Sarah Verhoeff

9 General introduction and outline of this thesis on clinical anatomical imaging techniques are no longer sufficient. For example, the International Metastatic RCC Database Consortium (IMDC) risk score based on the level of hemoglobin, platelets, calcium, performance score and time from diagnosis to start systemic therapy, predicts survival of patients with metastatic RCC treated with systemic therapy7. This risk assessment is validated for patients treated with vascular endothelial growth factor (VEGF) targeted therapy but does not apply to the newest treatment options including immune checkpoint inhibitors (ICI) targeting programmed cell death 1 or its ligand (PD-1/PD-L1). So far, favorable responses to ICI have been associated with high tumor PD-L1 expression and high T-cell infiltration. Accordingly, the registration of pembrolizumab in e.g., SCCHN and NSCLC has been limited to patients with a high tumor PD-L1 expression as determined by immunohistochemistry8,9. The use of tissue biopsies for molecular diagnostics and evaluation of protein expression such as PD-L1 has been intensified with the introduction of ICI. Despite the advances made in tissue analysis techniques, its use is limited by sampling errors. The previously mentioned intra- and intertumoral heterogeneity and dynamics of the TME could be missed by evaluating only a fraction of the tumor cells10,11. Also, the factor of time needs to be taken into consideration when analyzing an archival biopsy since the target expression may alter during disease12. For molecular purposes, tissue biopsies are still of great value but should be interpreted with caution in heterogeneous tumors. Molecular imaging Molecular imaging can function as a complementary tool to blood and tissue sampling. This technique allows for non-invasive visualization and characterization of tumor lesions, based on biological processes at a molecular and cellular level. Several imaging modalities are available for molecular imaging, including computed tomography (CT), optical imaging (OI), nuclear imaging involving positron emitting tomography (PET) and single photon emission computed tomography (SPECT), ultrasound imaging and magnetic resonance imaging (MRI). Conventional CT and MRI imaging are used for the detection and quantification of tumor size. Both imaging modalities are regularly used in standard patient care and provide accurate anatomical configuration with excellent spatial resolution for tumor imaging. In contrast to MRI, CT is limited in delineating tumor lesions located in bone and soft tissue. These imaging modalities provide details on the anatomical location and lesion size, but not on the underlying tumor biology. This is where nuclear imaging is of additional value. Nuclear imaging Nuclear imaging requires the radiolabeling of a (tumor) targeting agent using a radionuclide that matches the targeting agent’s half-life. Small molecules or peptides with fast pharmacokinetics can be labeled with radionuclides with a short half-life like fluorine-18 (110 minutes). A well-known radiotracer is fluorine-18-fluorodeoxyglucose ([18F]FDG). The uptake of [18F]FDG reflects the increased glucose metabolism in tumors13,14. 1