Handbook of Brain Tumor Chemotherapy (eBook)

Herbert B. Newton (Herausgeber)

eBook Download: EPUB

2005 | 1. Auflage
586 Seiten
Elsevier Science (Verlag)
978-0-08-045593-8 (ISBN)

Infos

Treatment of patients with a brain tumor remains one of the most challenging and difficult areas of modern oncology. Recent advances in the molecular biology of these neoplasms have improved our understanding of the malignant phenotype and have lead to the development of novel forms of chemotherapy, including targeted agents. The Handbook of Brain Tumor Chemotherapy reviews the state-of-the-art of chemotherapy development and clinical treatment of patients with this devastating disease.
Handbook of Brain Tumor Chemotherapy offers a unique cutting-edge compendium of basic science and clinical information on the subject of brain tumor chemotherapy, reviewing what has been accomplished thus far and how the field will continue to evolve with the development of more specific and efficacious chemotherapeutic agents. This book represents the most complete single-volume resource available for information on the subject of brain tumor chemotherapy.

* Provides the most up to date information regarding conventional forms of cytotoxic chemotherapy, as well as the basic science and clinical application of molecular therapeutics, for the treatment of brain tumors
* Broadly appeals to anyone interested in the field of Neuro-Oncology and in the treatment of patients with brain tumors
* Useful to clinicians interested in a thorough overview of the use of chemotherapy in patients with a broad range of brain tumors as well as serving as a source of background information to basic scientists and pharmaceutical researchers with an interest in the molecular therapeutics of brain tumors

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Treatment of patients with a brain tumor remains one of the most challenging and difficult areas of modern oncology. Recent advances in the molecular biology of these neoplasms have improved our understanding of the malignant phenotype and have lead to the development of novel forms of chemotherapy, including "e;targeted agents. The Handbook of Brain Tumor Chemotherapy reviews the state-of-the-art of chemotherapy development and clinical treatment of patients with this devastating disease. Handbook of Brain Tumor Chemotherapy offers a unique cutting-edge compendium of basic science and clinical information on the subject of brain tumor chemotherapy, reviewing what has been accomplished thus far and how the field will continue to evolve with the development of more specific and efficacious chemotherapeutic agents. This book represents the most complete single-volume resource available for information on the subject of brain tumor chemotherapy. - Provides the most up to date information regarding conventional forms of cytotoxic chemotherapy, as well as the basic science and clinical application of molecular therapeutics, for the treatment of brain tumors- Broadly appeals to anyone interested in the field of Neuro-Oncology and in the treatment of patients with brain tumors- Useful to clinicians interested in a thorough overview of the use of chemotherapy in patients with a broad range of brain tumors as well as serving as a source of background information to basic scientists and pharmaceutical researchers with an interest in the molecular therapeutics of brain tumors

Inhalt

Handbook of Brain Tumor Chemotherapy 3
Handbook of Brain Tumor Chemotherapy 5
Dedication 7
Preface 9
Contents 11
Contributors 17
Section I Pharmacology and Clinical Applications 43
Chapter 1 Overview of Brain Tumor Epidemiology and Histopathology 45
Epidemiology of Brain Tumors 45
Pathology of Central Nervous System Tumors—Introduction 47
Pathology of Tumors of Neuroepithelial Origin 48
Pathology of Tumors of The Meninges 58
Pathology of Primary CNS Lymphoma 59
Pathology of Intracranial Germ Cell Tumors 60
Acknowledgments 61
Chapter 2 Clinical Pharmacology of Brain Tumor Chemotherapy 63
Introduction 63
Pharmacology and Drug Distribution 63
Supportive Therapeutics 64
Delivery of Chemotherapeutic Agents 66
Chemotherapeutic Agents 67
Alkylating Agents 67
Natural Products 73
Antimetabolites 74
Topoisomerase Inhibitors 76
Miscellaneous Agents 77
Molecular Therapeutic Agents 79
Conclusions 79
Acknowledgments 80
Chapter 3 Chemotherapy and Anti-Epileptic Drug Interactions 86
Introduction 86
Anti-Epileptic Drugs in Neuro-Oncology Patients 86
Drug Metabolism and Resistance 87
AED Effects on Hepatic Metabolism 88
EIAEDs Effects on Chemotherapy 89
Chemotherapy Effects on AEDs 91
Practical Effects of AED–Chemotherapy Interactions 91
Practical Management 92
Conclusions 96
Acknowledgment 96
Chapter 4 Brain Tumor Models for Cancer Therapy 100
Rat Brain Tumor Models 100
Blood–Brain Barrier in Rat Brain Tumor Models 100
Local Delivery in Rat Brain Tumor Models 101
Immunological Approaches in Rat Brain Tumor Models 103
Chemotherapy and Boron Neutron Capture in Rat Brain Tumor Models 103
Human Brain Tumor Xenograft Models 104
Blood–Brain Barrier in Human Brain Tumor Xenograft Models 105
Local Delivery in Human Brain Tumor Xenograft Models 105
Chemotherapy in Human Brain Tumor Xenograft Models 106
Angiogenesis in Brain Tumor Models 107
Conclusions 111
Chapter 5 Microarray Analysis and Proteomic Approaches to Drug Development 116
Introduction 116
Microarray Analysis 116
Disease Proteomics 118
Implementation of Protein Microarrays 119
Gene Expression Patterns in Normal and Diseased Tissues 119
Tumor Expression Profiling: Medulloblastoma 120
Tumor Expression Profiling: Glioma 121
Drug Discovery 123
Gene Expression As a Predictor of Chemosensitivity 126
Gene Expression in Response To Drug Therapy 126
Summary 126
Chapter 6 Chemotherapy Resistance 131
Common Chemotherapeutic Agents in Gliomas 131
Dna Repair and Chemotherapy Resistance 132
Detoxification and Other Mechanisms of Resistance 137
Summary 140
Chapter 7 Clinical Trial Design and Implementation 147
Introduction 147
Phase I Trials 148
Phase II Trials 149
Phase III Clinical Trials 151
Special Challenges of Brain Tumor Trials 151
Conclusions 153
Section II Molecular Biology and Basic Science 155
Chapter 8 Molecular Genetics of Brain Tumors—An Overview 157
Introduction 157
Descriptive Modeling of The Molecular Pathology of Brain Tumors 157
Predictive Modeling of Therapeutic Vulnerability of Brain Tumors 159
Future Directions 162
Chapter 9 Regulation of the Cell Cycle and Interventional Developmental Therapeutics 165
Overview 165
G1 Phase 167
S-Phase 170
M-Phase 171
Therapeutic Small-Molecule Inhibitors of The Cell Cycle 172
Type I Inhibitors: Direct Inhibitors of CDK Catalytic Activity 173
Type II Inhibitors: Inhibitors of CDK Regulatory Mechanisms 176
Summary 176
Chapter 10 Apoptosis Pathways and Chemotherapy 183
Architecture of The Major Apoptotic Pathways 183
Deregulation of Apoptotic Pathways in Brain Tumors 187
Chemotherapeutic Drugs: Mechanism of Action and Impact on Brain Tumors 189
Novel Approaches For The Induction of Apoptosis 190
Perspective 193
Chapter 11 Growth Factor Signaling Pathways and Receptor Tyrosine Kinase Inhibitors 197
Introduction 197
Glioma Cell Resistance To Conventional Therapeutic Modalities 197
Platelet-Derived Growth Factor As A Dominant Glioma Mitogen 198
Egfr Amplification/ Overexpression In Glioma Progression 198
Strategies For Direct Inhibition of Growth Factor Pathway Activation 202
STI571 As A Potential Pdgfr Inhibitor 203
ZD1839 As A Potential Egfr Inhibitor 204
Other Small Molecule EGFR Inhibitors 206
Inhibition of Growth Factor Signaling May Interfere With Angiogenesis and Tumor Invasion 206
Interference With Growth Factor Receptor Signaling May Potentiate Other Therapies 207
Summary 207
Acknowledgment 208
Chapter 12 Ras Signaling Pathways and Farnesyltransferase Inhibitors 215
Introduction 215
Understanding p21-Ras Structure And Function 216
Role of p21-Ras Mutations In Different Malignancies 220
Farnesyl Transferase Inhibitors (FTIs) 220
Conclusion and Future Directions 222
Chapter 13 PI3-Kinase, PKB/Akt, mTOR, and Internal Signaling Pathways 227
Overview of The Biology of PI3-Kinase and Its Effectors 227
Multi-Level Dysregulation of PI3-Kinase: Implications For Gliomagenesis 229
Therapeutic Implications 230
Chapter 14 Tumor Invasiveness and Anti-invasion Strategies 235
Pathologic Features of Malignant Brain Tumor Invasion 235
Clinical and Pathological Evaluation of Tumor Infiltration 235
Patterns of Failure 236
Therapeutic Considerations 236
Environmental Influences 237
Molecular Targets 237
Therapeutic Strategies 254
Other Considerations 255
Summary 255
Chapter 15 Mechanisms of Angiogenesis in Brain Tumors and their Translation into Therapeutic Anti-tumor Strategies 261
Summary 261
Introduction 261
The Hypoxic Tumor Microenvironment and HIF Activation 262
The Hypoxic Tumor Microenvironment, Angiogenesis, And Edema 264
The Hypoxic Tumor Microenvironment and Angiogenic Cellular Cross Talk 266
Anti-Angiogenesis Strategies As Novel Anti-Tumor Therapies 268
Future Perspectives 272
Acknowledgments 272
Chapter 16 Biology of the Blood–Brain and ‘‘Blood–Brain Tumor’’ Barriers 278
The Normal Blood–Brain Barrier: Ultrastructural and Cellular Considerations 278
Functions Of The Blood–Brain Barrier General Factors Affecting Overall Function
Drug Movement Across The BBB and Determinants of CNS Drug Concentration 281
The ‘‘Blood–Brain Tumor’’ Barrier Effect of Tumors On The BBB
Therapeutic Disruption or Circumvention of The BBB 283
Conclusions 284
Section III Innovative Approaches to Chemotherapy Delivery 287
Chapter 17 Intra-Arterial Chemotherapy 289
Introduction 289
Pharmacological Rationale 289
Single-Agent IA Chemotherapy of Newly Diagnosed Gliomas 291
Combination IA Chemotherapy of Newly Diagnosed Gliomas 294
Single-Agent IA Chemotherapy of Recurrent Gliomas 295
Combination IA Chemotherapy of Recurrent Gliomas 297
IA Chemotherapy For Primary CNS Lymphoma 299
IA Chemotherapy For Brain Metastases 299
Toxicity of IA Chemotherapy 299
Conclusions 300
Acknowledgments 301
Chapter 18 Blood–Brain Barrier Disruption Chemotherapy 304
Introduction 304
Pre-Clinical BBB Delivery Studies 305
Clinical BBBD Technique 306
Clinical BBBD Results 309
Pre-Clinical Studies of Thiol Chemoprotection 310
Clinical Studies of Thiol Chemoprotection 311
Future BBBD Directions 312
Summary 313
Acknowledgments 313
Chapter 19 Interstitial Chemotherapy and Polymer-Drug Delivery 316
Introduction 316
Physiologic and Pathological Barriers To Anti-Neoplastics in The CNS 317
Delivery Systems and Strategies For Brain Tumor Targeted Delivery 318
Development of Polymer-Based Local Delivery Systems 320
BCNU (Gliadel ) 320
Other Chemotherapeutics 327
Future Directions 330
Conclusions 330
Disclosure 332
Chapter 20 Intratumoral Administration and Convection-Enhanced Delivery 337
General Overview 337
Physical Principles 337
Animal Studies 339
Convection-Enhanced Delivery in Animal Brain Tumor Models 340
Human Studies 341
Challenges 344
Chapter 21 Marrow Ablative Chemotherapy with Hematopoietic Stem Cell Rescue 347
Introduction 347
Marrow Ablative Therapies 349
Results of High-Dose Chemotherapy and Auto-Transplantation 351
Conclusions 354
Chapter 22 CSF Dissemination of Primary Brain Tumors 358
Introduction 358
General Overview 358
Primary Brain Tumors 360
Treatment 364
Conclusions 368
Chapter 23 Chemotherapy-Activating Gene Therapy 374
Basic Concepts of Gene Therapy 374
Activation of Chemotherapy With Gene Therapy 374
Clinical Trials 380
Limitations and Problems 382
Conclusions 382
Further Information 382
Section IV Chemotherapy of Specific Tumor Types 387
Chapter 24 Chemotherapy of High-Grade Astrocytomas 389
Introduction 389
Overview of Initial Treatment 389
Chemotherapy of AA and GBM—Historical Overview 390
Concomitant Chemotherapy and Irradiation Approaches 393
Neoadjuvant Chemotherapy Approaches 395
Adjuvant Chemotherapy Approaches 397
Chemotherapy for Recurrent High-Grade Astrocytomas 398
Conclusions 401
Acknowledgments 401
Chapter 25 Chemotherapy of Low-Grade Astrocytomas 406
Background 406
Pathologic Nomenclature 406
Epidemiology 407
Location 407
Clinical Presentation and Imaging Findings 407
Prognostic Factors 407
Progression and Outcome of LGA 408
A Single Randomized Trial 408
Phase II Trials 408
Pending Study 411
Chapter 26 Chemotherapy of Oligodendrogliomas 413
Introduction 413
Genetics 413
Prognosis 414
Anaplastic Oligodendroglioma 415
Low-Grade Oligodendroglioma 419
Chapter 27 Chemotherapy of Oligoastrocytomas 424
Introduction 424
Genetics 425
Prognosis 425
Anaplastic Oligoastrocytomas 427
Low-Grade Oligoastrocytomas 431
Chapter 28 Chemotherapy for Primary Central Nervous System Lymphoma 437
Overview 437
Management 438
Methotrexate 438
Intra-Arterial MTX 439
Maintenance Therapy 439
HD-MTX Based Combination Chemotherapy for Pcnsl (Table 28.4) 439
Non-Methotrexate Combination Regimens 443
Intrathecal Chemotherapy 443
Salvage Therapy 444
Primary Intraocular Lymphoma 445
HIV-Related PCNSL 445
Chapter 29 Chemotherapy of Medulloblastoma 449
Introduction 449
Neuro-Imaging and Initial Treatment 450
Chemotherapy of Infants and Very Young Children 451
Chemotherapy of Children and Adolescents 453
Chemotherapy of Adult Patients 456
Chemotherapy With Bone Marrow Transplantation 457
Molecular Genetics and ‘‘Targeted’’ Therapeutics 457
Overview and Future Considerations 461
Acknowledgments 463
Chapter 30 Chemotherapy of Ependymoma 468
Background 468
Trials Dedicated To Ependymoma 469
Trials Including Ependymoma 471
Chapter 31 Chemotherapy for Glioneuronal Tumors 474
Introduction 474
General Neurocytoma 474
Ganglioglioma and Gangliocytoma 475
Desmoplastic Infantile Ganglioglioma (DIG) and Desmoplastic Infantile Astrocytoma (DIA) 476
Dysembryoplastic Neuroepithelial Tumor 477
Dysplastic Gangliocytoma of the Cerebellum 477
Cerebellar Liponeurocytoma 477
Chapter 32 Chemotherapy of Pineal Parenchymal Tumors 481
Pineal Anatomy and Physiology 481
Epidemiology 482
Biology and Molecular Genetics 483
Clinical Presentation 484
Neuro-Imaging and Laboratory Diagnosis 484
Initial Evaluation and Treatment 485
Chemotherapy of Pineal Parenchymal Tumors 486
Conclusions 487
Acknowledgments 488
Chapter 33 Current Therapeutic Management Strategies for Primary Intracranial Germ Cell Tumors 490
Introduction 490
Epidemiology 491
Clinical Presentation 491
Prognostic Variables 492
Therapeutic Effectiveness and Consequent Prognosis 493
Long-Term Complications of The Disease and Its Therapy 500
Conclusions 501
Chapter 34 Chemotherapy of Meningiomas 505
Introduction and Epidemiology 505
Biology and Molecular Genetics 506
Clinical Presentation 508
Neuro-Imaging 509
Initial Evaluation and Treatment 510
Chemotherapy of Meningiomas 511
Conclusions 514
Acknowledgments 514
Chapter 35 Chemotherapy for Brain Metastases 517
Introduction 517
Biology and Molecular Genetics 518
Clinical Presentation and Prognostic Factors 519
Traditional Chemotherapeutic Approaches 519
Temozolomide 522
Intra-Arterial Treatment Approaches 524
Interstitial Chemotherapy 525
Molecular Treatment Approaches 526
Overview and Future Considerations 527
Chapter 36 The Role of Chemotherapy in Pediatric Gliomas 532
Introduction 532
Low-Grade Gliomas 533
Optic Pathway/ Hypothalamic Gliomas 535
High-Grade Gliomas 536
Diffuse Intrinsic Pontine Gliomas 536
High-Dose Chemotherapy and Autologous Stem Cell Rescue in Pediatric Gliomas 537
Index 541

Textauszug

CHAPTER 1 Overview of Brain Tumor Epidemiology and Histopathology

Herbert B. Newton, Abhik Ray-Chaudhury

ABSTRACT:

Primary brain tumors (PBT) comprise a diverse group of neoplasms that are often malignant and refractory to treatment. Between 30 000 and 35 000 new PBT are diagnosed each year in the USA (approximately 14 per 100 000). Tumors of neuroepithelial origin are the largest histological class of PBT and include the glioma sub-group (e.g., glioblastoma multiforme, anaplastic astrocytoma, oligodendroglioma), which represent the most frequently diagnosed tumors in adults. Other important tumors in adults include meningiomas, primary brain lymphoma, and oligoastrocytoma. Commonly diagnosed tumors in children include medulloblastoma, cerebellar astrocytoma, and optic pathway glioma. This chapter will review the microscopic and molecular pathology of PBT that are most likely to require treatment with chemotherapy, utilizing the classification system of the World Health Organization.

EPIDEMIOLOGY OF BRAIN TUMORS

Brain tumors remain a significant health problem in the USA and worldwide. Overall, they comprise some of the most malignant tumors known to affect humans and are generally refractory to all modalities of treatment. It is estimated that between 30 000 and 35 000 new cases of primary brain tumors (PBT) will be diagnosed in the upcoming year in the USA (1–2 per cent of newly diagnosed cancers overall) [1–6]. Metastatic brain tumors (MBT) are even more common and affect between 100 000 and 150 000 new patients each year in this country [7]. Most studies suggest that approximately 14 per 100 000 people in the USA will be diagnosed with a PBT each year. Among this cohort with newly diagnosed tumors, 6 to 8 per 100 000 will have a high-grade neoplasm. Recent epidemiological studies suggest an increasing incidence rate for development of PBT in children less than 14 years of age and in patients 70 years or older [8]. For people in the 15- to 44-year-old age group, the overall incidence rates have remained fairly stable. The cause of the increased incidence of PBT in some age groups remains unclear, but may be due to improvements in diagnostic neuro-imaging such as magnetic resonance imaging (MRI), greater availability of neurosurgeons, improved patterns of access to medical care for children and elderly patients, and more aggressive approaches to health care for elderly patients [5,8].

The prognosis and survival of patients with brain tumors remains poor [1–7]. Although an uncommon neoplasm, PBT are among the top 10 causes of cancer-related deaths in the USA and account for 2.4 per cent of all yearly cancer-related deaths [9]. The median survival for a patient with glioblastoma multiforme (GBM) is approximately 12–14 months, and has not improved substantially over the past 30 years. For patients with a low-grade astrocytoma or oligodendroglioma, the median survival is still significantly curtailed and is about 6–10 years. For PBT patients in the USA as a whole, across all age groups and tumor types, the 5-year survival rate is 20 per cent [3]. If a patient with a PBT survives for an initial 2 years, the probability of surviving another 3 years is 76.2 per cent. In general, for any given tumor type, survival is better for younger patients than for older patients. The only exception to this generalization is for children with medulloblastoma and embryonal tumors, in which patients under three years of age have poorer survival rates than children between 3 and 14 years of age [10]. The 5-year survival rate for all children less than 14 years of age with a malignant PBT is 72 per cent.

The median age for diagnosis of PBT is between 54 and 58 years [1–6]. Among different histological varieties of PBT, there is significant variability in the age of onset. A small secondary peak is also present in the pediatric age group, in children between the ages of 4 and 9. Overall, PBT are more common in males than females, with the exception of meningiomas, which are almost twice as common in females. Tumors of the sellar region, and of the cranial and spinal nerves, are almost equally represented among males and females. In the USA, gliomas are more commonly diagnosed in Whites than Blacks, while the incidence of meningiomas is relatively equal between the two groups.

Numerous epidemiological studies have been performed in an attempt to define risk factors involved in the development of brain tumors (see Table 1.1) [2–6]. The vast majority of these potential risk factors have not been associated with any significant predisposition to brain tumors. One risk factor that has proven to be important is the presence of a hereditary syndrome with a genetic predisposition for developing tumors, some of which can affect the nervous system [4,5,11]. Several hereditary syndromes are associated with PBT, including tuberous sclerosis, neurofibromatosis types 1 and 2, nevoid basal cell carcinoma syndrome, Li-Fraumeni syndrome, and Turcot’s syndrome. However, it is estimated that hereditary genetic predisposition may be involved in only 2–8 per cent of all cases of PBT. Familial aggregation of brain tumors has also been studied, with conflicting results [5,11]. The relative risk for developing a tumor among family members of a patient with a PBT are quite variable and range from 1 to 10. One study that performed a segregation analysis of families of more than 600 adult glioma patients showed that a polygenic model most accurately explained the inheritance pattern [12]. A similar analysis of 2141 first-degree relatives of 297 glioma families did not reject a multifactorial model, but concluded that an autosomal recessive model fit the inheritance pattern more accurately [13]. Critics of these studies suggest that the common exposure of a family to a similar pattern of environmental agents could lead to a similar clustering of tumors. Other investigators have focused on genetic polymorphisms that might influence genetic and environmental factors to increase the risk for a brain tumor [4,5]. Alterations in genes involved in oxidative metabolism, detoxification of carcinogens, DNA stability and repair, and immune responses might confer a genetic predisposition to tumors. For example, Elexpuru-Camiruaga and colleagues demonstrated that cytochrome P-4502D6 and glutathione transferase theta were associated with an increased risk for brain tumors [14]. Other studies have not supported these results, but have found an increased risk for rapid N-acetyltransferase acetylation and intermediate acetylation [15]. In general, further studies with larger cohorts of patients will be necessary to determine if genetic polymorphisms of key metabolic enzyme systems play a significant role in the risk for developing a brain tumor.

TABLE 1.1 Risk Factors that have been Investigated in Epidemiological Studies of Primary Brain Tumors

Hereditary syndromes (proven): tuberous sclerosis, neurofibromatosis types 1 and 2, nevoid basal cell carcinoma syndrome, Turcot’s syndrome, and Li-Fraumeni syndrome Family History of brain tumors Constitutive polymorphisms: glutathione transferases, cytochrome P-450 2D6 and 1A1, N-acetyltransferase, and other carcinogen metabolizing, DNA repair, and immune function genes History of prior cancer Exposure to infectious agents Allergies (possible reduced risk) Head trauma Drugs and medications Dietary history: N-nitroso compounds, oxidants, antioxidants Tobacco usage Alcohol consumption Ionizing radiation exposure (proven) Occupational and industrial chemical exposures: pesticides, vinyl chloride, synthetic rubber manufacturing, petroleum refining and production, agricultural workers, lubricating oils, organic solvents, formaldehyde, acrylonitrile, phenols, polycyclic aromatic hydrocarbons Cellular telephones Power frequency electromagnetic field exposure

Data adapted from references [2–6,11–23]

Cranial exposure to therapeutic ionizing radiation is a potent risk factor for subsequent development of a brain tumor, and is known to occur after a wide range of exposures [1–6]. Application of low doses of irradiation (1000 to 2000 cGy), such as for children with tinea capitis or skin hemangiomas, have been associated with relative risks of 18 for nerve sheath tumors, 10 for meningiomas, and 3 for gliomas [5,16]. Gliomas and other PBT are also known to occur after radiotherapy for diseases such as leukemia, lymphoma, and head and neck cancers [5,17,18]. In addition, alternative methods of radiation exposure, such as nuclear bomb blasts and employment at nuclear production facilities, have also been implicated as significant risk factors for development of brain tumors [19,20].

Many other risk factors have been evaluated for their potential role in the genesis of brain tumors [1–6]. The majority of these factors have been proven to have little, if any, relationship to brain tumor development or have an...

Produkt-Details

• Erscheint lt. Verlag: 19.12.2005
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Neurologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Studium ► 2. Studienabschnitt (Klinik) ► Pathologie
• Themenwelt: Naturwissenschaften ► Biologie ► Humanbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• ISBN-10: 0-08-045593-X / 008045593X
• ISBN-13: 978-0-08-045593-8 / 9780080455938