Molecular Imaging in Oncology (Recent Results in Cancer Research (216))

Preface
	References
Contents
Technology and Probe Design
1 Advanced X-ray Imaging Technology
	1.1 Introduction
	1.2 Dual-Energy and Spectral CT
		1.2.1 Basic Principles
		1.2.2 State of the Art in Dual-Energy CT
		1.2.3 Benchmarking Quantitative and Material-Specific CT Imaging
		1.2.4 Clinical Implications for Oncological Imaging
	1.3 Application Examples in Oncology
		1.3.1 Improved Lesion CNR in Iodine Material Density CT Images
		1.3.2 Quantification of Iodine Material Density CT Imaging
	1.4 Future: Spectral Photon-Counting CT
	1.5 Phase-Contrast and Dark-field X-ray Imaging
		1.5.1 Basic Principles and Milestones
		1.5.2 Early Years of Phase-Contrast Imaging
		1.5.3 Milestones in Grating-Based Imaging
	1.6 Image Formation and Preclinical Results
		1.6.1 From 2D to 3D: Multi-contrast X-ray CT
	1.7 Application Examples in Oncology
	1.8 Present Stage of Clinical Translation
	References
2 Computed Tomography and Magnetic Resonance Imaging
	2.1 Imaging Targets in Cancer
		2.1.1 Introduction
		2.1.2 Physiological Imaging Targets
		2.1.3 Molecular Targets
		2.1.4 Cellular Targets
		2.1.5 Image-Guided Drug Delivery
	2.2 Recent Technological Developments in X-Ray Computed Tomography of Cancer
		2.2.1 Basics of Multi-slice Spiral Computed Tomography
			2.2.1.1 Brief History
			2.2.1.2 Data Acquisition
			2.2.1.3 Image Reconstruction
			2.2.1.4 Radiation Dose
		2.2.2 Multi-energy Computed Tomography
		2.2.3 Preclinical Computed Tomography
		2.2.4 Dedicated Imaging Systems and New Developments
		2.2.5 Multimodality Imaging with CT
	2.3 Recent Technological Developments in Magnetic Resonance Imaging of Cancer
		2.3.1 Magnetic Resonance Imaging: Introduction
		2.3.2 MRI Signal Formation and Contrast
		2.3.3 Magnetic Field Strength and Signal Sensitivity
		2.3.4 Imaging Gradients, Signal Encoding, and Signal Reception Chain
		2.3.5 MRI Pulse Sequences, Parametric Mapping
		2.3.6 Compressed Sensing
		2.3.7 Contrast-Enhanced MRI
		2.3.8 Multimodality Imaging with MRI
			2.3.8.1 PET/MRI
			2.3.8.2 SPECT/MRI
	2.4 Imaging Biomarkers in Cancer
		2.4.1 Imaging Biomarkers: X-Ray Computed Tomography
		2.4.2 Imaging Biomarkers: Magnetic Resonance Imaging
			2.4.2.1 Angiogenesis and Vessel Architecture
			2.4.2.2 Perfusion and Vascular Permeability
			2.4.2.3 Oxygenation and Hypoxia Imaging
			2.4.2.4 Diffusion-Weighted Imaging
			2.4.2.5 Intracellular and Extracellular Sodium Concentrations
			2.4.2.6 Cancer Metabolism and Metabolite Concentration Using MRS
			2.4.2.7 Extracellular pH
			2.4.2.8 Intracellular Protein Content and pH (CEST MRI)
			2.4.2.9 Multiparametric MRI
	2.5 Magnetic Resonance Imaging Probes in Cancer
		2.5.1 Introduction
		2.5.2 Non-Targeted Probes
			2.5.2.1 Low-Molecular Weight Agents
			2.5.2.2 High Molecular Weight Agents
			2.5.2.3 Protein-Based MR Agents
			2.5.2.4 Lipid-Based Nanoparticles
			2.5.2.5 Dendrimers
			2.5.2.6 Linear Polymers (Polylysine, PEG and Polysaccharide Complexes)
			2.5.2.7 Iron Oxides
			2.5.2.8 Gadofullerenes and Gadonanotubes
		2.5.3 Targeted Probes
		2.5.4 Responsive Probes
		2.5.5 Reporter Genes
			2.5.5.1 Transferrin Receptor Reporter Gene
			2.5.5.2 Ferritin Reporter Gene
			2.5.5.3 Tyrosinase MR Reporter Gene
			2.5.5.4 β-Galactosidase and MagA Reporter Gene
			2.5.5.5 Alternate Approaches
	2.6 Future Perspectives
	References
3 (Hybrid) SPECT and PET Technologies
	3.1 Introduction
	3.2 SPECT and PET Technology
		3.2.1 Basic SPECT and PET Physics
		3.2.2 Image Reconstruction
		3.2.3 SPECT and PET Detector Technology
			3.2.3.1 Requirements
			3.2.3.2 Detection Principle
				Scintillators
				Photodetectors
			3.2.3.3 Detector Designs
	3.3 Hybridizing SPECT and PET
		3.3.1 Motivation for Hybrid Imaging
		3.3.2 Challenges with Respect to MR Compatibility
	3.4 State-of-the-Art Hybrid Systems
		3.4.1 PET-CT
		3.4.2 SPECT-CT
		3.4.3 PET-MRI
		3.4.4 SPECT-MRI
	3.5 Conclusion
	References
4 Ultrasound Imaging
	4.1 Introduction
	4.2 Ultrasound Image Formation
		4.2.1 Spatial and Temporal Resolution
		4.2.2 Ultrasonic Signals and Speckle Noise
		4.2.3 Attenuation
		4.2.4 Image Contrast
	4.3 Imaging Techniques
		4.3.1 Line-Oriented Image Acquisition
		4.3.2 Ultrafast Imaging Techniques
		4.3.3 Harmonic Imaging
	4.4 Ultrasound Bioeffects
		4.4.1 Thermal Effects
		4.4.2 Mechanical Effects
	4.5 Contrast-Enhanced Ultrasound Imaging (CEUS)
		4.5.1 Contrast Agents
		4.5.2 Contrast Specific Imaging
		4.5.3 Super-Resolution Vascular Imaging by Microbubble Localization
	References
5 Optical and Optoacoustic Imaging
	5.1 Surgical Vision Through Fluorescence
	5.2 Selection of Fluorescence Agent
	5.3 Need for Standardization in Clinical Fluorescence Imaging
	5.4 Multispectral Optoacoustic Tomography (MSOT)
	5.5 MSOT Imaging of Endogenous Absorption Contrast
	5.6 Molecular Sensing with MSOT
	5.7 Clinical Translation of Optoacoustic Imaging
	5.8 The Future of Fluorescence and MSOT Imaging
	Acknowledgments
	Conflicts of Interest
	References
6 Multifunctional Magnetic Resonance Imaging Probes
	6.1 The Role of Non-invasive Imaging Methods in Oncology
	6.2 Magnetic Resonance Imaging of Cancer—Imaging Techniques and Contrast Agents
		6.2.1 Intrinsic Contrasts in MR Imaging—T1/T2/T2*
		6.2.2 Contrast Agents in MRI
			6.2.2.1 Gadolinium Agents
			6.2.2.2 Iron Oxide Particles
			6.2.2.3 Manganese-Based Contrast Agents
		6.2.3 CEST MRI
	6.3 Multifunctional Imaging Probes
		6.3.1 Inorganic Nanoparticles
			6.3.1.1 (Ultrasmall) Superparamagnetic Iron Oxide (U)SPIO Nanoparticles
			6.3.1.2 Other Metal-Oxygen Compounds
			6.3.1.3 Other Metal Compounds
		6.3.2 Other Materials for Imaging Probe Design
		6.3.3 Multifunctional Probes for 19F MRI
		6.3.4 CEST Probes
	6.4 Theranostics
	6.5 Novel Imaging Approaches
		6.5.1 Magnetic Particle Imaging (MPI)
		6.5.2 Hyperpolarized Multifunctional MRI Probes
	6.6 Outlook
	References
7 Single Photon Emission Computed Tomography Tracer
	7.1 Introduction
	7.2 General Aspects for the Design of SPECT Tracers
	7.3 Peptide-Receptor Radionuclide Imaging
		7.3.1 Somatostatin Analogs
		7.3.2 Bombesin Analogs
		7.3.3 Neurotensin Analogs
		7.3.4 Other Peptide-Based Radiotracers
	7.4 Antibodies and Antibody Fragments
		7.4.1 Targeting Fibronectin Extra-Domain B: Antiangiogenic Antibody Fragment L19
	7.5 Vitamin-Based Radiotracers
		7.5.1 Folic Acid Conjugates
		7.5.2 Vitamin B12 Conjugates
		7.5.3 Other Vitamin Targeting Agents—Pretargeting
	7.6 Intracellular Targets
		7.6.1 99mTc-Carbohydrate Complexes
		7.6.2 Radiolabeled Nucleoside Analogs for Targeting Human Thymidine Kinase
		7.6.3 Radioiodinated meta-Iodobenzylguanidine (MIBG)
	7.7 Glutamate-Ureido-Based Inhibitors of Prostate-Specific Membrane Antigen (PSMA)
		7.7.1 123I- and 131I-Labeled PSMA Radioligands
		7.7.2 99mTc-Labeled PSMA Radioligands
	7.8 Sentinel Lymph Node (SNL) Localization
	7.9 Optimization of SPECT Tracer Design and Potential Reasons for Failure
	7.10 Summary and Conclusion
	References
8 18F-Labeled Small-Molecule and Low-Molecular-Weight PET Tracers for the Noninvasive Detection of Cancer
	8.1 Introduction
	8.2 2-Deoxy-2-[18F]Fluoro-d-Glucose ([18F]FDG) for Imaging Glucose Metabolism
	8.3 18F-Labeled Amino Acids for Imaging Amino Acid Transport and Protein Synthesis
		8.3.1 O-(2-[18F]Fluoroethyl)-l-Tyrosine ([18F]FET)
		8.3.2 6-[18F]Fluoro-3,4-Dihydroxy-l-Phenylalanine ([18F]FDOPA)
		8.3.3 Anti-1-Amino-3-[18F]Fluorocyclobutane-1-Carboxylic Acid ([18F]Fluciclovine, [18F]FACBC)
	8.4 18F-Labeled Choline Derivatives for Imaging Membrane Lipid Synthesis
		8.4.1 Dimethyl-[18F]Fluoromethyl-2-Hydroxyethylammonium ([18F]Fluoromethylcholine, [18F]FCH)
		8.4.2 Dimethyl-2-[18F]Fluoroethyl-2-Hydroxyethylammonium ([18F]Fluoroethylcholine, [18F]FECH)
	8.5 18F-Labeled Nucleoside Derivatives for Imaging Cell Proliferation
		8.5.1 3′-Deoxy-3′-[18F]Fluorothymidine ([18F]FLT)
		8.5.2 1-(2′-Deoxy-2′-[18F]Fluoro-β-D-Arabinofuranosyl)-5-Methyluracil ([18F]FMAU)
	8.6 18F-Labeled Nitroimidazole Derivatives for Imaging of Tumor Hypoxia
		8.6.1 1H-1-(3-[18F]Fluoro-2-Hydroxypropyl)-2-Nitroimidazole ([18F]Fluoromisonidazole, [18F]FMISO)
		8.6.2 1-(5-Deoxy-5-[18F]Fluoro-α-d-Arabinofuranosyl)-2-Nitroimidazole ([18F]FAZA)
	8.7 16α-[18F]Fluoro-17β-Estradiol ([18F]FES) for Imaging Estrogen Receptor Status
	8.8 18F-Labeled Glu-Ureido–Based Inhibitors for Imaging Prostate-Specific Membrane Antigen (PSMA)
		8.8.1 (3S,10S,14S)-1-(4-(((S)-4-Carboxy-2-((S)-4-Carboxy-2-(6-[18F]Fluoronicotinamido)Butanamido)Butanamido)Methyl)Phenyl)-3-(Naphthalen-2-Ylmethyl)-1,4,12-Trioxo-2,5,11,13-Tetraazahexadecane-10,14,16-Tricarboxylic Acid ([18F]PSMA-1007)
		8.8.2 2-(3-(1-Carboxy-5-[(6-[18F]Fluoro-Pyridine-3-Carbonyl)-Amino]-Pentyl)-Ureido)-Pentanedioic Acid ([18F]DCFPyL)
	8.9 Sodium [18F]Fluoride (Na[18F]F) for Imaging Bone Mineralization
	8.10 Conclusion
	References
9 Ultrasound Molecular Imaging of Cancer: Design and Formulation Strategies of Targeted Contrast Agents
	9.1 Introduction
	9.2 Bubbles and Their Interaction with Ultrasound: The Basis for Ultrasound Contrast Physics
	9.3 Microbubbles In Vivo: How and When Molecular Imaging Could Happen
	9.4 Preparation of Ultrasound Contrast Particles
	9.5 Microbubble Shell Design
	9.6 Targeting Ligand Attachment to Microbubble Shell
	9.7 Bubble Targeting Tumors In Vivo: Microbubbles in Animal Models
	9.8 Nanobubbles: A Smaller-Size Approach to Molecular Ultrasound Imaging
	9.9 Targeted Ultrasound Contrast in Clinic and Clinical Trials
	9.10 Conclusion
	Acknowledgments
	References
10 Optical and Optoacoustic Imaging Probes
	10.1 Unspecific, Perfusion-Type Optical Probes
	10.2 Targeted Contrast Agents
		10.2.1 Binding Moieties
			10.2.1.1 Antibodies and Antibody Fragments
			10.2.1.2 Peptides
			10.2.1.3 Small Molecules
		10.2.2 Signalling Molecules
			10.2.2.1 Blue Dyes
			10.2.2.2 Cyanine Dyes
			10.2.2.3 Quenchers in OAI
			10.2.2.4 Quantum Dots
			10.2.2.5 Nanoparticles
		10.2.3 Linkers/Spacers
	10.3 Smart Probes
	10.4 Summary
	References
Preclinical Studies
11 Preclinical SPECT and SPECT-CT in Oncology
	11.1 Introduction
	11.2 Part I: Evaluating the Potential Role of SPECT-CT Imaging in a Preclinical Oncology Research Application
		11.2.1 Choice and Implications of Various Small Animal Models of Cancer
		11.2.2 Choice of Imaging Modality
		11.2.3 SPECT Versus SPECT-CT
		11.2.4 SPECT-MRI
	11.3 Part II: Technical Considerations When Implementing SPECT-CT in Preclinical Oncology Research
		11.3.1 Anesthesia and Animal Handling
		11.3.2 Availability of Radiopharmaceuticals and Evaluation of Their Biodistribution Characteristics
		11.3.3 Injection of the Radiopharmaceutical
		11.3.4 Injection of Contrast Agents
		11.3.5 Radiation Exposure
	11.4 Part III: State of the Art of Preclinical SPECT-CT Systems
		11.4.1 SPECT-CT System Design
		11.4.2 Radiation Detector
		11.4.3 Collimator
		11.4.4 Image Reconstruction Techniques
		11.4.5 Quantitative SPECT-CT
		11.4.6 Quality Assurance
		11.4.7 A Sampling of Available Small Animal SPECT and SPECT-CT Systems
	11.5 Part IV: SPECT-CT as Applied in the Preclinical Oncology Setting
		11.5.1 Cancer Detection
		11.5.2 Characterizing Tumorigenesis and Malignant Spread
		11.5.3 Imaging the Targeting Abilities of Molecules in the Development of Potential Therapeutics and Molecular Imaging Agents
		11.5.4 Small Molecules
		11.5.5 Theranostics
		11.5.6 Predicting Therapeutic Response and Monitoring Response to Therapy
		11.5.7 Imaging Cell Trafficking
		11.5.8 Imaging Gene Transfer and Expression
		11.5.9 Imaging Drug Delivery and Using SPECT in Drug Design
		11.5.10 Imaging Other Pathologic Processes Associated with Cancer or Cancer Therapies
	11.6 Part V: Areas of Rapid Advancement of the Science of Molecular Imaging with SPECT-CT
		11.6.1 Next-Generation Imaging Systems
		11.6.2 Imaging Immune Activation
		11.6.3 Multimodality Probes
		11.6.4 Radiomics and Computational Advances
	11.7 Conclusion
	References
12 Preclinical Applications of Magnetic Resonance Imaging in Oncology
	12.1 Introduction
	12.2 Experimental Models of Cancer
	12.3 Small Animal Molecular Imaging
	12.4 Magnetic Resonance Imaging and Spectroscopy
		12.4.1 Contrast Agents
		12.4.2 Dynamic Contrast-Enhanced MRI
		12.4.3 Steady-State Susceptibility-Contrast MRI
		12.4.4 Diffusion-Weighted MRI
		12.4.5 Arterial Spin Labeling
		12.4.6 13C Hyperpolarization
	12.5 Applications
		12.5.1 Metabolism
		12.5.2 Hypoxia
		12.5.3 Angiogenesis
		12.5.4 Cellular Imaging
	12.6 Summary and Outlook
	Acknowledgments
	References
13 Optical and Optoacoustic Imaging
	13.1 Introduction
	13.2 Fluorescence Imaging
		13.2.1 Principles of Fluorescence
		13.2.2 Fluorescence Imaging Technologies
			13.2.2.1 Fluorescence Reflectance Imaging (FRI)
			13.2.2.2 Fluorescence Transillumination Imaging (FTI)
			13.2.2.3 Fluorescence Tomography
		13.2.3 Optical Domains
			13.2.3.1 Intensity Domain
			13.2.3.2 Time Domain
		13.2.4 In Vivo Applications of Fluorescence Imaging
			13.2.4.1 Imaging of Tumors
				Activatable Probes
				Sensing Probes
				Theranostic Probes
			13.2.4.2 Imaging of Apoptosis
			13.2.4.3 Imaging of Angiogenesis
			13.2.4.4 Cell Tracking
			13.2.4.5 Imaging of Autofluorescence
			13.2.4.6 Intraoperative Fluorescence Imaging
			13.2.4.7 Conclusion
	13.3 Bioluminescence Imaging
		13.3.1 Basics of Bioluminescence Imaging
		13.3.2 Factors Affecting BLI
		13.3.3 Genetically Engineered Luciferases, Modified Substrates, and Multicolor Reporter Systems
		13.3.4 Applications of BLI
			13.3.4.1 Imaging of Cancer
			13.3.4.2 Imaging of Cancer-Related Inflammation and the Immune System
			13.3.4.3 Tracking of Immune Cells/T Cell Imaging
			13.3.4.4 Stem Cell Tracking
			13.3.4.5 Imaging of Protein–Protein Interactions
		13.3.5 Bioluminescence Imaging Versus Fluorescence Imaging
	13.4 Optoacoustic Imaging
		13.4.1 Modes of Action
		13.4.2 Sources of Contrast
			13.4.2.1 Hemoglobin
			13.4.2.2 Melanin
			13.4.2.3 Lipids
			13.4.2.4 Exogenous Probes
				Fluorescent Dyes
				Nanoparticles
	13.5 Summary
	References
14 Applications of Small Animal PET
	14.1 Introduction
	14.2 Challenges of Small Animal PET
	14.3 Tumor Characterization
	14.4 Evaluation of Therapy Response
	14.5 Therapy Development
	14.6 Multimodal PET Imaging
	14.7 Conclusion
	References
15 Molecular Ultrasound Imaging
	15.1 Introduction
	15.2 Ultrasound Contrast Agents
		15.2.1 Microbubbles
		15.2.2 Liposomes
		15.2.3 Nanobubbles
		15.2.4 Phase-Change Nanodroplets
	15.3 Active and Passive Targeting
	15.4 Ligands for Molecular CEUS
	15.5 Detection of Targeted Contrast Agents
		15.5.1 Dwell-Time Imaging
		15.5.2 Destruction-Replenishment Imaging
		15.5.3 Sensitive Particle Acoustic Quantification (SPAQ)
	15.6 Preclinical Applications
		15.6.1 Imaging Angiogenesis
			15.6.1.1 Vascular Endothelial Growth Factor Receptor 2
			15.6.1.2 αvβ3 Integrin
			15.6.1.3 Endoglin
		15.6.2 Further Molecular Targets
		15.6.3 Nanobubbles and Nanoparticles for Preclinical Molecular Ultrasound Imaging
			15.6.3.1 Nanobubbles
			15.6.3.2 Phase-Shift Nanoparticles
	15.7 Clinical Application
	15.8 Targeted Ultrasound-Mediated Drug Delivery
	References
16 Molecular Imaging in Oncology: Advanced Microscopy Techniques
	16.1 Introduction
	16.2 Fluorescence and Labelling
		16.2.1 Chemical Labelling
		16.2.2 Immunofluorescence
		16.2.3 Fluorescent Proteins
		16.2.4 Photo-Switching Dyes
	16.3 Fluorescence Microscopy Techniques
		16.3.1 Confocal Microscopy
			16.3.1.1 Limitations
		16.3.2 Light-Sheet Microscopy—LSM
			16.3.2.1 Limitations
		16.3.3 Two-Photon Microscopy
			16.3.3.1 Limitations
		16.3.4 Super-Resolution Microscopy Techniques
			16.3.4.1 Limitations
		16.3.5 Single-Molecule Localization Microscopy—SMLM
			16.3.5.1 Limitations
		16.3.6 Structured Illumination Microscopy—SIM
			16.3.6.1 Limitations
	16.4 Applications
		16.4.1 Confocal Microscopy
		16.4.2 Light-Sheet Microscopy—LSM
		16.4.3 Two-Photon Microscopy
			16.4.3.1 Ex Vivo
			16.4.3.2 Metabolic Imaging
			16.4.3.3 Multiphoton Imaging of Skin
			16.4.3.4 Intravital Imaging with Two-Photon Microscopy
			16.4.3.5 Second Harmonic Generation Imaging of Collagen
			16.4.3.6 Higher Order Fluorescence and Harmonics
			16.4.3.7 Endomicroscopy
		16.4.4 Super-Resolution Microscopy
		16.4.5 Multimodal Techniques
	16.5 Conclusion
	References
Clinical Applications
17 Quantitative SPECT/CT—Technique and Clinical Applications
	17.1 Introduction
	17.2 Quantitative SPECT/CT
		17.2.1 SPECT/CT Instrumentation
		17.2.2 Registration of Multimodal Images
		17.2.3 Attenuation Correction of SPECT
		17.2.4 Image Reconstruction
		17.2.5 Scatter Correction
		17.2.6 Partial Volume Correction
		17.2.7 Calibration
	17.3 Quantitative Accuracy
	17.4 Clinical Aspects of Quantitative SPECT
	17.5 Summary and Outlook
	References
18 Fluorescence Imaging of Breast Tumors and Gastrointestinal Cancer
	18.1 Introduction
	18.2 Fluorescence Imaging of Breast Cancer
		18.2.1 Basics of Breast Optical Imaging and Endogenous Tumor Contrast
		18.2.2 Contrast Agents for Breast Optical Imaging
		18.2.3 Breast Tumor Detection by ICG Using Vascular Contrast
		18.2.4 Breast Tumor Imaging and Differentiation by ICG Using Vessel Permeability
		18.2.5 Imaging of Breast Cancer with Omocianine
		18.2.6 Fluorescence-Guided Breast Cancer Surgery
	18.3 Cancer and Early Malignancies of the Gastrointestinal Tract
		18.3.1 Protoporphyrin IX as Tumor Marker
		18.3.2 Time-Gated Fluorescence Imaging of Protoporphyrin IX
		18.3.3 Targeted Molecular Imaging in Gastrointestinal Endoscopy
	18.4 Outlook
	References
19 FDG PET Hybrid Imaging
	19.1 Introduction
	19.2 Clinical Applications of FDG PET/CT in Oncology
		19.2.1 Non-small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC)
			19.2.1.1 Diagnosis, Staging and Radiation Treatment Planning in NSCLC Patients
			19.2.1.2 Therapy Response Assessment in NSCLC Patients
			19.2.1.3 Staging in SCLC Patients
		19.2.2 Thyroid Cancer
			19.2.2.1 Diagnosis, Staging and Re-staging
		19.2.3 Head and Neck Cancer
			19.2.3.1 Diagnosis, Staging and Re-staging
			19.2.3.2 Therapy Response Assessment
		19.2.4 Oesophageal Cancer
			19.2.4.1 Diagnosis, Staging and Re-Staging
			19.2.4.2 Therapy Response Assessment
		19.2.5 Gastric Cancer and Gastrointestinal Stromal Tumour (GIST)
			19.2.5.1 Diagnosis, Staging and Re-staging in Gastric Cancer Patients
			19.2.5.2 Diagnosis, Staging and Re-staging in GIST Patients
			19.2.5.3 Therapy Response Assessment in GIST Patients
		19.2.6 Colorectal Cancer
			19.2.6.1 Diagnosis, Staging and Re-staging
			19.2.6.2 Therapy Response Assessment
		19.2.7 Pancreatic Cancer
			19.2.7.1 Diagnosis, Staging and Re-Staging
		19.2.8 Melanoma
			19.2.8.1 Diagnosis, Staging and Re-staging
			19.2.8.2 Therapy Response Assessment
		19.2.9 Lymphoma
			19.2.9.1 Diagnosis, Staging and Re-staging
			19.2.9.2 Therapy Response Assessment
		19.2.10 Sarcoma
			19.2.10.1 Diagnosis, Staging and Re-staging
			19.2.10.2 Therapy Response Assessment
		19.2.11 Breast Cancer
			19.2.11.1 Diagnosis, Staging and Re-staging
			19.2.11.2 Therapy Response Assessment
		19.2.12 Ovarian Cancer
			19.2.12.1 Diagnosis, Staging and Re-staging
			19.2.12.2 Therapy Response Assessment
		19.2.13 Testicular Cancer
			19.2.13.1 Diagnosis, Staging and Re-staging
			19.2.13.2 Therapy Response Assessment
		19.2.14 Penile Cancer
			19.2.14.1 Diagnosis, Staging and Re-staging
		19.2.15 Prostate Cancer
			19.2.15.1 Diagnosis, Staging and Re-staging
		19.2.16 Cancer of Unknown Primary
			19.2.16.1 Diagnosis/Detection and Staging
	References
20 Non-FDG PET/CT
	20.1 Introduction to Non-FDG PET Tracers
	20.2 Clinical Applications of 11C/18F-Choline
	20.3 Clinical Applications of 11C-Acetate
	20.4 Clinical Applications of 68Ga-PSMA
	20.5 Clinical Applications of 18F-FACBC
	20.6 Clinical Applications of 11C-Methionine
	20.7 Clinical Applications of 18F-FET
	20.8 Clinical Applications of 18F-DOPA
	20.9 Clinical Applications of 68Ga-DOTA-Peptides
	20.10 Clinical Applications of 18F-FLT
	20.11 Clinical Applications of 18F-Fluoride
	20.12 Clinical Applications of 124I-Na
	20.13 Clinical Potential of PET Tracers for Hypoxia
	20.14 Clinical Potential of PET Tracers for Angiogenesis
	20.15 Clinical Potential of Immune-PET Tracers
	References
21 Clinical MR Biomarkers
	21.1 Diffusion-Weighted Imaging (DWI)
		21.1.1 Diffusion-Weighted Imaging in Brain Cancer Patients
		21.1.2 Prostate MRI with Diffusion-Weighted Imaging
		21.1.3 MR Mammography Using Diffusion-Weighted Imaging
	21.2 Perfusion MRI
		21.2.1 Perfusion MRI in the Brain
		21.2.2 Arterial Spin Labeling (ASL) in Brain Tumors
		21.2.3 Breast Perfusion Imaging
		21.2.4 Prostate Perfusion Imaging
		21.2.5 Abdominal Perfusion MRI
	21.3 Susceptibility-Weighted Imaging (SWI)
	21.4 Magnetic Resonance Spectroscopy (MRS)
	21.5 Protein-Weighted MRI Using Chemical Exchange Saturation Transfer (CEST)
		21.5.1 Brain Tumors
		21.5.2 Applications of CEST MRI in Other Organs
	21.6 Dynamic Glucose-Enhanced (DGE) MRI
	21.7 MR Fingerprinting for Quantitative Relaxometry (T1 and T2 Mapping)
		21.7.1 Prostate Relaxometry
		21.7.2 Brain Relaxometry
	21.8 Challenges to Implement Clinical MR Biomarkers in Multicenter Trials
	References
22 Clinical PET/MR
	22.1 Fundamental Differences Between PET/MR and PET/CT Imaging in Oncology
	22.2 Clinical Studies Evaluating PET/MR in Different Oncological Diseases
		22.2.1 Head and Neck Cancers
		22.2.2 Non-small Cell Lung Cancer
		22.2.3 Gastrointestinal Cancers and Neuroendocrine Tumors
		22.2.4 Gynecologic Malignancies
		22.2.5 Breast Cancer
		22.2.6 Lymphoma
		22.2.7 Prostate Cancer
		22.2.8 PET/MR in Children
	22.3 Conclusions
	References
23 Advanced Ultrasound Imaging for Patients in Oncology: DCE-US
	References
24 Image-Guided Radiooncology: The Potential of Radiomics in Clinical Application
	24.1 Introduction
		24.1.1 Definition of “Radiomics”
			24.1.1.1 First-Order Intensity Features
			24.1.1.2 Morphology Features
			24.1.1.3 Second-Order Texture Features
			24.1.1.4 Image Filtering
		24.1.2 Machine Learning—The Toolbox for the Generation of Radiomics Models
		24.1.3 Moving the Field Forward—The Role of “Deep Learning”
		24.1.4 Radiomics and Molecular Imaging
		24.1.5 Technical Challenges of Radiomics
	24.2 The Clinical Potential of Radiomics
		24.2.1 Radio-Oncomics
		24.2.2 Radiogenomics
		24.2.3 The Radiomics Target Volume Concept
	24.3 Clinical Applications of Radiomics
		24.3.1 NSCLC
		24.3.2 HNSCC
		24.3.3 Soft-Tissue Sarcoma (STS)
		24.3.4 Glioma
		24.3.5 Challenges Before Clinical Applications
	24.4 Conclusion
	References
25 Non-invasive Imaging Techniques: From Histology to In Vivo Imaging
	25.1 Introduction
	25.2 Raman Spectral Imaging/Spectroscopy
	25.3 Coherent Raman Spectroscopy and Spectromicroscopy: CARS and SRS
	25.4 Non-linear Processes (SHG, THG, TPEF)
	25.5 Fluorescence Lifetime Imaging (FLIM)
	25.6 Machine Learning for Spectral and Image Data
	25.7 Summary
	References
26 Image-Guided Brain Surgery
	26.1 Introduction
	26.2 Conventional Intraoperative Imaging
		26.2.1 Ultrasound
		26.2.2 Neuronavigation
		26.2.3 Intraoperative MRI (iMRI)
	26.3 Fluorescence-Guided Brain Surgery
		26.3.1 5-Aminolevulinic Acid (5-ALA)
			26.3.1.1 5-Aminolevulinic Acid in High-Grade Gliomas
			26.3.1.2 5-Aminolevulinic Acid in Recurrent High-Grade Gliomas
			26.3.1.3 5-Aminolevulinic Acid in Low-Grade Gliomas
			26.3.1.4 5-Aminolevulinic Acid in Other Brain Tumors
		26.3.2 Fluorescein
			26.3.2.1 Critical Points/Problems with the Usage of Fluorescein
			26.3.2.2 Fluorescein-Guided Surgery for High-Grade Gliomas
			26.3.2.3 Fluorescein-Guided Surgery for Cerebral Metastases
			26.3.2.4 Fluorescein-Guided Surgery for Other CNS Tumors
		26.3.3 Indocyanine Green (ICG)
	26.4 Novel Techniques
		26.4.1 Tumor-Targeted Alkylphosphocholine Analogs for Intraoperative Visualization
		26.4.2 Confocal Endomicroscopy
		26.4.3 Raman Spectroscopy
		26.4.4 BLZ-100 Fluorescence-Guided Brain Tumor Surgery
	26.5 Combination of Different Techniques for Intraoperative Imaging
	26.6 Future Directions
	References
Image Guided Radiooncology
27 Molecular Imaging in Photon Radiotherapy
	27.1 Brain Tumours
		27.1.1 Gliomas
	27.2 Meningiomas
	27.3 Head and Neck Cancer
	27.4 Lung Cancer
	27.5 Esophageal Cancer
	27.6 Prostate Cancer
		27.6.1 Localized Prostate Cancer and Dose Escalation
		27.6.2 Lymph Node Metastases
		27.6.3 Recurrence
		27.6.4 Bone Metastases
	27.7 Uterine Cancer
		27.7.1 Cervical Cancer
		27.7.2 Endometrial Cancer
	27.8 Conclusion and Outlook
	References
28 Molecular Imaging for Particle Therapy: Current Approach and Future Directions
	28.1 Introduction
	28.2 Sidenote: In situ beam monitoring by PET
	28.3 Metabolic Activity: Imaging of Glucose Metabolism in Oncology
	28.4 The New Tracer FAPI
	28.5 Tumor-Specific Tracers: PSMA
	28.6 Metabolic Activity: Amino Acid Metabolism in Brain Tumors
	28.7 Tumor-Specific Markers: DOTATOC
	28.8 Future Directions: Individualized Adaptive Treatment Planning Based on Functional and Biological Characteristics
	References
29 Internal Radiation Therapy
	29.1 Non-specific Therapy
		29.1.1 Selective Internal Radiotherapy (SIRT)
		29.1.2 Radiopharmaceuticals with Accumulation in Areas of Bone Remodeling
		29.1.3 Specific Procedures
		29.1.4 Peptide Receptor Radionuclide Therapy (PRRT)
		29.1.5 Somatostatin Receptor Ligands
		29.1.6 Cholecystokinin (CCK) Receptor Ligands
		29.1.7 Vasoactive Intestinal Peptide (VIP) Receptor Ligands
		29.1.8 Bombesin (BN) Receptor Ligands
		29.1.9 Glucagon-like Peptide 1 (GLP1) Receptor Ligands
		29.1.10 Neurotensin (NT) Receptor Ligands
		29.1.11 Other Targets
		29.1.12 Prostate-Specific Membrane Antigen
		29.1.13 Endoradiotherapy with Antibodies and Small Molecules
	References
Future Challenges
30 Future Challenges of Multimodality Imaging
	30.1 Introduction
	30.2 Technology and Probe Design
		30.2.1 SPECT/CT
		30.2.2 PET/CT
		30.2.3 SPECT/MRI and PET/MRI
	30.3 Tracers
	30.4 Future and Conclusions
	References