| 1. |
- Lilja, Johan, 1977-
(författare)
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[18F]Flutemetamol PET image processing, visualization and quantification targeting clinical routine
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is the leading cause of dementia and is alone responsible for 60-70% of all cases of dementia. Though sharing clinical symptoms with other types of dementia, the hallmarks of AD are the abundance of extracellular depositions of β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles of hyper phosphorylated tau proteins and synaptic depletion. The onset of the physiological hallmarks may precede clinical symptoms with a decade or more, and once clinical symptoms occur it may be difficult to separate AD from other types of dementia based on clinical symptoms alone. Since the introduction of radiolabeled Aβ tracer substances for positron emission tomography (PET) imaging it is possible to image the Aβ depositions in-vivo, strengthening the confidence in the diagnosis. Because the accumulation of Aβ may occur years before the first clinical symptoms are shown and even reach a plateau, Aβ PET imaging may not be feasible for disease progress monitoring. However, a negative scan may be used to rule out AD as the underlying cause to the clinical symptoms. It may also be used as a predictor to evaluate the risk of developing AD in patients with mild cognitive impairment (MCI) as well as monitoring potential effects of anti-amyloid drugs.Though currently validated for dichotomous visual assessment only, there is evidence to suggest that quantification of Aβ PET images may reduce inter-reader variability and aid in the monitoring of treatment effects from anti-amyloid drugs.The aim of this thesis was to refine existing methods and develop new ones for processing, quantification and visualization of Aβ PET images to aid in the diagnosis and monitoring of potential treatment of AD in clinical routine. Specifically, the focus for this thesis has been to find a way to fully automatically quantify and visualize a patient’s Aβ PET image in such way that it is presented in a uniform way and show how it relates to what is considered normal. To achieve the aim of the thesis registration algorithms, providing the means to register a patient’s Aβ PET image to a common stereotactic space avoiding the bias of different uptake patterns for Aβ- and Aβ+ images, a suitable region atlas and a 3-dimensional stereotactic surface projections (3D SSP) method, capable of projecting cortical activity onto the surface of a 3D model of the brain without sampling white matter, were developed and evaluated.The material for development and testing comprised 724 individual amyloid PET brain images from six distinct cohorts, ranging from healthy volunteers to definite AD. The new methods could be implemented in a fully automated workflow and were found to be highly accurate, when tested by comparisons to Standards of Truth, such as defining regional uptake from PET images co-registered to magnetic resonance images, post-mortem histopathology and the visual consensus diagnosis of imaging experts.
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| 2. |
- Aarnio, Mikko
(författare)
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Visualization of Peripheral Pain Generating Processes and Inflammation in Musculoskeletal Tissue using [11C]-D-deprenyl PET
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An objective visualization and quantification of pain-generating processes in the periphery would alter pain diagnosis and represent an important paradigm shift in pain research. Positron emission tomography (PET) radioligand [11C]-D-deprenyl has shown an elevated uptake in painful inflammatory arthritis and whiplash-associated disorder. However, D-Deprenyl’s molecular binding target and uptake mechanism in inflammation and musculoskeletal injuries are still unknown. The present thesis aimed to gain insight into the mechanisms of D-deprenyl binding and uptake and to verify whether pain-associated sites and inflammation in acute musculoskeletal injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET-computed tomography (PET/CT).To identify the D-deprenyl binding target, a high-throughput analysis and competitive radioligand binding studies were performed. D-deprenyl inhibited monoamine oxidase A (MAO-A) activity by 55%, MAO-B activity by 99% and angiotensin-converting enzyme (ACE) by 70%, which identified these enzymes as higher-affinity targets. Furthermore, radioligand receptor binding assays pointed favorably towards the concept of MAO-B as the primary target. To investigate the biochemical characteristics of the binding site, we used radioligand binding assays to assess differences in the binding profile in inflamed human synovial membranes exhibiting varying levels of inflammation. D-deprenyl bound to a single, saturable population of membrane-bound protein in synovial membrane homogenates and the level of inflammation correlated with an increase in D-deprenyl binding affinity.To verify whether D-deprenyl can visualize pain-generating processes, patients with musculoskeletal injuries were investigated and followed-up with [11C]-D-deprenyl PET/CT. In the study of eight patients with ankle sprain, the molecular aspects of inflammation and tissue injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. The pain coexisted with increased [11C]-D-deprenyl uptake. In the study of 16 whiplash patients, an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self-rated disability.To further evaluate D-Deprenyl’s usefulness as a marker of inflammation, three PET tracers were compared in an animal PET/CT study. Preliminary findings showed that [11C]-D-deprenyl had an almost identical uptake pattern when compared with [11C]-L-deprenyl. The two deprenyl enantiomers showed no signs of specific binding or trapping and therefore may not be useful to study further in models of inflammatory pain, surgical pain, or both.This thesis demonstrates that D-deprenyl visualizes painful inflammation in musculoskeletal injuries and that the probable underlying mechanism of [11C]-D-deprenyl uptake is binding to MAO.
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| 3. |
- 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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| 4. |
- Regula, Naresh Kumar, 1985-
(författare)
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PET in Prostate Cancer – Detection, Tumour Biology and Prognosis
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer (PCa) is the most common non-cutaneous malignancy in men and the leading cause of cancer-related deaths in Sweden. Despite the major advances, the current diagnostic modalities fall short of standards, specifically, precise localization required for effective management of the PCa. positron emission tomography (PET) combined with computed tomography (CT) has evolved as a promising diagnostic imaging technique for PCa. The progression of the PCa is often associated with metabolic alterations and overexpression of several proteins. Increased de novo fatty acid synthesis and prostate-specific membrane antigen (PSMA) overexpression are some of the distinctive features linked with PCa growth and the potential targets for the development of PET radiotracers. This thesis is based on four original articles and focuses on the utilization of some of several different PET tracers available to visualize PCa spread. The work can be divided into two distinctive parts: (1) evaluate the prognostic value of 11C-acetate PET/CT towards survival in the setting of biochemical relapse after surgery, investigate tumour biology using single-tissue compartment model derived parametric images of 11C-acetate dynamic PET/CT both at patient and cell level and (2) the comparison of 68Ga-PSMA-11 PET/CT with 11C-acetate PET/CT and 18F-NaF PET/CT in patients with PCa relapse depicting different aspects of PCa biology.We demonstrated that quantification of 11C-acetate accumulation in PCa lesions was a strong predictor of survival in patients with biochemical relapse. Furthermore, parametric images of 11C-acetate dynamic PET/CT enabled visualization of tumour biology exhibiting elevated extraction of 11C-acetate associated with cancer aggressiveness also confirmed in in-vitro studies. 68Ga-PSMA-11 PET/CT located more widespread disease and performed significantly better in locating lymph node and bone metastases compared to 11C-acetate PET/CT. Similarly, 68Ga-PSMA-11 PET/CT was able to detect most of the bone lesions detected with 18F-NaF PET/CT along with additional soft tissue lesions.In conclusion, we showed the role of 11C-acetate PET/CT in PCa prognosis with additional understanding of tumour biology. Further, we successfully showed better performance of 68Ga-PSMA-11 PET/CT in locating PCa relapse and established it as a promising option for PCa re-staging.
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| 5. |
- Sun, Aijun, 1973-
(författare)
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Radiolabeled acetate PET in oncology imaging : studies on head and neck cancer, prostate cancer and normal distribution
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The use of positron emission tomography (PET) for imaging in oncology has grown rapidly in recent years. 2-[18F]-fluorodeoxyglucose (FDG) is the most common tracer of PET, although drawbacks exist. Radiolabeled 1-[11C]-acetate (C-AC) is a simple probe for evaluation of perfusion, anabolism (lipogenesis) and catabolism (oxidative metabolism) in all living tissues. This study explored the potential of AC PET in head and neck cancer, benign and malignant lymph nodes in prostate cancer and normal distribution. In head and neck cancer, C-AC PET detected more primaries and lymph node metastases than FDG PET. The mean primary tumor volumes delineated by C-AC was 51% larger than that of FDG before radiotherapy (RT). Both FDG and C-AC PET tumor volumes must be carefully validated before used in clinical routine. Baseline tumor clearance rate (kmono) was higher in complete responders (CR) than that in partial responders (PR). kmono tended to correlate inversely with FDG SUV at baseline. Radiosensitive tumors might rely predominantly on oxidative metabolism for their biogenetic needs. kmono increased in PR during RT. The potential reversibility of impaired kmono in radioresistant tumors imply that treatment targeting the intermediary metabolism might improve the outcome. Tumor relative perfusion index (rF) and kmono were coupled in CR throughout the RT, but not in PR. Dynamic C-AC PET provides a new non-invasive method to simultaneously evaluate the tumor oxidative metabolism and perfusion which link the RT response in patients by a single tracer injection. In prostate cancer, elevated C-AC accumulation is common in benign inguinal lymph nodes, probably due to increased lipogenesis rather than lymphatic drainage. CT Hounsfield unit of benign nodes was lower than that of metastases, suggesting that density measurement using CT might improve the specificity of nodal staging of prostate cancer. A novel tracer 2-[18F]-fluoroacetate (F-AC) was synthesized and used for dynamic PET-CT imaging in animals. Compared with C-AC PET-CT, F-AC showed prolonged blood retention, no detectable trapping in myocardium and salivary glands, rapid excretion from liver to bile and urine and de-fluorination resulting in intensive skeletal activity. F-AC does not mimic the normal physiologic path of C-AC and appears to be of little use for assessment of perfusion, intermediary metabolism or lipogenesis.
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| 6. |
- Heurling, Kerstin, 1982-
(författare)
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Characterization of [18F]flutemetamol binding properties : A β-amyloid PET imaging ligand
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The criteria for diagnosing Alzheimer’s disease (AD) have recently been revised to include the use of biomarkers for the in vivo presence of β-amyloid, one of the neuropathological hallmarks of AD. Examples of such biomarkers are positron emission tomography (PET) β-amyloid specific ligands, including [18F]flutemetamol. The aim of this thesis was to characterize the binding properties of [18F]flutemetamol from a tracer kinetic perspective as well as by validating binding measures through comparison with tissue pathology assessments. The applicability of previously developed kinetic models of tracer binding for voxel-based analysis was examined and compared to arterial input compartment modelling, the “gold standard” for PET quantification. Several voxel-based methods were found to exhibit high correlations with compartment modelling, including the semi-quantitative standardized uptake value ratio (SUVR). The kinetic components of [18F]flutemetamol uptake were also investigated without model assumptions using the data driven method spectral analysis, with binding to β-amyloid shown to relate to a slow kinetic component. The same component was also found to predominate in the uptake of white matter, known to be free of β-amyloid accumulation. White matter uptake was however possible to separate from β-amyloid binding based on the relative contribution of the slow component to the total volume of distribution. Uptake of [18F]flutemetamol as quantified using SUVR or assessed visually was found to correlate well with tissue pathology assessments. Classifying the brains of 68 deceased subjects who had undergone [18F]flutemetamol PET scanning ante mortem, based on the spatial distribution of β-amyloid according to pre-defined phases, revealed that abnormal uptake patterns of [18F]flutemetamol were only certain to be found in the last phase of β-amyloid accumulation. In the same cohort however, [18F]flutemetamol was also shown to accurately distinguish between subjects with AD and non-AD dementia. While this supports the use of [18F]flutemetamol in clinical settings for ruling out AD, the association of abnormal [18F]flutemetamol uptake to late phases of β-amyloid accumulation may limit the detection of early accumulation and pre-clinical stages of AD. It remains to be investigated whether application of voxel-based methods and slow component filtering may increase sensitivity, particularly in the context of clinical trials.
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| 7. |
- Jonasson, My
(författare)
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Towards Clinical Implementation of Dynamic Positron Emission Tomography in Neurodegenerative Diseases
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders worldwide. Positron emission tomography (PET), together with suitable biomarkers, can aid in the clin-ical evaluation as well as in research investigations of these diseases. Straightforward and quantitative assessments of the parameters of inter-est estimated on a voxel-level, as parametric images, are possible when PET data is acquired over time. Prerequisites to facilitate clinical use of dynamic PET are simplified analysis methods and scan protocols suita-ble for clinical routine.The aim of this thesis was to validate simplified analysis methods, suitable for clinical use, for quantification of dopamine transporter (DAT) availability in patients with parkinsonism using [11C]PE2I PET and tau accumulation in AD patients with [18F]THK5317 PET.The included subjects comprised of both healthy controls and pa-tients with parkinsonism, AD or mild cognitive impairment and each subject underwent a dynamic PET scan with either [11C]PE2I or [18F]THK5317. Models for quantitative voxel-based analysis, resulting in parametric images of tracer binding and overall brain function, were validated in both patients and controls. These parametric methods were compared to region-based values acquired using both plasma- and refer-ence-input models. Clinically feasible scan durations were evaluated for both [11C]PE2I and [18F]THK5317, and a clustering method to obtain a reference time activity curve directly from the dynamic PET data was validated. Furthermore, images of DAT availability and overall brain functional activity, generated from one single dynamic [11C]PE2I PET scan, were compared to a dual-scan approach using [123I]FP-CIT single photon emission computed tomography (SPECT) and [18F]FDG PET, for differential diagnosis of patient with parkinsonism.Study I-III supply valuable information on the feasibility of dynamic [11C]PE2I in a clinical setting for differential diagnosis of parkinsonian disorders, by having easily accessible images of DAT availability and overall brain functional activity. The work in study IV-V showed that reference methods can be used for quantification of tau accumulation, and suggests that simplified analysis methods and shorter scan durations can be applied to further facilitate applications of dynamic [18F]THK5317 PET.
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| 8. |
- Nordström, Jonny
(författare)
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Quantitative cardiac 15O-water PET : Assessment of left-ventricular function, remodeling, and impact of patient motion
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- International guidelines advocate the use of noninvasive cardiac imaging as the initial diagnostic test for coronary artery disease, the global leading cause of death according to the world health organization. Within the wide spectrum of cardiac imaging, 15O-water PET is the gold standard for noninvasive quantification of myocardial blood flow (MBF). However, because 15O-water is a metabolically inert and freely diffusible tracer, the net retention of 15O-water in the myocardium is zero and there is no contrast between the myocardial wall and the cavity in a standard uptake image of 15O-water. The lack of contrast poses difficulties for the measurement of cardiac function and remodeling, paramount assessments for coronary artery disease evaluation along with MBF. Part one of the aim of this thesis is the development and evaluation of methods for assessment of cardiac function and remodeling in terms of left-ventricular (LV) volumes and ejection fraction (EF), LV mass (LVM), and LV wall thickness (WT). Part two is focused on patient motion, which occurs frequently in all cardiac PET studies and represents a possible source for induced error in the quantification of MBF. The feasibility of LV volumes and EF calculations was shown in paper I, where cardiac-gated parametric blood-pool images and first-pass images were imported into a commercially available software for SPECT. The method was, however, too laborious for clinical practice but served as an important proof-of-concept. In paper II, LV volumes and EF calculations were performed using first-pass images in the same software used for standard analysis of 15O-water PET and MBF assessment. The results were improved compared to paper I and the method was feasible for clinical implementation. In paper III, LVM and WT calculations were performed using segmentation of perfusable tissue fraction (PTF) images. The results showed high accuracy compared to cardiac magnetic resonance (MR) imaging, and the method was highly automated, allowing for ready clinical implementation. In papers IV-V, the impact of patient motion on the quantitative accuracy of 15O-water PET was investigated. Simulations showed a minimal impact of PET-CT misalignment on MBF, but did show that impact of dynamic motion during PET acquisition was more pronounced. Visual inspection of clinical scans showed frequent motion, but at a small amplitude with generally limited impact according to the simulations. An automated motion detection algorithm was developed which was highly accurate in detecting larger types of motion. A clear pattern of motion-induced artifacts were discovered, which may help improve their visual detection.
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| 9. |
- Strandberg, Sara, 1976-
(författare)
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11C-Acetate-PET/CT in Primary Staging of High-Risk Prostate Cancer
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer (PC) is the second most common cancer in men worldwide, affecting ~12%. Although most are clinically insignificant low-risk cancers, the more aggressive high-risk cancers require correct staging, prior to curative radiotherapy or surgery. Standard staging procedures and tools include clinical examination, estimated nomogram risk of pelvic lymph node (LN) metastases, and bone scintigraphy (BS). Additional staging information can be obtained with magnetic resonance imaging (MRI), computed tomography (CT) and positron-emission tomography/computed tomography (PET/CT). PET/CT can provide information on both functional and morphological changes.The aims of the present thesis were to investigate the diagnostic and prognostic value of 11C-acetate (ACE)-PET/CT in high-risk PC, and to optimize the ACE-PET protocol. In study I and II, higher detection rates of LN metastases and bone metastases were found with ACE-PET/CT, than with standard methods nomogram risk and BS. The higher ACE uptake in the prostate (prostate lipogenic tumor burden), the higher the risk of suspected LN metastases (N+ disease) on PET/CT. ACE-PET/CT findings correlated better than BS with follow-up data, and influenced therapy in 11-43%. In study III, PET reconstruction algorithm with resolution recovery showed more accurate functional tumor volumes compared to CT, and higher measurements of lipogenic activity, than reconstruction algorithm without resolution recovery. Study IV was part of an interventional radiotherapy study (PARAPLY) on high-risk PC, with addition of image-guided simultaneous integrated boost to delineated prostate tumors and pelvic LN metastases reported in ACE-PET/CT and MRI. Comparative analyses of clinical risk parameters and baseline ACE-PET/CT parameters showed significant associations between nomogram risk and prostate lipogenic tumor burden, between N+ disease on PET/CT and prostate lipogenic tumor burden, but surprisingly not between nomogram risk and N+ disease on PET/CT. PET with resolution recovery was superior in detection of N+ disease.In conclusion, ACE-PET/CT showed a higher detection rate of suspected metastases compared to standard methods clinical nomogram and BS, in high-risk PC. PET reconstruction with resolution recovery seems to improve the diagnostic added value of ACE-PET/CT. Prostate lipogenic tumor burden could serve as a predictor of N+ disease. The prognostic value of ACE-PET/CT remains to be investigated in future studies.
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| 10. |
- von Below, Catrin
(författare)
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PET and MRI of Prostate Cancer
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer (PCa) is the most common non-skin malignancy of men in developed countries. In spite of treatment with curative intent up to 30-40% of patients have disease recurrence after treatment, resulting from any combination of lymphatic, hematogenous, or contiguous local spread.The concept of early detection of PCa offer benefits in terms of reduced mortality, but at the cost of over-diagnosis and overtreatment of indolent disease. This is largely due to the random nature of conventional biopsies, with a risk of missing significant cancer and randomly hitting indolent disease.In the present thesis, diagnostic performance of MRI DWI and 11C Acetate PET/CT lymph node staging of intermediate and high risk PCa, was investigated, and additionally, predictive factors of regional lymph node metastases were evaluated. Further, additional value of targeted biopsies to conventional biopsies, for detection of clinically significant PCa, was investigated.In paper one and two, 53 and 40 patients with predominantly high risk PCa underwent 11C Acetate PET/CT and 3T MRI DWI, respectively, for lymph node staging, before extended pelvic lymph node dissection (ePLND). The sensitivity and specificity for PET/CT was 38% and 96% respectively. The sensitivity and specificity for MRI DWI was 55% and 90% respectively.In paper three, 53 patients with newly diagnosed PCa were included. All patients underwent multi-parametric MRI, followed by two cognitive targeted biopsies. Five more clinically significant cancers were detected by adding targeted biopsies to conventional biopsies.In paper four the value of quantitative and qualitative MRI DWI and 11C Acetate PET/CT parameters, alone and in combination, in predicting regional lymph node metastases were examined. ADCmean in lymph nodes and T-stage on MRI were independent predictors of lymph node metastases in multiple logistic regression analysis.In conclusion the specificity of diffusion weighted MRI and 11C Acetate PET/CT for lymph node staging was high, although the sensitivity was low. Predictive factors of regional lymph node metastases could be retrieved from diffusion weighted MRI and 11C Acetate PET/CT. By combining targeted biopsies with conventional biopsies the detection rate of clinically significant PCa could be increased.
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