In neurosurgery, the extent of resection (EOR) is crucial, particularly in the management of malignant gliomas. These tumors are characterized by a diffuse infiltration into the surrounding brain parenchyma. Delineation between tumor and normal brain parenchyma can therefore often be challenging. In recent years, researchers and surgeons have developed and implemented various techniques to improve the visualization of tumors during surgery. This chapter explores current approaches to intraoperative imaging in brain tumor surgery, comprising conventional techniques such as neuronavigation, techniques using fluorescence guided surgery, and further highly precise developments such as targeted-fluorescence, Raman spectroscopy, and hyperspectral imaging. These innovative methods aim to enhance surgeons' ability to identify and remove tumor tissue more effectively, potentially improving patient outcomes.
Radiotheranostics integrates molecular imaging and targeted radionuclide therapy to provide personalized cancer treatment. By using radiolabeled agents that bind tumor-specific targets, clinicians can both visualize and treat malignancies, guided by the principle of "treat what you see." Diagnostic tools such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) confirm target presence, while therapeutic radioisotopes deliver cytotoxic radiation to tumor cells, enabling real-time monitoring and individualized treatment.These agents pair a targeting molecule-such as a peptide, small molecule, or antibody-with either a diagnostic or therapeutic radioisotope. Beta and alpha emitters offer different radiation profiles, suited for specific clinical needs. This strategy has already improved outcomes in diseases like neuroendocrine tumors and prostate cancer, and new applications are rapidly emerging. Radiotheranostics provides a systemic alternative to external beam radiotherapy, allowing for personalized dosimetry to enhance efficacy and minimize side effects.The field has evolved significantly from early radioiodine therapy, driven by advances in radiochemistry and imaging. While treatments are generally safe, potential toxicities-such as bone marrow suppression or glandular damage-require careful management. As radiotheranostics advances toward broader clinical use, overcoming challenges in isotope supply, infrastructure, and workforce training will be critical. Its integration into multidisciplinary oncology teams promises to make it a cornerstone of precision cancer care.
Defining artificial intelligence (AI) remains a complex challenge, given its rapidly evolving nature. Nevertheless, one broadly accepted definition-endorsed by the European Union-describes AI as a suite of algorithms that learn from data to make predictions. Since the early 2010s, AI has emerged as a highly effective approach for analyzing, processing, and even generating medical image data.In this chapter, we provide an overview of key AI paradigms-radiomics, deep learning (DL), and foundation models-and examine their current and potential applications in medical image analysis within radiation oncology. We focus on topics, such as image classification, treatment planning, and response assessment, as well as novel strategies involving vision language models (VLMs). Through this exploration, we offer insights into how AI is transforming clinical workflows and shaping future directions in radiation oncology.
With modern targeted cancer drugs, not all patients will respond to treatment in the same way. The challenge is to select the most appropriate treatment for an individual patient, which could reduce healthcare costs and improve patient management. MRI with hyperpolarized 13C-labelled and 2H-labelled substrates offers potentially unique insights into the metabolism of tumours in the clinic, where these techniques can be used to grade tumours and to both predict and then detect their very early responses to treatment. We discuss here the basic principles of how these metabolic imaging techniques work and give examples of how different labelled substrates can be used, with a focus on those substrates that have already gone into the clinic or are about to go into the clinic.
The convergence of targeted imaging agents with intraoperative guidance systems is reshaping oncologic surgery to enable precision tumor resection and reduce residual disease. We examine the evolving role and integration of cancer theranostics with advanced image-guided intraoperative imaging to improve surgical precision and the targeted removal of diseased tissue while sparing normal vital structures. Molecularly engineered probes, for instance, the EGFR-targeted antibody conjugated with IRDye800CW and the folate receptor alpha-targeting agent, OTL38, delineate tumor margins with high sensitivity and specificity, and investigational tumor-targeting probes that combine preoperative PET imaging with real-time surgical navigation maximize tumor detection and removal for improving patient outcomes. These approaches exploit near-infrared (NIR) optical windows to overcome limitations at visible wavelengths, including shallow light penetration and autofluorescence, and enhance sensitivity and spatial resolution. In parallel, advances in imaging hardware and software have led to new artificial intelligence (AI)-powered surgical navigation devices, multispectral cameras, gamma probes, and Cerenkov luminescence systems that complement the molecular precision of these probes by offering enhanced depth detection and/or dynamic visualization. The integration of AI and augmented reality further refines image registration and quantitative analysis, ensuring that intraoperative feedback is accurate and actionable. The synthesis of molecular targeting and state-of-the-art imaging addresses the critical clinical need of achieving complete tumor resection, a key determinant of patient prognosis and recurrence. Recent Phase 2 and Phase 3 trials underscore the translational potential of these theranostic approaches, which are rapidly advancing toward routine practice. By enabling personalized and adaptive surgical strategies, the integration of cancer theranostics and intraoperative imaging represents a vital step forward in precision oncology, promising significant improvements in long-term patient outcomes.
The principal role of molecular imaging with positron emission tomography (PET) in contemporary clinical practice is centered on oncological applications. Among radiopharmaceuticals, [18F]FDG continues to serve as the cornerstone of nuclear oncology, maintaining its position as the most extensively utilized positron-emitting agent to date. Nevertheless, the progressive elucidation of cancer biology over recent decades has unveiled numerous metabolic and pathogenic pathways within malignant cells, thereby catalyzing the innovation of a diverse array of novel PET tracers. This chapter provides an overview of a curated selection of non-FDG PET tracers, highlighting their integration into clinical workflows and their respective contributions to advancing oncological imaging.
Molecular imaging with positron emission tomography (PET) using tumour-targeting radiopharmaceuticals has gained widespread acceptance in oncology with numerous clinical applications. The hybrid imaging modality PET/CT (computed tomography) allows simultaneous assessment of both molecular and morphologic information. Therefore, PET/CT represents an efficient tool for comprehensive whole-body staging and restaging within single imaging session. In oncology, the glucose analogue 18-F-fluorodeoxyglucose (FDG) is the most widely used PET/CT radiopharmaceutical in clinical routine. FDG PET and FDG PET/CT have been used for staging and restaging of tumour patients in numerous studies. This chapter will discuss the applications and primary indications of FDG PET/CT in oncology with particular emphasis on lung cancer, lymphoma, head and neck cancer, melanoma and breast cancer, among other tumour entities. A review of the current literature is presented, focusing on primary diagnosis, staging and detection of recurrent disease. Besides its established role in diagnosis, staging and restaging of disease in oncology, there is growing evidence that FDG PET/CT is valuable in assessment of therapy response, potentially influencing treatment planning and therapeutic decision making by evaluating tumour control, which will also be discussed in this chapter.
Optical imaging offers a high potential for noninvasive detection and therapy of cancer in humans. Recent advances in instrumentation for diffuse optical imaging have led to new capabilities for the detection of cancer in highly scattering tissue such as the female breast. In particular, fluorescence imaging is a promising method to image molecular probes in vivo. We review recent developments in the detection of breast cancer and fluorescence-guided surgery of the breast by contrast agents available for application on humans. Detection of cancer has been investigated with the unspecific contrast agents "indocyanine green" and "omocianine" so far. Hereby, indocyanine green was found to offer high potential for the differentiation of malignant and benign lesions by exploiting vessel permeability for macromolecules as a cancer-specific feature. Tumor-specific molecular targeting and activatable probes have been investigated in clinical trials for fluorescence-guided detection of tumor margins. In this application, high spatial resolution can be achieved, since tumor regions are visualized mainly at the tissue surface. As another example of superficial tumor tissue, imaging of lesions in the gastrointestinal tract is discussed. Promising results have been obtained on high-risk patients with Barrett's esophagus and with ulcerative colitis by administering 5-aminolevulinic acid, which induces the accumulation of protoporphyrin IX serving as a tumor-specific fluorescent marker. Time-gated fluorescence imaging and spectroscopy are effective ways to suppress the underlying background from tissue autofluorescence. Furthermore, recently developed tumor-specific molecular probes have been demonstrated to be superior to white-light endoscopy, offering new ways for early detection of malignancies in the gastrointestinal tract.
During the last decades, radiation oncology has undergone transformative technological advancements including the clinical implementation of ion beam therapy, most commonly using protons and carbon ions and more recently also helium ions as a high-precision treatment modality. Due to its distinct physical and biological advantages, which lead to superior dose distribution with a steep dose-fall-off at the distal end of the irradiation field, ion beam therapy benefits particularly from image guidance. Especially, molecular imaging can provide functionally related insights not only for target volume delineation, but also into tumour subpopulations, and enables individualized treatment adaptation, such as dose escalation and de-escalation or a local boost in regions where higher doses are required. This article provides an overview of clinical molecular imaging with positron emission tomography (PET) with particular relevance in ion beam therapy. As in-vivo beam range verification is of particular interest in ion beam therapy and also related to PET, this article covers this topic as well.
Ultrasound is a noninvasive imaging modality that provides anatomical and functional information of various human body areas. It is one of the most widely used imaging modalities worldwide, with frequent use in oncology. Novel ultrasound techniques, such as elastography and contrast-enhanced ultrasound, have evolved and have led to new clinical applications beyond conventional anatomical imaging with conventional ultrasound or blood flow assessment using Doppler ultrasound. Contrast-enhanced ultrasound (CEUS) uses microbubbles as a contrast medium, and specific contrast-enhanced ultrasound techniques have been developed, making CEUS an extremely sensitive imaging modality. Classic microbubbles remain strictly intravascular due to their size and can be detected down to the capillary level. Together with the most recent techniques (super-resolution imaging), bubbles even allow for an extremely high spatial resolution ultrasound imaging beyond the wavelength barrier. This chapter within Recent Results in Cancer Research Under Molecular Imaging in Oncology provides an overview of current applications in humans. Since specific microbubbles are not yet available as commercial products and their wide clinical use is still limited, results of first experiences with molecular ultrasound imaging in humans are presented. Furthermore, to give an overview in a broader sense-not only of molecular ultrasound imaging but also of contrast-enhanced ultrasound for molecular or specific diagnosis-also related studies with nonspecific, commercial ultrasound contrast agents are briefly described within the field of molecular diagnosis and monitoring of targeted therapies in oncology. Furthermore, first experiences in humans with super-resolution ultrasound imaging as a potential breakthrough technique are presented.
Cancer immunotherapy aims to enhance or reactivate immune system function by leveraging both adaptive and innate immunity mechanisms. Key approaches to stimulate tumor-specific immune responses include cytokine therapies, cancer vaccines, and immune checkpoint blockade. The field experienced transformative growth after the 2011 approval of ipilimumab (targeting CTLA-4), paving the way for subsequent inhibitors of PD-1 and PD-L1 pathways that demonstrated unprecedented survival benefits across multiple malignancies. These breakthroughs have catalyzed advancements in adoptive T cell therapies, particularly genetically modified CAR T cell infusions showing promising clinical efficacy, signaling a paradigm shift in oncology treatment approaches. Meanwhile, response assessment has faced new challenges. In fact, immunotherapy response patterns often contrast with conventional chemotherapy, particularly regarding phenomena like pseudoprogression, delayed clinical effects, and extended disease stabilization. To address these unique dynamics, revised response assessment guidelines have been established to enhance therapeutic development and clinical decision-making. This chapter examines the progression of immune-specific evaluation standards, their application in clinical trials, and their practical consequences, concluding with insights into future advancements in response classification systems.
Molecular imaging in oncology sits at the intersection of science, technology, and patient care, offering powerful tools for advancing diagnosis and personalized treatment. Future developments are driven by scientific ambition and clinical need, aiming to improve patient outcomes by translating complex biological insights into practical applications. Key opportunities include improved biomarkers, higher-resolution imaging, and multimodal integration. Chronobiology adds the time dimension, enabling dynamic monitoring of tumor processes, though challenges remain in quantifying kinetics due to technical and procedural constraints. Risks include tool-driven research, where technology dictates clinical questions, rather than vice versa. This calls for needs-based development guided by clear scientific objectives. AI, especially deep learning, promises integration of complex datasets, though ethical and professional responsibility in its use is critical. Barriers include high costs, limited reimbursement, regulatory hurdles, and logistical challenges. Clinical translation is often delayed by insufficient funding and a lack of standardized protocols. Despite these, real-world clinical benefit is increasingly influencing adoption. Interdisciplinary collaboration is essential, supported by translational centers and data-sharing networks. Ultimately, molecular imaging enhances the continuum between anatomical imaging, histology, and molecular profiling. It enables dynamic, noninvasive assessment of cancer biology, supporting adaptive and personalized treatment strategies and reinforcing its role in precision oncology.
Single photon emission computed tomography (SPECT) is the state-of-the-art imaging modality in nuclear medicine despite the fact that only a few new SPECT tracers have become available in the past 20 years. Critical for the future success of SPECT is the design of new and specific tracers for the detection, localization, and staging of a disease and for monitoring therapy. The utility of SPECT imaging to address oncologic questions is dependent on radiotracers that ideally exhibit excellent tissue penetration, high affinity to the tumor-associated target structure, specific uptake and retention in the malignant lesions, and rapid clearance from non-targeted tissues and organs. In general, a target-specific SPECT radiopharmaceutical can be divided into two main parts: a targeting biomolecule (e.g. peptide, antibody fragment) and a γ-radiation emitting radionuclide (e.g. 99mTc, 123I). If radiometals are used as the radiation source, a bifunctional chelator is needed to link the radioisotope to the targeting entity. In a rational SPECT tracer design these single components have to be critically evaluated in order to achieve a balance among the demands for adequate target binding, and a rapid clearance of the radiotracer. The focus of this chapter is to depict recent developments of tumor-targeted SPECT radiotracers for imaging of cancer diseases. Possibilities for optimization of tracer design and potential causes for design failure are discussed and highlighted with selected examples.
Oncologic imaging has been a major focus of clinical research on PET/MR over the last 10 years. Studies so far have shown that PET/MR with 18F-Fluorodeoxyglucose (FDG) overall provides a similar accuracy for tumor staging as FDG PET/CT. The effective radiation dose of whole-body FDG PET/MR is more than 50% lower than for FDG PET/CT, making PET/MR particularly attractive for imaging of children. However, the longer acquisition times and higher costs have so far limited broader clinical use of PET/MR technology for whole-body staging. With the currently available technology, PET/MR appears more promising for locoregional staging of diseases for which MR is the anatomical imaging modality of choice. These include brain tumors, head and neck cancers, gynecologic malignancies, and prostate cancer. For instance, PET imaging with ligands of prostate-specific membrane antigen, combined with multi-parametric MR, appears promising for detection of prostate cancer and differentiation from benign prostate pathologies as well as for detection of local recurrences. The combination of functional parameters from MR, such as apparent diffusion coefficients, and molecular parameters from PET, such as receptor densities or metabolic rates, is feasible in clinical studies, but clinical applications for this multimodal and multi-parametric imaging approach still need to be defined.
Ultrasound imaging plays an important role in oncological imaging for more than five decades now. It can be applied in all tissues that are not occluded by bone or gas-filled regions. The quality of ultrasound images benefitted strongly from improved electronics and increased computational power. To the morphological imaging, several functional imaging methods were added: Flow visualization became possible by Doppler techniques and as a recent addition the elastic properties of tissues can be imaged by elastographic methods with transient shear wave imaging. In the beginning of molecular imaging, ultrasound with its contrast based on mechanical tissue properties was an unlikely candidate to play a role. However, with contrast agents consisting of micrometer-sized gas bubbles, which can be imaged with high sensitivity, ligands addressing targets in the vascular wall could be used. Because even single bubbles can be detected, this led to various ultrasound molecular imaging techniques and the ongoing development of clinical molecular contrast media. In this chapter, the basic properties of ultrasonic imaging like its contrast mechanisms and spatiotemporal resolution are discussed. The image formation and its ongoing change from line-oriented scanning to full-volume reconstructions are explained. Then, the ultrasound contrast media and imaging techniques are introduced and emerging new methods like super-resolution vascular imaging demonstrate the ongoing development in this field.
Noninvasive magnetic resonance imaging (MRI) techniques are increasingly applied in the clinic with a fast-growing body of evidence regarding their value in diagnostic radiology. In contrast to biochemical or histological markers, the key advantages of imaging biomarkers are the noninvasive nature and the spatial and temporal resolution of these approaches. This chapter focuses on clinical applications of novel MR biomarkers in humans with a strong focus on oncologic diseases. These include both clinically established biomarkers (parts 1-4) and novel MRI techniques that recently demonstrated high potential for clinical utility (parts 5-7).
The continuous development of single photon emission computed tomography (SPECT) over the past 50 years has led to improved image quality and increased diagnostic confidence. The most influential developments include the realization of hybrid SPECT/computed tomography (CT) devices, as well as the implementation of attenuation correction and iterative image reconstruction techniques. These developments have led to a preference for SPECT/CT devices over SPECT-only systems and to the widespread adoption of the former, strengthening the role of SPECT/CT as the workhorse of nuclear medicine imaging.New trends in the ongoing development of SPECT/CT are diverse. For example, whole-body SPECT/CT images, consisting of acquisitions from multiple consecutive bed positions in the manner of PET/CT, are increasingly performed. Additionally, in recent years, some interesting approaches in detector technology have found their way into commercial products. For example, some SPECT cameras dedicated to specific organs employ semiconductor detectors made of cadmium telluride or cadmium zinc telluride, which have been shown to increase the obtainable image quality by offering a higher sensitivity and energy resolution.However, the advent of quantitative SPECT/CT which, like PET, can quantify the amount of tracer in terms of Bq/mL or as a standardized uptake value could be regarded as most important development. It is a major innovation that will lead to increased diagnostic accuracy and confidence, especially in longitudinal studies and in the monitoring of treatment response.The current work comprises two main aspects. At first, physical and technical fundamentals of SPECT image formation are described, and necessary prerequisites of quantitative SPECT/CT are reviewed. Additionally, the typically achievable quantitative accuracy based on reports from the literature is given. Finally some examples of clinical applications which benefit from quantitative SPECT/CT are provided.
Targeted therapies are applied to increase the efficiency of antitumor treatment by simultaneously decreasing side effects. This can be achieved using carrier molecules which specifically bind to target structures or areas with remodeling activity. These carrier molecules may be coupled to chemotherapeutic drugs or to radioactive isotopes. In most cases, these carrier molecules are antibodies against tumor antigens, peptides, or small molecules which are binders for overexpressed receptors on tumor cells. The paradigm of endoradiotherapy is exemplified by the peptidic tracer DOTATOC which binds to somatostatin receptors and recently also small molecule inhibitors with high affinity for the prostate-specific membrane antigen.
Contrast-enhanced ultrasound (CEUS) imaging is a valuable tool for preclinical and clinical diagnostics. The most frequently used ultrasound contrast agents are microbubbles. Besides them, novel nano-sized materials are under investigation, which are briefly discussed in this chapter. For molecular CEUS, the ultrasound contrast agents are modified to actively target disease-associated molecular markers with a site-specific ligand. The most common markers for tumor imaging are related to neoangiogenesis, like the vascular endothelial growth factor receptor-2 (VEGFR2) and αvβ3 integrin. In this chapter, applications of molecular ultrasound to longitudinally monitor receptor expression during tumor growth, to detect neovascularization, and to evaluate therapy responses are described. Furthermore, we report on first clinical trials of molecular CEUS with VEGFR2-targeted phospholipid microbubbles showing promising results regarding patient safety and its ability to detect tumors of prostate, breast, and ovary. The chapter closes with an outlook on ultrasound theranostics, where (targeted) ultrasound contrast agents are used to increase the permeability of tumor tissues and to support drug delivery.
In this chapter, we will introduce and review molecular-sensitive imaging techniques, which close the gap between ex vivo and in vivo analysis. In detail, we will introduce spontaneous Raman spectral imaging, coherent anti-Stokes Raman scattering (CARS), stimulated Raman scattering (SRS), second-harmonic generation (SHG) and third-harmonic generation (THG), two-photon excited fluorescence (TPEF), and fluorescence lifetime imaging (FLIM). After reviewing these imaging techniques, we shortly introduce chemometric methods and machine learning techniques, which are needed to use these imaging techniques in diagnostic applications.
