| 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. |
- Söderman, Tomas
(författare)
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Radiological methods in rheumatoid arthritis and osteoarthritis
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The dissertation's theme is the critical role of radiology when evaluating two different groups of patients. Firstly, patients with rheumatoid arthritis (RA) of the cervical spine were studied to evaluate upper spine instability with dynamic computed tomography (CT). Secondly, after anterior cruciate ligament (ACL) reconstruction, patients with a long-term follow-up were studied to evaluate osteoarthritis (OA). In paper I, 21 consecutive patients with atlantoaxial subluxation due to RA planned for atlantoaxial fusion were included. Radiographs were obtained in neutral and flexed positions, CT and Magnetic Resonance Imaging (MRI) was performed with the neck in the neutral position and CT also in flexion. Radiographs and CT measurements of atlantoaxial subluxation correlated but were larger using radiographs than CT in flexion. The spinal cord compression was significantly worse at CT obtained in flexed position than MRI in the neutral position. In papers II and III, the cohort consisted of 60 patients, and in paper IV, 73 patients. Mean follow-up was 31 years after ACL reconstruction. MRI, radiographs, International Knee Documentation Committee (IKDC) clinical assessment, Knee injury Osteoarthritis Outcome Score (KOOS), Short Form-36 (SF-36), Tegner Activity Scale, and KT-1000 arthrometer were used in order to evaluate the patients. Thirty-three patients showed an intact ACL graft, and 40 a ruptured ACL graft. Forty-nine patients had tibiofemoral OA, and 28 patients had patellofemoral OA. Patients with ruptured ACL grafts had more OA in the medial tibiofemoral compartment than those with an intact ACL graft. Sport and Recreation Function and Quality of life scores were higher in patients with an intact ACL graft than those with a ruptured ACL graft. All subscales of KOOS were higher in the group without OA. KOOS Quality of life score was lower than for a control group of men. The IKDC overall clinical assessment was worse in patients with a ruptured ACL graft. This thesis suggests that radiographs remain the primary imaging method for evaluating atlantoaxial instability. However, CT in flexed position is useful in the preoperative imaging workup. Patients with a ruptured ACL graft presented with more OA of the medial tibiofemoral compartment than those with an intact graft. Patients with an intact ACL graft and those without OA reported higher sports activity and recreation and better knee-related Quality of life. Knee-related Quality of life in the study group was reduced compared to a reference group.
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Vyakaranam, Achyut Ram
(författare)
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Nuclear medicine imaging and treatment in pheochromocytoma, paraganglioma, and role of the new tracer 11C-hydroxy ephedrine in diabetes mellitus
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Carbon-11 hydroxy ephedrine (11C-HED) is a norepinephrine analog which binds to the norepinephrine receptor present in adrenal medulla, lung, liver and pancreas. 11C-HED-positron emission tomography with concomitant computed tomography (PET/CT) can image these organs. Pheochromocytoma (PCC) and Paraganglioma (PGL) are rare, chromaffin cell tumors, which may mimic other diseases and can be difficult to diagnose because of vague and uncharacteristic symptoms. The diagnosis of PCC/PGL is reached either by detection of excessive catecholamines or metanephrines in plasma or urine, or may be detected incidentally on computed tomography (CT)/magnetic resonance imaging (MRI) as an “incidentaloma”. Also, these tumors are most heritable endocrine neoplasms, and can metastasize in up to 20% of patients. Better post-operative surveillance, re-staging on evidence of recurrent disease, biochemical recurrence and therapy monitoring is needed in these patients to improve care. Also, in inoperable cases and metastatic disease of neuroendocrine tumors (NETs), peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising nuclear medicine therapy. Recent studies have shown a connection between sympathetic nervous system and diabetes mellitus both type 1(T1D) and type 2(T2D), which are a global health burden. However, underlying pathophysiology of both types are not well understood. The aims of this thesis was, in Paper I to establish the role of 11C-HED PET/CT in complex clinical scenarios to diagnose or rule out primary tumors of PCC/PGL (n=102). In Paper II, to determine the outcome of treatment with 177Lu-DOTATATE in PCC/PGL (n=22), in Paper III to assess the additional clinical benefit of 11C-HED PET/CT in in patients with metastatic PCC/PGL in comparison to morphological imaging, CT/MRI and other available imaging (n=74), in Paper IV to establish 11C-HED PET/CT for non-invasive imaging of the pancreatic sympathetic innervation in individuals with T2D (n=25) and non-diabetics (n=64).We demonstrate that 11C-HED PET/CT is a valuable diagnostic tool to diagnose or rule out pheochromocytoma and paraganglioma. Also, it is excellent in surveilling metastatic disease post-surgery, monitoring therapy with parameters such as standardized uptake value (SUV) and total catecholamine transporter tumor volume (TCTTV) and provides additional benefit in complex clinical scenarios. Upon treatment with 177Lu-DOTATATE patients with PCC/PGL had a favorable outcome with low toxicity. There was focal accumulation of 11C-HED in the sympathetic innervation of the pancreas and CT helped in delineation and further segmentation. In conclusion, we showed the role of new radiotracer 11C-HED and theragnostic option, PRRT with 177Lu-DOTATATE successfully better nuclear medicine diagnosis and therapy in pheochromocytoma, paraganglioma and diabetes mellitus.
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