Kinetic modeling of 68Ga-PSMA-11 and validation of simplified methods for quantification in primary prostate cancer patients.

BACKGROUND: The positron emission tomography (PET) ligand 68Ga-Glu-urea-Lys(Ahx)-HBED-CC (68Ga-PSMA-11) targets the prostate-specific membrane antigen (PSMA), upregulated in prostate cancer cells. Although 68Ga-PSMA-11 PET is widely used in research and clinical practice, full kinetic modeling has not yet been reported nor have simplified methods for quantification been validated. The aims of our study were to quantify 68Ga-PSMA-11 uptake in primary prostate cancer patients using compartmental modeling with arterial blood sampling and to validate the use of standardized uptake values (SUV) and image-derived blood for quantification. RESULTS: Fifteen patients with histologically proven primary prostate cancer underwent a 60-min dynamic 68Ga-PSMA-11 PET scan of the pelvis with axial T1 Dixon, T2, and diffusion-weighted magnetic resonance (MR) images acquired simultaneously. Time-activity curves were derived from volumes of interest in lesions, normal prostate, and muscle, and mean SUV calculated. In total, 18 positive lesions were identified on both PET and MR. Arterial blood activity was measured by automatic arterial blood sampling and manual blood samples were collected for plasma-to-blood ratio correction and for metabolite analysis. The analysis showed that 68Ga-PSMA-11 was stable in vivo. Based on the Akaike information criterion, 68Ga-PSMA-11 kinetics were best described by an irreversible two-tissue compartment model. The rate constants K1 and k3 and the net influx rate constants Ki were all significantly higher in lesions compared to normal tissue (p < 0.05). Ki derived using image-derived blood from an MR-guided method showed excellent agreement with Ki derived using arterial blood sampling (intraclass correlation coefficient = 0.99). SUV correlated significantly with Ki with the strongest correlation of scan time-window 30-45 min (rho 0.95, p < 0.001). Both Ki and SUV correlated significantly with serum prostate specific antigen (PSA) level and PSA density. CONCLUSIONS: 68Ga-PSMA-11 kinetics can be described by an irreversible two-tissue compartment model. An MR-guided method for image-derived blood provides a non-invasive alternative to blood sampling for kinetic modeling studies. SUV showed strong correlation with Ki and can be used in routine clinical settings to quantify 68Ga-PSMA-11 uptake.

"We Are Here for You All the Way"-Patients' and Relatives' Experiences of Receiving Advanced Home Care.

BACKGROUND: It is of great importance to understand how patients and their close relatives experience the pros and cons of advanced home care so as to further develop this quickly growing choice of care. OBJECTIVE: The aim of this study was to explore the experiences of receiving advanced home care among patients affected by life-threatening illness and their close relatives. DESIGN: The study was an interview study conducted with patients in their homes. Some patient interviews were conducted together with a close relative participating. SETTING/PARTICIPANTS: Patients registered in advanced home care in 2017 were offered the opportunity to participate in the study. The selection criteria were that the patient was within grade 3 of the Eastern Cooperative Oncology Group's Performance Status, older than 18 years, able to orient to time and place, and not newly registered. ANALYSIS: The interviews were recorded and transcribed verbatim and analyzed with qualitative content analysis. RESULTS: A total of 11 interviews were conducted: 8 with patients and 1 or 2 close relatives together; and 3 with the patient alone. It resulted in 3 main categories: create a safe environment, see the person, and better to manage care at home. CONCLUSION: The results of this study show that patients and close relatives perceived that advanced home care was a safe and secure form of caring during advanced as well as end-of-life care.

Reproducibility of standardized uptake values of same-day randomized 68Ga-PSMA-11 PET/CT and PET/MR scans in recurrent prostate cancer patients.

OBJECTIVE: Positron emission tomography in association with magnetic resonance imaging (PET/MR) and 68Ga-PSMA-11 has shown superior detection in recurrent prostate cancer patients as compared to PET/computed tomography (PET/CT). There are, however, several technological differences between PET/CT and PET/MR systems which affect the PET image quality. The objective of this study was to assess the reproducibility of PET/CT and PET/MR SUV's in recurrent prostate cancer patients. We randomized the patients regarding the order of the PET/CT and PET/MR scans to reduce the influence of tracer uptake as a function of time. METHODS: Thirty patients, all with biochemical recurrence after radical prostatectomy, underwent whole-body PET/CT and PET/MR scans after intravenous injection of a single dose of 68Ga-PSMA-11. Fifteen patients underwent PET/CT first and 15 patients underwent PET/MR first. Volumes of interest on tumor lesions were outlined and maximum standardized uptake value (SUVmax) corrected for lean body mass was calculated. Correlation and agreement between scans were assessed by generalized linear mixed-effects models and Bland-Altman analysis. The association between SUV, patient characteristics and imaging parameters was assessed. RESULTS: Eighteen of the 30 evaluated patients had at least one positive lesion, giving an overall detection rate of 60%. In total, there were 34 visible lesions: 5 local recurrences, 22 lymph node metastases and 7 bone metastases. One group acquired PET/CT and PET/MR at median time points of 63.0 and 159.0 min, while the other group acquired PET/MR and PET/CT at median time points of 92.0 and 149.0 min. SUVmax between scans was linearly correlated, described by the equation Y(PET/CT SUVmax) = 0.75 + 1.00 × (PET/MR SUVmax), on average 20% higher on PET/CT than on PET/MR. SUV associated significantly only with type of lesion, scan time post-injection and acquisition time per bed position. CONCLUSIONS: SUVmax from PET/CT and PET/MR are linearly correlated, on average 20% higher on PET/CT than on PET/MR and should, therefore, not be used interchangeably in patient follow-up.

18F-ML-10, a PET tracer for apoptosis: first human study.

UNLABELLED: Clinical PET of apoptosis may have substantial value in advancing patient care. We report here the first-in-humans study with (18)F-labeled 2-(5-fluoropentyl)-2-methyl malonic acid ((18)F-ML-10), a small-molecule PET tracer for apoptosis. Presented are the dosimetry, biodistribution, stability, and safety profiles of this PET tracer in healthy human volunteers. Also reported is tracer binding to targeted apoptotic cells in testicular tissue, where a relative abundance of apoptotic cells is normally observed. METHODS: (18)F-ML-10 (233 ± 90 MBq) was intravenously administered to 8 healthy subjects, followed by whole-body PET/CT for 220 min. Serial blood and urine samples were collected for radioactivity measurement, and plasma tracer stability was assessed by high-performance liquid chromatography. Dosimetry calculations were performed using OLINDA/EXM software. RESULTS: (18)F-ML-10 manifested high stability in vivo and rapid distribution followed by fast clearance, with an elimination half-life of 1.3 ± 0.1 and 1.1 ± 0.2 h from the blood and from all other organs, respectively, and excretion through the urine. Dosimetry showed an average effective whole-body dose of 15.4 ± 3.7 µSv/MBq, with the urinary bladder being the dose-limiting organ. Selective accumulation and retention of the tracer in the testes was observed in all male subjects, a finding also demonstrated in mice using both small-animal PET and histopathology, confirming binding to apoptotic cells. Administration of (18)F-ML-10 was safe, without adverse effects. CONCLUSION: (18)F-ML-10 administered to healthy humans demonstrated a favorable dosimetry, biodistribution, stability, and safety profile. Binding to apoptotic sites was also demonstrated. These data support further development of this small-molecule probe for clinical PET of apoptosis.

Principal component analysis with pre-normalization improves the signal-to-noise ratio and image quality in positron emission tomography studies of amyloid deposits in Alzheimer's disease.

This study introduces a new approach for the application of principal component analysis (PCA) with pre-normalization on dynamic positron emission tomography (PET) images. These images are generated using the amyloid imaging agent N-methyl [(11)C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole ([(11)C]PIB) in patients with Alzheimer's disease (AD) and healthy volunteers (HVs). The aim was to introduce a method which, by using the whole dataset and without assuming a specific kinetic model, could generate images with improved signal-to-noise and detect, extract and illustrate changes in kinetic behavior between different regions in the brain. Eight AD patients and eight HVs from a previously published study with [(11)C]PIB were used. The approach includes enhancement of brain regions where the kinetics of the radiotracer are different from what is seen in the reference region, pre-normalization for differences in noise levels and removal of negative values. This is followed by slice-wise application of PCA (SW-PCA) on the dynamic PET images. Results obtained using the new approach were compared with results obtained using reference Patlak and summed images. The new approach generated images with good quality in which cortical brain regions in AD patients showed high uptake, compared to cerebellum and white matter. Cortical structures in HVs showed low uptake as expected and in good agreement with data generated using kinetic modeling. The introduced approach generated images with enhanced contrast and improved signal-to-noise ratio (SNR) and discrimination power (DP) compared to summed images and parametric images. This method is expected to be an important clinical tool in the diagnosis and differential diagnosis of dementia.

An automated method for delineating a reference region using masked volumewise principal-component analysis in 11C-PIB PET.

UNLABELLED: Kinetic modeling using a reference region is a common method for the analysis of dynamic PET studies. Available methods for outlining regions of interest representing reference regions are usually time-consuming and difficult and tend to be subjective; therefore, MRI is used to help physicians and experts to define regions of interest with higher precision. The current work introduces a fast and automated method to delineate the reference region of images obtained from an N-methyl-(11)C-2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole ((11)C-PIB) PET study on Alzheimer disease patients and healthy controls using a newly introduced masked volumewise principal-component analysis. METHODS: The analysis was performed on PET studies from 22 Alzheimer disease patients (baseline, follow-up, and test/retest studies) and 4 healthy controls, that is, a total of 26 individual scans. The second principal-component images, which illustrate the kinetic behavior of the tracer in gray matter of the cerebellar cortex, were used as input data for automatic delineation of the reference region. To study the variation associated with the manual and proposed automatic methods, we defined the reference region repeatedly. RESULTS: As expected, the automatic method showed no variation whereas the manual method varied significantly on repetition. Furthermore, the automatic method was significantly faster, more robust, and less biased. CONCLUSION: The automatic method is helpful in the delineation of the reference region of (11)C-PIB PET studies of the human brain and is much faster and more precise than manual delineation.

Masked-Volume-Wise PCA and "reference Logan" illustrate similar regional differences in kinetic behavior in human brain PET study using [11C]-PIB.

BACKGROUND: Kinetic modeling using reference Logan is commonly used to analyze data obtained from dynamic Positron Emission Tomography (PET) studies on patients with Alzheimer's disease (AD) and healthy volunteers (HVs) using amyloid imaging agent N-methyl [11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole, [11C]-PIB. The aim of the present study was to explore whether results obtained using the newly introduced method, Masked Volume Wise Principal Component Analysis, MVW-PCA, were similar to the results obtained using reference Logan. METHODS: MVW-PCA and reference Logan were performed on dynamic PET images obtained from four Alzheimer's disease (AD) patients on two occasions (baseline and follow-up) and on four healthy volunteers (HVs). Regions of interest (ROIs) of similar sizes were positioned in different parts of the brain in both AD patients and HVs where the difference between AD patients and HVs is largest. Signal-to-noise ratio (SNR) and discrimination power (DP) were calculated for images generated by the different methods and the results were compared both qualitatively and quantitatively. RESULTS: MVW-PCA generated images that illustrated similar regional binding patterns compared to reference Logan images and with slightly higher quality, enhanced contrast, improved SNR and DP, without being based on modeling assumptions. MVW-PCA also generated additional MVW-PC images by using the whole dataset, which illustrated regions with different and uncorrelated kinetic behaviors of the administered tracer. This additional information might improve the understanding of kinetic behavior of the administered tracer. CONCLUSION: MVW-PCA is a potential multivariate method that without modeling assumptions generates high quality images, which illustrated similar regional changes compared to modeling methods such as reference Logan. In addition, MVW-PCA could be used as a new technique, applicable not only on dynamic human brain studies but also on dynamic cardiac studies when using PET.

Unidirectional Influx and Net Accumulation of PIB.

The compound {N-methyl-[(11)C]}2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, "PIB", measured by positron emission tomography, has been demonstrated to image brain beta-amyloid deposition in Alzheimer's disease (AD). In the present study the benefit of measuring the PIB accumulation rate together with the unidirectional influx of PIB into the brain was investigated in healthy control subjects and patients with AD. In a monkey changes in the influx rate constant K(1) of PIB closely followed changes in CBF, caused by alteration of Pa(CO2). In addition, K(1) was high both in the monkey and in humans, suggesting that this parameter reflects CBF. Most AD patients studied showed clearly higher accumulation rate for PIB than the controls in cortical brain areas, while a few patients showed as low accumulation as the controls. K(1) did not correlate with the accumulation rate, indicating that K(1) for PIB provides extra information besides the accumulation rate.

PET imaging of amyloid deposition in patients with mild cognitive impairment.

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3+/-7.8 (S.D.) years) underwent PET studies with (11)C-PIB, and (18)F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1+/-6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps<0.01). The PIB retention in MCI converters was comparable to AD patients (p>0.01). Correlations were observed in the MCI patients between PIB retention and CSF Abeta(1-42), total Tau and episodic memory, respectively.

Two-year follow-up of amyloid deposition in patients with Alzheimer's disease.

Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 +/- 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) after 2.0 +/- 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test-retest). Relative PIB retention in cortical regions differed by 3-7% in the test-retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 +/- 3.7 (mean +/- standard deviation) to 22.7 +/- 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 +/- 3.5 to 15.6 +/- 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 +/- 3.1 to 25.9 +/- 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.