The aim of this thesis was to investigate the role of imaging in the management of PTLD, with focus on [18F]FDG PET/CT. Additionally, we set out to explore new diagnostic methods with potential for clinical translation. In Part I (chapters 2-7), we reviewed the published literature on the role of different imaging modalities in PTLD and evaluated the diagnostic performance of [18F]FDG PET/CT for PTLD lesion detection in adults and children. Furthermore, we explored the role of [18F]FDG PET/CT semiquantification in PTLD for lesion classification and prognostication. In Part II (chapters 8-10) we proceeded to explore new avenues of research including: radiomics, identification of radiotracers adjunct to [18F]FDG and cfDNA analysis.

This thesis explores the role of Positron Emission Tomography (PET) in infections associated with immune dysfunction. PET is a medical imaging technique that images biological processes in the body. Whole body PET provides 3-dimensional images which allows it to display infections from various regions and deep within the body cavity. The thesis examined three infections: Human immunodeficiency virus (HIV), tuberculosis (TB) and invasive fungal infections (IFIs). All three infections require treatment over long periods of time and usually require monitoring of the efficacy of the treatment or the side effects of some drugs.
In HIV, PET can evaluate and follow-up infections and malignancies associated with HIV. The metabolic uptake in the lymph nodes reflects viral replication and allows staging of HIV.
In TB and IFIs, PET provides detection of early sites of infection and all sites of disease in the body in a single examination, and allows monitoring of treatment of these infections. Monitoring of infections is useful in complex IFIs and TB, where traditional methods of monitoring are often suboptimal.
PET was found to have a predictive value in both TB and IFIs, which can help clinicians consider different treatment options early in the course of infection.
PET imaging is done with different tracers which allow evaluation of different biochemical processes in the body. In the thesis, the advantages of imaging TB with different tracers and the potential role of imaging hypoxia in TB were explored.

Nuclear medicine techniques for imaging inflammation have had huge progress and have enormously expanded over the past 20 years. In this monography we have focused mainly on the contribution and the role of molecular nuclear medicine to detect early phases of chronic inflammation by the use of radiolabeled peptides and monoclonal antibodies (mAbs). Even though there is not one single ideal radiopharmaceutical for imaging all chronic inflammatory diseases, a combination of a few of them could be used for the complete understanding of the histopathology and, therefore, to identify a specific and tailored cure. Moreover those novel tools can detect cell bound and the presence of cytokines in inflammatory sites in patients suspected on an inflammatory condition based on laboratory tests. It can also demonstrate active inflammation in patients without systemic inflammatory response and can predict response to treatment. Today clinicians have the possibility to choose between different options according to the purpose and clinical requirements, from radiolabeled cytokines and monoclonal antibodies to radiolabeled somatostatin receptors for diagnostic purposes and for treatment decisions.

Infective endocarditis is a life-threatening disease that needs an aggressive diagnostic workup and therapeutic management. Current practice is not yet optimised, leaving room for improvement in the care for patients with (suspected) endocarditis. Due to the complexity of this disease, a high level of expertise from the involved medical specialties and a multidisciplinary approach are needed. We have set up a multidisciplinary research team: “IDENTICAL”, acronym for “Improving Diagnosis of Endocarditis and its Therapy with a focus on prosthetIC material”. In this thesis “Endocarditis, improving the chain of care”, we demonstrated that the diagnostic workup for endocarditis could be improved by using non-invasive imaging techniques (FDG-PET/CT, CTA, leukocyte scintigraphy) in addition to echocardiography. Furthermore, identification of pathogens could be achieved more frequently by sonication of heart valves that were surgically explanted during the active phase. There is also room for therapeutic improvement. Dosing antimicrobial agents, such as gentamicin according to a pharmacokinetic model adjusted to the increased volume distribution in patients admitted to the intensive care-unit, led to optimized serum levels in patients with endocarditis. Furthermore, surgical correction with stentless bioprostheses was a valuable option for a more standardized treatment of severe aortic valve endocarditis complicated by extensive abscess formation. Important changes in the daily care of patients were accomplished based on the research described in this thesis: it led to updates of the hospital protocol for endocarditis. Ultimately, regular multidisciplinary Endocarditis Team meetings are needed to reach a final diagnosis and define the most accurate therapy for each patient.

The expression of estrogen receptors (ER), determined in biopsies via immunohistochemistry, is a well-established predictive and prognostic biomarker in breast cancer. Biopsies of metastases are however not always feasible in a patient, as the lesion may be unsafe to biopsy. If one lesion is biopsied, heterogeneity of tumor characteristics amongst lesions throughout the body is still unknown. In vivo imaging of hormone receptors has the potential to guide clinical decision making. The UMCG has extensive experience in PET imaging of ER with the tracer 18F-fluoroestradiol (FES).
In this thesis recommendations on the use and interpretation of FES-PET scans for breast cancer patients are described. For instance we show how previous radiation therapy affects FES PET results. And in a clinical pilot study we show that the FES-PET can identify metastases that are less likely to respond to the combination of letrozole plus palbociclib.
The search for new biomarkers and drug targets continues, and as such the androgen receptor (AR) is of interest. The role of this receptor in breast cancer is reviewed in this thesis. We show that the AR on metastases can be visualized throughout the body by 18F-fluorodihydrotestosterone (FDHT) PET in breast cancer patients and the effect of an AR-blocker can also be visualized.
Prior to further implementation of these novel imaging techniques in routine clinical practice, additional steps are needed. We summarize the route of PET tracers from pre-clinical to first-in-human molecular imaging studies, and the potential steps to implement more PET tracers into clinical practice.