| 1. |
- Silins, Isabella, 1983-
(författare)
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Improved adrenocortical PET imaging
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Adrenal tumours can either be benign or malignant, hormone secreting or not, and they can be discovered through clinical examination of the patient or by pure chance. Increased knowledge in the area, plus the widespread use of imaging techniques, have resulted in a rising number of patients with adrenal tumours that subsequently need to be diagnosed. Improved imaging is needed for primary aldosteronism (PA) and adrenocortical carcinoma (ACC) but the positron emission tomography (PET) tracer currently in use, [11C]metomidate (MTO), has many important limitations. This thesis aims to improve adrenocortical PET imaging.Methods: Paper 1 investigated the pre-clinical properties of Para-Chloro-2-[18F]fluoroethyl-etomidate (CETO), by autoradiography, binding studies, ex vivo biodistribution on rats and in vivo imaging using mice and one non-human primate (NHP). Paper II investigated the clinical properties of [18F]CETO and included patients with various kinds of adrenocortical tumours, and healthy volunteers. Metabolic and kinetic analyses were performed and three out of five healthy volunteers also underwent [15O]water PET/CT to measure adrenal blood flow. Test-retest was performed on all healthy volunteers. Paper III assessed the in vivo and in-human radiation dosimetry of [18F]CETO. Ex vivo uptake data from rats and in vivo PET/CT from NHP and humans were used to calculate residence times. Paper IV evaluated the use of the block-sequential regularized expectation maximization (BSREM) reconstruction algorithm (Q.Clear, GE Healthcare, Milwaukee, USA) for [11C]MTO PET/CT in patients with PA.Results: Papers I and II demonstrated that [18F]CETO is highly specific to the adrenal cortex both in vitro and in vivo. The non-specific binding of [18F]CETO in the liver was significantly lower than that of [11C]MTO. [18F]CETO metabolizes rapidly and the single tissue irreversible (1T1k) kinetic model provided the best fit. [15O]water PET/CT results indicated that the adrenal [18F]CETO uptake was flow limited. Several retest values, including adrenal blood flow, were lower than the test values. Paper III found that the effective dose based on human data was 18.2 μSv/MBq and that the adrenal glands were the limiting organ regardless of species used. Paper IV showed that the BSREM reconstruction algorithm improves image quality, without compromising SUVmax quantification, and a β-value between 70 and 130 was found optimal.Conclusion: [18F]CETO PET/CT is a promising method for adrenocortical imaging and is safe for clinical imaging in terms of radiation dose. [18F]CETO PET/CT should be further investigated in patients with PA or ACC, preferably in conjunction with BSREM reconstruction.
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| 2. |
- Lindström, Elin
(författare)
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Evaluation of Regularized Image Reconstruction for Clinical Positron Emission Tomography
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Positron emission tomography (PET) combined with computed tomography (CT) is a widely used noninvasive molecular imaging modality with a broad range of clinical applications in oncology, neurology, and cardiology. Producing imperative image quality and accurate quantification are important driving forces behind the technological advances within PET image reconstruction and system development. To ensure clinical quality and to understand how the modern state-of-the-art PET/CT systems and image reconstruction methods compare with older systems and reconstruction methods they need to be evaluated and assessed in a clinical setting. This thesis summarizes six studies assessing the effect of state-of-the-art image reconstruction methods and the introduction of digital PET on image quality and quantitative outcomes of clinical PET scans in oncology, neurology, and cardiology. The overall aim was to evaluate, optimize, and compare quantitative results of regularized image reconstruction with the current standard reconstruction method used in routine clinical practice, ordered subsets expectation maximization (OSEM).The optimal setting of regularized image reconstruction by block-sequential regularized expectation maximization (BSREM) was found to be tracer dependent, and a potential clinical benefit in terms of image quality measures of BSREM over OSEM was found when applied for whole-body 18F-FDG, 68Ga-DOTATOC, 18F-fluorde, 11C-acetate, and 68Ga-PSMA-11 PET imaging. Software-aided assessment of neurodegenerative disease evaluated with 18F-FDG and 18F-flutemetamol was affected by image reconstruction methods and should be used with caution when employing other image reconstruction methods than those used for acquisition of the normal database. In contrast, changes in reconstruction settings were shown to not implicate myocardial blood flow (MBF) based on 15O-water PET analyzed using automated software. This shows that diagnostic MBF cutoff values can be consistently used for 15O-water. Also, large variations in image noise with three different image reconstruction methods did not impact quantitative cerebral blood flow (CBF) in white and gray matter volumes of interest with 15O-water brain PET to any large extent.BSREM image reconstruction shows a great potential clinical benefit providing improved image quality measures with a subsequent possibility of shortening image acquisition durations and/or lowering amount of radioactivity needed for each examination.
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| 3. |
- Jahn, Ulrika
(författare)
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Peptide Receptor Radionuclide Therapy in Neuroendocrine Neoplasms : Aspects of tumour characteristics, receptor recycling and peptide mass
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroendocrine neoplasm (NEN) can arise in any part of the body, but most commonly in the lungs, bronchi, and the gastrointestinal tract including the pancreas. They combine neuroendocrine and tissue-of-origin-specific characteristics; explaining different symptoms depending on the organ of origin. NEN is divided into slow-growing neuroendocrine tumours (NETs) and the rarer aggressive neuroendocrine cancers (NECs). Some hormone producing NETs give rise to symptoms (functioning), generally detected earlier than the non-functioning NETs, which often are larger and metastatic at diagnosis. NETs commonly express an abundance of somatostatin receptors (SSTR). Synthetic copies of somatostatin (somatostatin analogues, SSA), supress hormonal symptoms such as diarrhoea and flush. The SSA-SSTR ligand-receptor complex interaction instantly internalises into the cells, separate, and the SSTR re-surface. Gallium-68 (68Ga)-labelled SSAs are used for PET/CT-camera visualisation of NETs, and SSA labelled with a therapeutic radionuclide, provide a means for internal radio-therapy, peptide receptor radionuclide therapy (PRRT).The aim of the thesis was to compare the tumour response to PRRT in small intestinal NET (SI-NET) and pancreatic NET (P-NET). Study I, II and IV are retrospective and include patients who underwent PRRT with 177Lu-DOTA-TATE at the Uppsala University Hospital. Study I, quantified and related the radiation dose in 25 SI-NETs to tumour shrinkage using two- and three-dimensional measurements, although no dose-response relationship was demonstrated. A relationship between tumour shrinkage and the total administered activity was however found. Study II compared the tumour response between SI-NETs from study I with P-NETs included in an earlier report, now re-evaluated by adding more tumour parameters, and with longer observation time. There radiation dose in P-NETs was the same as in SI-NETs. The radiation dose in P-NETs was highest at the first PRRT cycles, and then decreased significantly in consecutive cycles, which was not observed in SI-NETs.The prospective study III, mapped the recirculation time of SSTR in SI-NETs and normal organs. Twelve tumours were measured at repeated 68Ga-DOTA-SSA-PET examinations. Larger tumours (>4 cm) showed a faster SSTR turn-over rate than small tumours, demonstrating a turnover resembling that in the normal organs. These results open the possibility that pre-treatment could protect normal tissues during PRRT, and probably increase radioactivity tumour uptake and hence, the radiation dose.The retrospective study IV investigated the effects of various amounts of SSA delivered in the PRRT preparation, although the absorbed radiation dose to tumours and normal tissues, was unrelated to the amount of peptide and to the patient’s total tumour burden.
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| 4. |
- Pettersson, Olof
(författare)
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Monitoring of neuroendocrine tumor patients undergoing systemic therapies
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Monitoring of neuroendocrine tumor (NET) patients undergoing systemic therapies is troublesome as biomarkers capable of detecting tumor responses have been difficult to establish. Changes in the sum of target lesion diameters are used to evaluate the effects of therapy according to the response evaluation criteria in solid tumors (RECIST 1.1). However, as NETs tend to stabilize or increase in size when responding to therapies, monitoring based on changes in tumor diameters is often ineffective.The overall aim of these doctoral studies was to investigate novel methods for therapy monitoring in NET patients undergoing systemic therapies.In patients with pancreatic NETs (PanNETs) who underwent Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE at Uppsala University Hospital (n=151), we investigated if arterial-phase tumor attenuation and contrast-enhancement in the liver metastases on computed tomography (CT) changed during PRRT (Paper I).Tumor growth rate (TGR) allows for quantitative assessment of tumor dynamics expressed as percentage per month. In the same cohort as described above, TGR was calculated before and during/after PRRT (Paper II).While 68Ga-DOTA-somatotstatin analog (SSA) PET/CT is essential in the evaluation of NET patient eligibility for PRRT, temporal changes in the tumor uptake of 68Ga-DOTA-SSA have not been shown to reflect PRRT outcome. Tumor-to-blood (TBR) ratio may be closer correlated than SUV to the net influx rate (Ki). The institutional database of the University Hospital in Essen was screened for NET patients, who had undergone at least two cycles of PRRT and 68Ga-DOTA-SSA PET/CT. TBR and tumor-spleen ratio (TSR) were calculated in up to nine lesions per patient (Paper III).Data on imaging were investigated for possible associations with outcome parameters such as progression-free survival and overall survival (Papers I-III).46 PanNET patients with data on Ki-67 from at least two biopsies (Botling et al. 2019) at Uppsala University Hospital were screened for inclusion to describe TGR in PanNET patients. TGR was calculated to elucidate if changes in tumor grade may be reflected in changes in TGR. (Paper IV).In summary, the thesis investigates tools based on morphologic and functional imaging for monitoring of NET patients undergoing systemic therapies.
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