This thesis aims to enhance the diagnosis of infective endocarditis: a challenging disease involving the heart’s inner lining or implanted materials like artificial valves or cardiac implanted electronic devices (CIEDs). The research primarily focuses on the role of [18F]FDG PET/CT, exploring its current clinical use, particularly after the 2015 ESC guidelines integrated it as a major criterion for suspected prosthetic valve endocarditis.
An overview of infective endocarditis, its history, diagnosis, and treatment challenges introduces the thesis. Subsequent chapters examine the indications for of [18F]FDG PET/CT for suspected infective endocarditis and the need for standardisation of this technique; the benefits of motion corrected FDG PET/CT for improved image quality, and the significance of mediastinal lymph node activity – which was unfortunately unreliable as an indicator for endocarditis.
The thesis also includes a systematic review and meta-analysis on [18F]FDG PET/CT for infections involving Left Ventricular Assist Devices (LVADs), highlighting its high sensitivity and specificity for these infection. They include a proposal for standardizing diagnostic criteria for LVAD infections.
The effectiveness of [18F]FDG PET/CT’s was also evaluated in a two-centre cohort study, emphasizing the complementary role of semi-quantitative analysis next to visual analysis in accurately identifying LVAD infections.
Finally, it presents a proof-of-concept on using machine learning to enhance the modified Duke criteria’s predictive power for endocarditis. These models showed promising results, though they would require careful further validation before clinical implementation could be considered.

Whole-body PET imaging in metastatic breast cancer with a focus on hormone receptors

Breast cancer is the most common type of cancer diagnosed in women. Some of these women will develop distant metastases. The clinical course of the disease depends on the expression of hormone receptors. Whole-body PET imaging can be of added value. The estrogen receptor is expressed by the large majority of breast cancers, and can be visualized by means of [18F]-FES-PET. This scan can help to solve clinical dilemmas that may remain after standard workup, such as determining the extent of metastatic disease, unclear estrogen receptor status of the tumor, and inability to determine which primary tumor caused the metastases. In addition, we conclude that fasting, which is less patient-friendly, is not necessary to improve the quality of the [18F]-FES-PET scan. We have also constructed a flowchart for assessment of the estrogen receptor status of liver metastases with [18F]-FES-PET/CT.

The [18F]-FES-PET scan can also be combined with [18F]-FDG-PET to determine estrogen receptor heterogeneity. The tumor estrogen receptor heterogeneity percentage may potentially identify the patients who benefit from the treatment with aromatase inhibitor letrozole and the CDK 4/6 inhibitor palbociclib. [18F]-FDG-PET is also a useful tool to detect metastases, including invasive lobular carcinomas.

Like the estrogen receptor, the androgen receptor is another potential endocrine target in breast cancer. This receptor could be visualized by [18F]-FDHT-PET and changes in [18F]-FDHT uptake during androgen receptor antagonist bicalutamide treatment can be detected.

Infectious and inflammatory diseases are amongst the most common reasons for patients to visit the hospital, often presenting with symptoms such as fever and general malaise. In most cases, physicians can establish the correct diagnosis by recognizing guiding symptoms or conventional diagnostics. Some patients, however, may not exhibit any guiding symptoms, or may be suspected of multiple potential sources of infection. Especially in patients with bacteremia of unknown origin, it is of vital importance to identify the infection focus as soon as possible, as this allows targeted treatment and reduces morbidity and mortality. 18F-FDG-PET/CT is a nuclear imaging technique that allows visualization of glucose uptake throughout the entire body. As most inflammatory diseases and infection foci exhibit increased glucose uptake, it is a very promising technique in patients who are suspected of such a disease. The research in this thesis was aimed at exploring the added value of FDG-PET/CT in these patients. In patients with bacteremia of unknown origin, FDG-PET/CT can correctly identify the infection focus in approximately two thirds of patients. And in children with fever of unknown origin, the correct diagnosis can be established in approximately half of all patients based on FDG-PET/CT. Several factors that may affect the diagnostic sensitivity of FDG-PET/CT were analyzed as well, such as the use of antibiotics or immunosuppressants before the procedure, serum glucose level, infection parameters, and detected pathogens. Bottlenecks of FDG-PET/CT and promising new technologies are discussed as well.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by dryness of the mouth and eyes. Besides the involvement of exocrine glands, multiple sites and organ systems can be affected. As pSS patients can present with a wide range of signs, diagnosing pSS can be complicated. The general aim of this thesis was to improve diagnosis and classification of the systemic autoimmune disease pSS by focusing on one of the main target organs: the salivary glands. The studies described in this thesis focused on salivary gland histopathology and salivary gland imaging. We showed that the addition of three histopathological features to the workup of salivary gland biopsies increased the diagnostic accuracy of the biopsy and also increased the specificity of the classification criteria. The three histopathological features are: presence of intraepithelial B-lymphocytes in striated ducts, a relative increase in IgG plasmacells, presence of germinal centers. Furthermore, we showed that ultrasonography of the parotid gland and histopathology of the parotid gland assess different (or at best partly related) constructs. Therefore, we concluded that ultrasonography cannot directly replace the salivary gland biopsy in the diagnostic work-up of pSS. Salivary gland imaging by using the nuclear medicine technique FDG-PET/CT currently has no place in the work-up of pSS, as it was not able to differentiate between salivary glands from pSS patients and salivary glands of two control groups. However, we showed that FDG-PET/CT imaging was useful to detect pSS-associated lymphomas and to detect systemic disease activity outside the salivary glands.

DFIs and VGEIs represent two difficult scenarios from a diagnostic point of view and the prompt identification of the infection benefit from a multidisciplinary and multimodal approach in which NM plays a crucial role.
As far as DFIs is concerned, a plethora of radiological and NM modalities are available and can be used and combined for the diagnosis, but at the moment no definite diagnostic flowchart exists (Chapter 2). In Chapter 3, MRI, 99mTc-HMPAO WBC scintigraphy and [18F]FDG PET/CT showed a comparable sensitivity in detecting pedal OM. In Chapter 4, we compared MRI, 99mTc-HMPAO WBC scintigraphy and [18F]FDG PET/CT in detecting OM, STIs and Charcot in a large population of diabetic patients.
VGEI is another condition in which standardized diagnostic algorithms and a unanimous consensus on the most appropriate imaging modality are still needed. CTA, WBC scintigraphy and [18F]FDG PET/CT play a complementary role being CTA always the first-choice imaging modality (Chapter 5).
From our retrospective comparative study on CTA, radiolabelled WBCs and [18F]FDG PET/CT (Chapters 6), the addition of a NM examination resulted in a better patient’s management in our population. Recently published EANM guidelines (Chapter 7) fully assessed the role of different imaging modalities in the diagnostic setting of VGEI according to time elapsed from surgery. WBC scintigraphy can be performed at any time from surgery, given its high accuracy in discriminating post-surgical inflammation from an infection. [18F]FDG PET/CT should be performed at least 4 months after surgery, given the possibility of false positive findings due to sterile inflammation.