndromes
Historical Background and Definitions.
Epidemiology of Pediatric Acute Myeloid Leukemia and Myelodysplastic Syndrome
Biologic Basis of Acute Myeloid Leukemia and Myelodysplastic Syndrome: From Normal Progenitors to Leukemia
Methodologies for Classifying Myeloid Malignancies
Defining Subtypes: Evolution of Diagnostic Classification of Myeloid Malignancies
Clinical and Laboratory Presentation
Prognostic Factors and Implications of Risk Group Stratification on Treatment
Evolution of Risk Adapted Therapy
Unique Aml Subtypes and Settings
The Treatment of Relapsed or Refractory Acute Myeloid Leukemia
Survivorship
17B Myeloproliferative Neoplasms of Childhood
Chronic Myeloid Leukemia
Juvenile Myelomonocytic Leukemia
Polycythemia Vera and Essential Thrombocythemia
18 Hodgkin Lymphoma
Biologic Considerations
Epidemiology, Pathogenesis &
Pathology
Clinical Presentation
Treatment and Outcome
Nodular Lymphocyte Predominant Hodgkin Lymphoma
Approach to Patients with Primary Refractory Disease or Relapse of Hodgkin Lymphoma
Late Effects
Future Considerations
19 Malignant Non-Hodgkin Lymphomas in Children
Non-Hodgkin Lymphoma Overview
NHL Cellular Classifications: Specific Biologic and Clinical Considerations
Conclusions
Management Summary
20 Lymphoproliferative Disorders and Malignancies Related to Immunodeficiencies
Viral Pathogens and the Development of Malignancies
Epstein-Barr Virus and Malignancies
Human herpesvirus-8 and Malignancies in Immunodeficient Patients
Malignancies in Primary Immunodeficiencies
Secondary Immunodeficiency and Cancer
Malignancies in the Posttransplant Patient
Summary
21 Histiocytoses
Langerhans Cell Histiocytosis
Hemophagocytic Lymphohistiocytosis
Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)
Juvenile Xanthogranuloma.
Malignant Histiocytic Diseases
Summary
Management Summary
22A Gliomas, Ependymomas, and Other Nonembryonal Tumors of the Central Nervous System
Epidemiology
Inherited Syndromes Associated with Central Nervous System Tumors
Ionizing Radiation and Central Nervous System Tumors
Pathologic Classification of Central Nervous System Tumors
Clinical Presentation
Neuroimaging in Pediatric Central Nervous System Tumors: Current Status and Future Directions
Neurosurgery: Diagnosis and Treatment
Radiation Therapy
Principles of Chemotherapy
Ependymoma
Low-Grade Gliomas
Tumors of the Optic Pathway
Supratentorial High-Grade Gliomas
Brainstem Gliomas
Craniopharyngioma
Choroid Plexus Neoplasms
Intramedullary Spinal Cord Tumors
Sequelae of Treatment
22B Tumors of the Central Nervous System: Embryonal and Pineal Region Tumors
Embryonal Tumors
Medulloblastoma
Atypical Teratoid/Rhabdoid Tumor
Embryonal Tumors with Multilayered Rosettes
Other Rare Embryonal Tumors
Pineal Region Tumors
Germ Cell Tumors
23 Neuroblastoma
Epidemiology
Genetic Predisposition
Molecular Pathogenesis
Pathology
Clinical Presentation
Paraneoplastic Syndromes
Clinical and Laboratory Evaluation
Staging and Treatment Response
Prognostic Considerations
Principals of Initial Therapy
Late Effects
Future Considerations
24 Renal Tumors
Epidemiology
Genetics and Molecular Biology
Pathology
Clinical Presentation and Diagnostic Workup
Prognostic Factors
Treatment of Wilms Tumor
Clear Cell Sarcoma of the Kidney
Malignant Rhabdoid Tumor
Renal Cell Carcinoma
Congenital Mesoblastic Nephroma
25 Rhabdomyosarcoma
Epidemiology and Genetic Susceptibility
Molecular Biology
Animal Models
Pathology
Patterns of Spread and Clinical Presentation.
Methods of Diagnosis.