PEDIATRIC ONCOLOGY
Neuro-
blastoma
123
With 51 Figures and 48 Tables
Nai-Kong V. Cheung Susan L. Cohn
(Eds.)
Nai-Kong V. Cheung, MD, PhD (e-mail: cheungn@mskcc.org)
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York,
NY 10021, USA Susan L. Cohn, MD
(e-mail: scohn@northwestern.edu)
Department of Pediatrics and the Comprehensive Robert H. Lurie Cancer Center, Northwestern University, Feinberg School of Medicine, Children’s Memorial Hospital
2300 Children’s Plaza, Chicago, IL 60614, USA
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The rapid advances in our understanding of the biol- ogy and treatment of neuroblastoma make it difficult to keep up to date. The clinical facets of neuroblas- toma are endlessly fascinating. Its “natural history”
overtly displays the difference between cancer and a truly extraordinary non-malignant proliferative dis- ease. An interesting and potentially promising re- search emphasis is to unravel the difference between the “good” and “bad” forms of the disease. Our inter- est in neuroblastoma was kindled by clinical obser- vations going back many decades. For example, is it likely that neuroblastoma “metastasizes” from one adrenal to the other and to the posterior medi- astinum, or that malignant secondary deposits in these three unlikely sites will disappear spontaneous- ly? Our early observations of this phenomenon were made in the days when there were no effective treat- ments for neuroblastoma so it was easier willy-nilly to observe the natural history.
We have seen disease wax and wane over time, such as skin lesions which became increasingly ma- ture with each new “crop”; thus, the last one seen at 36 months was diagnosed as a neurofibroma. The re- sults coming from the screening programs underline these concepts. They have shown that many more in- fants actually harbor occult neuroblastoma than are diagnosed clinically (in the nonscreened cohort pop- ulation). This establishes that most such foci would have regressed spontaneously had they not been de-
tected through screening. Observations such as these suggest that 4S neuroblastoma could teach us more about what clonal growth implies than clonal growth teaches us about neuroblastoma.
Obviously neuroblastoma can be a relentless, ma- lignant disease, and these children need far better therapies than we now can muster. But the future may not lie so much in new classes of compounds or even drug adjuvants. It lies, instead, in the final under- standing of what makes neuroblastoma mature into ganglioneuroma or, even more importantly, what prompts it to disappear spontaneously. Success will be measured when widespread disease in children with high-risk neuroblastoma is made to vanish through molecular genetic manipulations. Then cure will have achieved its true and very special meaning:
disappearance of a life-threatening malignant dis- ease without incurring the side effects of currently available avenues of treatment.
Audrey E. Evans
Professor of Pediatrics, Emeritus at the University of Pennsylvania, Senior Physician, Children’s Hospital of Philadelphia, Philadelphia , Pennsylvania
Giulio J. D’Angio
Professor of Radiation Oncology, Radiology and Pe- diatrics, Emeritus at the University of Pennsylvania, Philadelphia, Pennsylvania
V
Preface
1 Epidemiology Andrew F. Olshan
1.1 Descriptive Epidemiology . . . 1
1.2 Risk Factors . . . 2
1.2.1 Pregnancy and Childhood Factors . . . 2
1.2.2 Medication Use . . . 3
1.2.3 Lifestyle Exposures . . . 3
1.2.4 Parental Occupation and Environmental Exposures . . . 4
1.3 Conclusions . . . 4
References . . . 5
2 Screening for Neuroblastoma William G. Woods
2.1 Introduction . . . 72.2 The Rationale for Neuroblastoma Screening . . 7
2.3 Early Pioneering Studies Investigating Neuroblastoma Screening in Japan . . . 8
2.4 Initial North American and European Neuroblastoma Screening Trials . 9 2.5 Follow-up Studies from Japan and Europe . . . . 11
2.6 Definitive Controlled Trials from Quebec and Germany . . . 11
2.6.1 Studies, Designs, and Logistics . . . 11
2.6.2 Studies’ Results . . . 15
2.7 Biologic, Psychologic, Economic, and Clinical Aspects of Neuroblastoma Screening . . . 17
2.7.1 Biologic Aspects . . . 17
2.7.2 Psychologic Aspects . . . 17
2.7.3 Economic Aspects . . . 17
2.7.4 Clinical Implications . . . 18
2.8 Conclusions . . . 18
References . . . 18
3 Genetics John M. Maris, Garrett M. Brodeur
3.1 Introduction . . . 213.2 Associated Genetic Conditions . . . 21
3.3 Constitutional Chromosomal Abnormalities . . . 22
3.4 Hereditary Neuroblastoma . . . 23
3.5 Genetic Studies of Familial Neuroblastoma . . . 25
3.6 Conclusions . . . 25
References . . . 26
4 Molecular Cytogenetics Manfred Schwab
4.1 Introduction . . . 274.2 Classical Cytogenetics . . . 27
4.3 Oncogene Expression Profiling . . . 28
4.4 “Neuroblastoma Suppressor Genes” and Loss of Heterozygosity . . . 29
4.4.1 Chromosome 1p Deletion . . . 29
4.4.1.1 One or More “Tumor Suppressor Gene” Loci in 1p. . . 31
4.4.2 Deletion of 11q . . . 31
4.4.2.1 Chromosome 11 Deletion and 17q Gain . . . 32
4.4.3 LOH of Additional Chromosomes . . . 32
4.4.4 LOH and Tumor Suppressor Genes: an Evasive Connection or Flawed Hypothesis? 32 4.5 Comparative Genomic Hybridization . . . 34
4.6 Tumor Cell Ploidy . . . 34
4.7 Conclusion . . . 35
References . . . 35 VII
Contents
VIII Contents
5 Molecular and Developmental Biology of Neuroblastoma
Akira Nakagawara
5.1 Neural Crest Development and Neuroblastoma 41 5.1.1 Genes of Neural Development
and Molecular Targets
of Neuroblastoma . . . 41
5.1.1.1 Bone Morphogenetic Proteins . . . 43
5.1.1.2 MASH1/hASH1. . . 43
5.1.1.3 Phox2a and Phox2b. . . 44
5.1.1.4 Id . . . 44
5.1.1.5 MYCN . . . 45
5.2 Molecular Bases of Differentiation and Programmed Cell Death . . . 45
5.2.1 Molecular Aspect of Spontaneous Regression . . . 45
5.2.2 Neurotrophic Factors and Their Receptors 46 5.2.2.1 Neurotrophins and Their Receptors in Neuroblastoma. . . 46
5.2.2.2 Neurotrophin Signaling in Neuroblastoma. . . 46
5.2.2.3 GDNF Family Receptors. . . 48
5.2.2.4 Other Factors and Receptors . . . 48
5.2.3 Functional Role of p53 Family Genes . . . . 48
5.2.4 Apoptotic Signals in Neuroblastoma . . . . 50
5.3 Conclusions . . . 50
References . . . 51
6 Cellular Heterogeneity Robert A. Ross
6.1 Introduction . . . 556.2 Neural Crest Differentiation . . . 55
6.3 Neuroblastoma Cellular Heterogeneity . . . 56
6.4 N-type Neuroblastic Cells . . . 56
6.5 S-type Non-Neural Cells . . . 57
6.6 I-type Stem Cells . . . 58
6.7 Transdifferentiation . . . 59
6.8 Conclusions . . . 60
References . . . 60
7 Clinical Presentation Frank Berthold, Thorsten Simon
7.1 Introduction . . . 637.2 Diagnosis . . . 64
7.2.1 Diagnostic Tumor Tissue . . . 64
7.3 Clinical Presentation . . . 65
7.3.1 Symptoms . . . 65
7.3.1.1 Frequent Symptoms . . . 65
7.3.1.2 Rare but Characteristic Symptoms . . . 66
7.3.2 Tumor Markers . . . 67
7.3.2.1 Catecholamine Metabolites . . . 68
7.3.2.2 Neuron-Specific Enolase . . . 68
7.3.2.3 Ferritin. . . 68
7.3.2.4 Lactate Dehydrogenase . . . 68
7.3.2.5 Other Tumor Markers . . . 68
7.3.3 Primary Tumors . . . 69
7.3.3.1 Sites of the Primary Tumor . . . 69
7.3.4 Metastases . . . 69
7.3.4.1 Metastatic Sites . . . 69
7.3.4.2 Bone Marrow Assessment . . . 70
7.3.4.3 Definition of Cortical Bone Metastases. . . . 72
7.4 Differential Diagnosis . . . 72
7.4.1 Small Blue Round Cell Tumors . . . 72
7.4.2 Adrenal Hemorrhage in the Newborn . . . 72
7.4.3 Nephroblastoma . . . 73
7.4.4 Esthesioneuroblastoma (Olfactory Neuroblastoma) . . . 73
7.4.5 Ganglioneuroma, Pheochromocytoma, Paraganglioma, Chemodectoma . . . 73
7.5 Clinical and Laboratory Evaluation . . . 73
7.5.1 Staging . . . 73
7.5.2 Biological Types of Neuroblastoma . . . . 75
7.5.2.1 Maturative Subtype. . . 75
7.5.2.2 Regressive Subtype. . . 76
7.5.2.3 Progressive Subtype . . . 77
7.5.3 Prognostic Risk Groups . . . 77
7.5.4 Response Criteria . . . 82
7.6 Conclusions . . . 82
References . . . 83
8 Pathology of Peripheral Neuroblastic Tumors Hiroyuki Shimada, Inge M. Ambros
8.1 Introduction . . . 878.2 Historical Overview . . . 88
8.3 Basic Morphology . . . 88
8.3.1 Neuroblastoma (Schwannian Stroma-poor) . . . 89
8.3.2 Ganglioneuroblastoma, Intermixed (Schwannian Stroma-rich) . . . 91
8.3.3 Ganglioneuroma (Schwannian Stroma-dominant) . . . 91
8.3.4 Ganglioneuroblastoma, Nodular (Composite, Schwannian Stroma-rich/ Stroma-dominant and Stroma-poor) . . . . 91
IX Contents
8.4 Prognostic Classification . . . 92
8.5 Biological Relevance . . . 92
8.5.1 Schwannian Development in Neuroblastic Tumors . . . 92
8.5.2 Correlation of Histopathology with MYCN Amplification and trkA Expression . . . 93
8.5.3 Composite Tumor . . . 93
8.6 Conclusion . . . 94
References . . . 94
9 Molecular Pathology of Neuroblastic Tumors Based on Genome-wide Expression Analysis William L. Gerald
9.1 Introduction . . . 979.2 Clinical Issues . . . 98
9.3 Technical Aspects of Gene Expression Analysis . 98 9.3.1 Transcript Profiling Methods . . . 98
9.3.2 Data Analysis . . . 100
9.3.3 The Impact of Tissue Heterogeneity on Gene Expression Analysis . . . 100
9.4 Gene Expression Analysis of NB . . . 100
9.4.1 The NB Transcriptome and Its Relationship to Neural Crest Development . . . 100
9.4.2 Gene Expression Associated with Clinically Relevant Subtypes of NB . . 103
9.4.3 Molecular Pathology of MYCN Amplification . . . 103
9.4.4 Distinct Molecular Features of NB Discovered Through Gene Expression Analysis . . . 105
9.5 Conclusion . . . 106
References . . . 106
10 Anatomic and Functional Imaging Sara J. Abramson, Barry L. Shulkin
10.1 Introduction . . . 10910.2 Imaging Modalities . . . 109
10.2.1 Ultrasonography . . . 109
10.2.2 Computerized Axial Tomography . . . 110
10.2.3 Magnetic Resonance Imaging . . . 112
10.2.4 Bone Scan . . . 113
10.2.5 MIBG Scintigraphy . . . 113
10.2.6 Octreotide Scanning . . . 115
10.2.7 Positron Emission Tomography Scanning . 115 10.2.8 Other Tracers . . . 115
10.3 Disease Evaluation . . . 116
10.3.1 Primary Site . . . 116
10.3.2 Local Invasion . . . 116
10.3.3 Distant Metastases . . . 116
10.3.3.1 Bone Metastases . . . 116
10.3.3.2 Bone-Based, Dural-Based, Leptomeningeal, and Brain Metastases . . . 116
10.3.3.3 Marrow Metastasis. . . 117
10.4 Prenatally Diagnosed Neuroblastoma . . . 118
10.5 Stage-4S Neuroblastoma . . . 118
10.6 Evaluation of Disease Response . . . 120
10.7 Conclusion . . . 120
References . . . 120
11 Treatment of Neuroblastoma
11.1 Low-Risk NeuroblastomaBrian H. Kushner, Susan L. Cohn
11.1.1 Introduction . . . 12411.1.2 Clinical Presentation . . . 124
11.1.3 Clinical Staging . . . 125
11.1.4 Biologic Prognostic Markers . . . 125
11.1.5 Treatment . . . 125
11.1.5.1 Localized Tumors with No Regional Spread 126 11.1.5.2 Regionally Invasive Unilateral Localized Tumors. . . 127
11.1.5.3 Stage 4S . . . 128
11.1.6 Future Directions . . . 129
11.1.7 Conclusion . . . 129
References . . . 129
11.2 Intermediate-Risk Neuroblastoma
Brian H. Kushner, Susan L. Cohn
11.2.1 Introduction . . . 13111.2.2 Clinical Presentation . . . 131
11.2.3 Clinical Staging . . . 133
11.2.4 Biologic Prognostic Markers . . . 133
11.2.5 Treatment . . . 133
11.2.5.1 Treatment for Stage-3 Neuroblastoma . . . 134
11.2.5.2 Treatment for Stage-4S Neuroblastoma. . . 134
11.2.5.3 Treatment of Infant Stage-4 Neuroblastoma 135 11.2.6 Future Directions . . . 136
11.2.7 Conclusion . . . 136
References . . . 137
11.3 High-Risk Neuroblastoma
Katherine K. Matthay, Nai-Kong V. Cheung
11.3.1 Treatment Approach for High-Risk Disease 138 11.3.2 Induction Therapy . . . 13911.3.3 Local Control . . . 141
11.3.4 Consolidation Therapy . . . 142
11.3.5 Therapy of Minimal Residual Disease . . . 144
11.3.6 Conclusion . . . 145
References . . . 145
X Contents
11.4 The Role of Surgery in the Treatment of Neuroblastoma
Michael P. La Quaglia
11.4.1 Introduction . . . 149
11.4.2 History . . . 149
11.4.3 Staging . . . 151
11.4.3.1 Stage 1. . . 151
11.4.3.2 Stage 2. . . 152
11.4.3.3 Stage 3. . . 152
11.4.3.4 Stage 4. . . 153
11.4.4 Risk Status and Surgical Intervention . . 155
11.4.4.1 Low-Risk Patients . . . 156
11.4.4.2 Intermediate Risk . . . 156
11.4.4.3 High Risk. . . 156
11.4.4.3.1 Gross Total Resection. . . 156
11.4.4.3.2 Rationale for Gross Total Resection in High-Risk Patients. . . 156
11.4.4.3.3 Local Control. . . 157
11.4.5 Surgical Complications and Mortality . 157 11.4.6 Surgical Technique . . . 158
11.4.6.1 Initial Biopsy . . . 158
11.4.6.2 Cervical Lesions . . . 159
11.4.6.3 Cervico-Thoracic Lesions . . . 159
11.4.6.4 Mediastinal Tumors . . . 159
11.4.6.5 Lesions in the Upper Abdomen and Retroperitoneum . . . 159
11.4.6.6 Pelvic Tumors . . . 159
11.4.7 Conclusion . . . 160
References . . . 161
11.5 Radiation Therapy
Suzanne L. Wolden, Daphne A. Haas-Kogan
11.5.1 Background . . . 16411.5.2 Radiation Approach According to Risk Stratification . . . 164
11.5.2.1 Low- and Intermediate-Risk Disease . . . 164
11.5.2.2 Intermediate-Risk Disease. . . 164
11.5.2.3 Stage-4S Disease. . . 165
11.5.2.4 High-Risk Disease . . . 165
11.5.3 Radiation Techniques . . . 167
11.5.3.1 General Technical Considerations . . . 167
11.5.3.2 Intraoperative Radiation Therapy . . . 169
11.5.4 Side Effects of Radiation . . . 170
11.5.5 Conclusion . . . 171
References . . . 171
11.6 Stem Cell Transplantation
Stephan A. Grupp
11.6.1 Introduction . . . 17311.6.2 Autologous Transplant in Neuroblastoma . . . 174
11.6.2.1 Children’s Cancer Group 3891. . . 174
11.6.2.2 Experimental HDC/SCR . . . 175
11.6.3 PBSC Collection . . . 177
11.6.3.1 Vascular Access . . . 177
11.6.3.2 Collection . . . 178
11.6.3.3 Techniques for Stem Cell Mobilization . . . 178
11.6.3.4 Target Dose for PBSC Infusion. . . 179
11.6.3.5 Processing and Storage of PBSC. . . 180
11.6.3.6 Tumor Cell Purging . . . 181
11.6.3.7 Storage. . . 182
11.6.4 Conclusion . . . 182
References . . . 182
11.7 Minimal Residual Disease Measurement
Irene Y. Cheung, Peter F. Ambros
11.7.1 Introduction . . . 18511.7.2 Techniques in the Detection of Tumor Cells in the Hematopoietic System . . . 186
11.7.2.1 Histology/Cytology . . . 186
11.7.3 Detection Methods for MRD . . . 186
11.7.3.1 Immunocytology/ Immuno histochemistry . . . 186
11.7.3.2 Automatic Immunofluorescence Detection Techniques . . . 187
11.7.3.3 Reverse Transcription-Polymerase Chain Reaction . . . 188
11.7.3.3.1 Real-Time Quantitative RT-PCR . . . 188
11.7.3.3.2 Molecular Targets . . . 188
11.7.3.3.3 Perspectives on Molecular Detection . . . 188
11.7.4 Clinical Relevance of MRD . . . 189
11.7.5 Future Directions . . . 190
References . . . 191
12 Treatment of Relapsed and Refractory Neuroblastoma Katherine K. Matthay, Brian H. Kushner
12.1 Introduction . . . 19312.2 Treatment Strategies for Resistant Disease . . . 195
12.2.1 Primary Refractory Disease . . . 195
12.2.2 Early Relapse . . . 196
12.2.3 Late Relapse . . . 196
12.2.4 Multiply Relapsed Disease . . . 196
12.3 Cytotoxic Chemotherapeutic Agents . . . 196
12.3.1 Alkylating and DNA Cross-Linking Agents 197 12.3.1.1 Ifosfamide and Cyclophosphamide . . . 197
12.3.1.2 Melphalan Combined with Buthionine Sulfoximine. . . 197
12.3.1.3 Platinum Compounds . . . 198
12.3.1.4 Temozolomide . . . 198
12.3.1.5 Tirapazamine. . . 199
XI Contents
12.3.2 Topoisomerase Inhibitors . . . 199
12.3.2.1 Irinotecan . . . 199
12.3.2.2 Topotecan . . . 200
12.3.2.3 Pyrazoloacridine . . . 200
12.3.2.4 Rebeccamycin . . . 201
12.4 Tumor-Targeted Biologic Agents . . . 201
12.4.1 Retinoids . . . 201
12.4.2 Tyrosine Kinase Inhibitors . . . 201
12.4.3 Modulators of Apoptotic Pathway and Angiogenesis . . . 201
12.4.3.1 Anti-Angiogenic Agents . . . 201
12.4.3.2 Arsenic Trioxide . . . 202
12.4.3.3 Demethylating Agents. . . 202
12.4.3.4 Histone Deacetylase Inhibitors . . . 202
12.5 Immunologic Therapy . . . 203
12.5.1 Anti-GD2 . . . 203
12.5.2 Interleukins . . . 203
12.5.3 Vaccines . . . 204
12.6 131I-Metaiodobenzylguanidine . . . 204
12.7 Conclusion . . . 204
References . . . 205
13 Management of Neurologic Complications Kim Kramer, Michael R. Pranzatelli
13.1 Introduction . . . 21313.2 Epidural Neuroblastoma . . . 213
13.3 Metastatic Disease to the Central Nervous System . . . 216
13.4 Opsoclonus–Myoclonus . . . 217
13.4.1 Immunology . . . 218
13.4.2 Pharmacology . . . 218
13.4.3 Laboratory Testing . . . 218
13.4.4 Treatment . . . 219
13.4.4.1 Neuromodulation . . . 219
13.4.4.2 Adjunctive Therapy . . . 220
13.4.4.3 Precautions. . . 220
13.5 Treatment-Related Neurologic Complications . . 220
13.6 Conclusions . . . 220
References . . . 221
14 Immunology and Immunotherapy Nai-Kong V. Cheung, Paul M. Sondel
14.1 Introduction: The Case for Immunotherapy . . . 22314.2 The Immunobiology of Neuroblastoma . . . 224
14.3 How Neuroblastoma Escapes the Innate and Adaptive Immune Systems . . . 225
14.4 Humoral Immunotherapy . . . 226
14.4.1 Effector Mechanisms of MAb . . . 226
14.4.2 Clinical Application of MAb . . . 227
14.4.2.1 Naked MAb. . . 227
14.4.2.2 Antibody in Combination with Cytokines . . 229
14.4.2.3 Antibody Immunoconjugates . . . 229
14.4.3 Humoral Vaccines . . . 232
14.4.3.1 Ganglioside-KLH Vaccines . . . 232
14.4.3.2 Anti-Idiotype Vaccine . . . 232
14.5 Cellular Immunotherapy . . . 232
14.5.1 Activation of NK and NKT Cells . . . 232
14.5.2 Activation of MHC-Restricted T Cells . . . 233
14.5.3 Pre-clinical and Clinical Testing of T-cell Based Therapy in Neuroblastoma 233 14.5.3.1 Immunostimulants. . . 233
14.5.3.2 Tumor Vaccines . . . 233
14.5.3.3 Adoptive Therapy Using Autologous Cytotoxic Lymphocytes . . . 234
14.5.3.4 Adoptive Therapy Using Allogeneic Lymphocytes. . . 234
14.6 Conclusions . . . 235
References . . . 235
15 Differentiation and Retinoids Carol J. Thiele, C. Patrick Reynolds
15.1 Introduction . . . 24315.1.1 Neural Crest Development . . . 243
15.1.2 NB as a Neural Crest Derivative . . . 244
15.1.3 NB and Adrenal Medullary Development . 244 15.1.4 Neural Crest Gene Expression During Development . . . 245
15.1.5 MYCN in Neural Crest Development . . . . 245
15.2 Neurotrophins in Neural Crest Development . . 245
15.2.1 TrkA and NB . . . 246
15.2.2 TrkB and NB . . . 247
15.3 Differentiation . . . 247
15.3.1 Retinoids . . . 247
15.3.2 Retinoic Acid Receptors . . . 248
15.4 13-cis-Retinoic Acid . . . 249
15.4.1 High-Dose, Pulse, 13-cis-RA . . . 250
15.4.2 13-cis-RA vs All Trans-Retinoic Acid . . . . 250
15.4.3 Post-Consolidation 13-cis-RA Therapy for High-Risk NB . . . 250
15.5 Fenretinide . . . 253
15.6 Conclusions . . . 254
References . . . 254
XII Contents
16 Angiogenesis
Darrell J. Yamashiro, Susan L. Cohn
16.1 Introduction . . . 257
16.2 Vascularity in Neuroblastoma . . . 258
16.3 Expression of Proangiogenic Factors . . . 258
16.3.1 VEGF and VEGF Receptors . . . 258
16.3.2 Matrix Metalloproteinases . . . 259
16.4 Expression of Angiogenesis Inhibitors . . . 260
16.4.1 Pigment Epithelium-Derived Factor . . . . 260
16.4.2 Secreted Protein Acidic and Rich in Cysteine . . . 260
16.4.3 Thrombospondin-1 . . . 260
16.5 Regulation of Angiogenesis by MYCN . . . 261
16.6 Preclinical Testing of Antiangiogenic Agents . . 261
16.6.1 VEGF Blockade . . . 261
16.6.2 TNP-470 . . . 261
16.6.3 Endostatin . . . 261
16.7 Conclusions . . . 262
References . . . 263
17 Experimental Therapeutics and Preclinical Models Jennifer K. Peterson, Peter J. Houghton
17.1 Introduction . . . 26717.2 Heterotransplant Models . . . 268
17.2.1 Cytotoxic Agents . . . 268
17.2.2 Signal Transduction Inhibitors . . . 270
17.2.3 Angiogenesis Inhibitors . . . 271
17.2.4 Viral-Based Therapies . . . 271
17.2.5 Immunotherapy and Radioimmunotherapy . . . 272
17.3 Transgenic Models . . . 272
17.4 Syngeneic Models . . . 273
17.5 Conclusion . . . 273
References . . . 274
18 Late Effects of Treatment Caroline Laverdière, James Gurney, Charles A. Sklar
18.1 Introduction . . . 27718.2 Long-Term Complications for Low- and Intermediate-Risk Neuroblastoma Survivors . . . 278
18.2.1 Musculoskeletal . . . 278
18.2.2 Neurological . . . 278
18.3 Long-Term Complications for Survivors of High-Risk Neuroblastoma . . . 279
18.3.1 Audiological . . . 279
18.3.2 Endocrine . . . 280
18.3.2.1 Thyroid Function. . . 280
18.3.2.2 Reproductive Endocrine Function. . . 281
18.3.2.3 Growth . . . 282
18.3.3 Musculoskeletal Complications and Neurological Deficits . . . 282
18.3.4 Dental . . . 282
18.3.5 Pulmonary . . . 282
18.3.6 Cardiac . . . 283
18.3.7 Renal . . . 283
18.3.8 Neurocognitive . . . 283
18.3.9 Subsequent Malignant Neoplasms . . . . 284
18.4 Health-Related Quality of Life . . . 284
18.5 Conclusion . . . 285
References . . . 285
19 Perspectives and Future Directions Nai-Kong V. Cheung, Susan L. Cohn
References . . . 291Subject Index
. . . 293Sara J. Abramson, MD
(e-mail: abramsos@mskcc.org) Department of Radiology,
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Inge M. Ambros, MD
(e-mail: inge.ambros@ccri.univie.ac.at) Children’s Cancer Research Institute, St. Anna Kinderspital, Kinderspitalgasse 6, 1090 Vienna, Austria
Peter F. Ambros, PhD
(e-mail: peter.ambros@ccri.univie.ac.at) Children’s Cancer Research Institute, St. Anna Kinderspital, Kinderspitalgasse 6, 1090 Vienna, Austria
Frank Berthold, MD
(e-mail: Frank.Berthold@medizin.uni-koeln.de) Children’s Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany
Garrett M. Brodeur, MD
(e-mail: brodeur@email.chop.edu)
Division of Oncology, The Children’s Hospital of Philadelphia and the University of Pennsylvania, Abramson Pediatric Research Center 902,
Philadelphia, PA 19104, USA
Irene Y. Cheung, ScD
(e-mail: cheungi@mskcc.org)
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York,
NY 10021, USA
Nai-Kong V. Cheung, MD, PhD (e-mail: cheungn@mskcc.org)
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York,
NY 10021, USA Susan L. Cohn, MD
(e-mail: scohn@northwestern.edu)
Department of Pediatrics and the Comprehensive Robert H. Lurie Cancer Center, Northwestern University, Feinberg School of Medicine, Children’s Memorial Hospital,
2300 Children’s Plaza, Chicago, IL 60614, USA William L. Gerald, MD
(e-mail: geraldw@mskcc.org)
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 275 York Avenue, New York,
NY 10021, USA
Stephan A. Grupp, MD, PhD (e-mail: grupp@email.chop.edu)
Director, Stem Cell Biology, Division of Oncology, Children’s Hospital of Philadelphia
and University of Pennsylvania,
3615 Civic Center Blvd., ARC 902, Philadelphia, PA 19104, USA
XIII
Contributors
Chapter 2
XIV Pediatric Cerebellar AstrocytomasContributors
James Gurney, MD
(e-mail: gurney@epi.umn.edu) Division of Pediatric Epidemiology,
University of Minnesota, Mayo Mail Code 715, 420 Delaware Street SE, Minneapolis,
MN 55455, USA
Daphne A. Haas-Kogan, MD
(e-mail: hkogan@radonc17.ucsf.edu) Department of Radiation Oncology,
School of Medicine, University of California at San Francisco, 2356 Sutter Street,
San Francisco, CA 94115-0226, USA Peter J. Houghton, PhD
(e-mail: peter.houghton@stjude.org) Department of Molecular Pharmacology, St. Jude Children’s Research Hospital,
332 Lauderdale, Memphis, TN 38105-2794, USA Kim Kramer, MD
(e-mail: kramerk@mskcc.org) Department of Pediatrics,
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Brian H. Kushner, MD
(e-mail: kushnerb@mskcc.org) Department of Pediatrics,
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Michael P. La Quaglia, MD
(e-mail: laquaglm@mskcc.org) Department of Surgery,
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Caroline Laverdière, MD
(e-mail: caroline.laverdiere@umontreal.ca) Sainte-Justine Hospital,
Recherche Clinique Hemato-Oncologie, 3175 Cote Ste-Catherine, Montreal, Quebec, Canada H3T 1C5
John M. Maris, MD
(e-mail: maris@email.chop.edu)
Division of Oncology, The Children’s Hospital of Philadelphia and the University of Pennsylvania, Abramson Pediatric Research Center 902,
Philadelphia, PA 19104, USA Katherine K. Matthay, MD
(e-mail: matthayk@peds.ucsf.edu)
Department of Pediatrics, M647, University of California San Francisco School of Medicine, 505 Parnassus, San Francisco, CA 94143-0106, USA Akira Nakagawara, MD
(e-mail: akiranak@chiba-cc.jp)
Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba, 260-8717, Japan
Andrew F. Olshan, MD
(e-mail: andy_olshan@unc.edu) Department of Epidemiology, School of Public Health, University
of North Carolina, Chapel Hill, NC 27599-7435, USA Jennifer K. Peterson, MD
(e-mail: Jennifer.Peterson@stjude.org) Department of Molecular Pharmacology, St. Jude Children’s Research Hospital,
332 Lauderdale, Memphis, TN 38105-2794, USA Michael R. Pranzatelli, MD
(e-mail: mpranzatelli@siumed.edu) Departments of Neurology and Pediatrics, National Pediatric Myoclonus Center,
Southern Illinois University School of Medicine, P.O. Box 19658, Springfield, IL 62794-9658, USA C. Patrick Reynolds, MD, PhD
(e-mail: preynolds@chla.usc.edu)
USC-CHLA Institute for Pediatric Clinical Research, Division of Hematology/Oncology MS 57,
Children’s Hospital Los Angeles, 4650 Sunset Blvd.,
Los Angeles, CA 90054-0700, USA
XV Contributors