Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH).

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival.

Optimal method for metabolic tumour volume assessment of cervical cancers with inter-observer agreement on [18F]-fluoro-deoxy-glucose positron emission tomography with computed tomography.

PURPOSE: Cervical cancer metabolic tumour volume (MTV) derived from [18F]-FDG PET/CT has a role in prognostication and therapy planning. There is no standard method of outlining MTV on [18F]-FDG PET/CT. The aim of this study was to assess the optimal method to outline primary cervical tumours on [18F]-FDG PET/CT using MRI-derived tumour volumes as the reference standard. METHODS: 81 consecutive cervical cancer patients with pre-treatment staging MRI and [18F]-FDG PET/CT imaging were included. MRI volumes were compared with different PET segmentation methods. Method 1 measured MTVs at different SUVmax thresholds ranging from 20 to 60% (MTV20-MTV60) with bladder masking and manual adjustment when required. Method 2 created an isocontour around the tumour prior to different SUVmax thresholds being applied. Method 3 used an automated gradient method. Inter-observer agreement of MTV, following manual adjustment when required, was recorded. RESULTS: For method 1, the MTV25 and MTV30 were closest to the MRI volumes for both readers (mean percentage change from MRI volume of 2.9% and 13.4% for MTV25 and - 13.1% and - 2.0% for MTV30 for readers 1 and 2). 70% of lesions required manual adjustment at MTV25 compared with 45% at MTV30. There was excellent inter-observer agreement between MTV30 to MTV60 (ICC ranged from 0.898-0.976 with narrow 95% confidence intervals (CIs)) and moderate agreement at lower thresholds (ICC estimates of 0.534 and 0.617, respectively for the MTV20 and MTV25 with wide 95% CIs). Bladder masking was performed in 86% of cases overall. For method 2, excellent correlation was demonstrated at MTV25 and MTV30 (mean % change from MRI volume of -3.9% and - 8.6% for MTV25 and - 16.9% and 19% for MTV30 for readers 1 and 2, respectively). This method also demonstrated excellent ICC across all thresholds with no manual adjustment. Method 3 demonstrated excellent ICC of 0.96 (95% CI 0.94-0.97) but had a mean percentage difference from the MRI volume of - 19.1 and - 18.2% for readers 1 and 2, respectively. 21% required manual adjustment for both readers. CONCLUSION: MTV30 provides the optimal correlation with MRI volume taking into consideration the excellent inter-reader agreement and less requirement for manual adjustment.

Amyloid PET imaging in clinical practice.

Amyloid positron emission tomography (PET) imaging enables in vivo detection of brain Aß deposition, one of the neuropathological hallmarks of Alzheimer's disease. There is increasing evidence to support its clinical utility, with major studies showing that amyloid PET imaging improves diagnostic accuracy, increases diagnostic certainty and results in therapeutic changes. The Amyloid Imaging Taskforce has developed appropriate use criteria to guide clinicians by predefining certain scenarios where amyloid PET would be justified. This review provides a practical guide on how and when to use amyloid PET, based on the available research and our own experience. We discuss its three main appropriate indications and illustrate these with clinical cases. We stress the importance of a multidisciplinary approach when deciding who might benefit from amyloid PET imaging. Finally, we highlight some practical points and common pitfalls in its interpretation.

IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer.

BACKGROUND: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. METHODS: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally. The primary endpoint was changed in FLT uptake; secondary endpoints included safety and tolerability of irosustat, changes in tumoral Ki67 and steroidogenic enzymes expression and circulating steroid hormone levels. RESULTS: Thirteen women were recruited, and ten started irosustat for 2 weeks, followed by repeat FLT-PET scans in eight. Defining response as decreases of ≥20% in standardized uptake value (SUV) or ≥30% in Ki, 1 (12.5% (95% CI 2-47%, p = 0.001)) and 3 (43% (95% CI 16-75%, p = <0.001) patients, respectively, responded. 6 out of 7 patients had a Ki67 reduction (range = -19.3 to 76.4%), and median percentage difference in Ki67 was 52.3% (p = 0.028). In one patient with a low baseline STS expression, a 19.7% increase in Ki67 was recorded. STS decreases were seen in tumours with high basal STS expression, significant decreases were also noted in aromatase, and 17ß-hydroxysteroid dehydrogenase type 1 and 2. Irosustat was generally well tolerated with all adverse event CTCAE Grade ≤2. CONCLUSIONS: Irosustat resulted in a significant reduction in FLT uptake and Ki67, and is well tolerated. These data are the first demonstrating clinical activity of irosustat in early breast cancer. Baseline expression of STS may be a biomarker of sensitivity to irosustat.

Hypoxia and tissue destruction in pulmonary TB.

BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

Alzheimer's disease heterogeneity revealed by neuroanatomical normative modeling.

INTRODUCTION: Overlooking the heterogeneity in Alzheimer's disease (AD) may lead to diagnostic delays and failures. Neuroanatomical normative modeling captures individual brain variation and may inform our understanding of individual differences in AD-related atrophy. METHODS: We applied neuroanatomical normative modeling to magnetic resonance imaging from a real-world clinical cohort with confirmed AD (n = 86). Regional cortical thickness was compared to a healthy reference cohort (n = 33,072) and the number of outlying regions was summed (total outlier count) and mapped at individual- and group-levels. RESULTS: The superior temporal sulcus contained the highest proportion of outliers (60%). Elsewhere, overlap between patient atrophy patterns was low. Mean total outlier count was higher in patients who were non-amnestic, at more advanced disease stages, and without depressive symptoms. Amyloid burden was negatively associated with outlier count. DISCUSSION: Brain atrophy in AD is highly heterogeneous and neuroanatomical normative modeling can be used to explore anatomo-clinical correlations in individual patients.

Higher extracellular fluid volume in women is concealed by scaling to body surface area.

OBJECTIVE: The objective was to assess body surface area (BSA) for scaling extracellular fluid volume (ECV) in comparison with estimated lean body mass (LBM) and total body water (TBW) across a range of body mass indices (BMI). METHODS: This was a multi-centre study from 15 centres that submitted raw data from routine measurement of GFR in potential kidney transplant donors. There were 819 men and 1059 women in total. ECV was calculated from slope-intercept and slope-only measurements of GFR. ECV was scaled using two methods: Firstly, division of ECV by the scaling variable (ratio method), and secondly the regression method of Turner and Reilly. Subjects were placed into five BMI groups: < 20, 20-24.9, 25-29.9, 30-34.9, and 35 + kg/m(2). LBM and TBW were estimated from previously published, gender-specific prediction equations. RESULTS: Ratio and regression scaling gave almost identical results. ECV scaled to BSA by either method was higher in men in all BMI groups but ECV scaled to LBM and TBW was higher in women. There was, however, little difference between men and women in respect to ECV per unit weight in any BMI group, even though women have 10% more adipose tissue. The relations between TBW and BSA and between LBM and BSA, but not between LBM and TBW, were different between men and women. CONCLUSION: Lean tissue in women contains more extracellular water than in men, a difference that is obscured by scaling to BSA. The likely problem with BSA is its insensitivity to body composition.

Visual atrophy rating scales and amyloid PET status in an Alzheimer's disease clinical cohort.

OBJECTIVES: Visual rating scales (VRS) are the quantification method closest to the approach used in routine clinical practice to assess brain atrophy. Previous studies have suggested that the medial temporal atrophy (MTA) rating scale is a reliable diagnostic marker for AD, equivalent to volumetric quantification, while others propose a higher diagnostic utility for the Posterior Atrophy (PA) scale in early-onset AD. METHODS: Here, we reviewed 14 studies that assessed the diagnostic accuracy of PA and MTA, we explored the issue of cut-off heterogeneity, and assessed 9 rating scales in a group of patients with biomarker-confirmed diagnosis. A neuroradiologist blinded to all clinical information rated the MR images of 39 amyloid-positive and 38 amyloid-negative patients using 9 validated VRS assessing multiple brain regions. Automated volumetric analyses were performed on a subset of patients (n = 48) and on a group of cognitively normal individuals (n = 28). RESULTS: No single VRS could differentiate amyloid-positive from amyloid-negative patients with other neurodegenerative conditions. 44% of amyloid-positive patients were deemed to have age-appropriate levels of MTA. In the amyloid-positive group, 18% had no abnormal MTA or PA scores. These findings were substantially affected by cut-off selection. Amyloid-positive and amyloid-negative patients had comparable hippocampal and parietal volumes, and MTA but not PA scores correlated with the respective volumetric measures. INTERPRETATION: Consensus guidelines are needed before VRS can be recommended for use in the diagnostic workup of AD. Our data are suggestive of high intragroup variability and non-superiority of volumetric quantification of atrophy over visual assessment.

A Subset of Non-Small Cell Lung Cancer Patients Treated with Pemetrexed Show 18F-Fluorothymidine "Flare" on Positron Emission Tomography.

Thymidylate synthase (TS) remains a major target for cancer therapy. TS inhibition elicits increases in DNA salvage pathway activity, detected as a transient compensatory "flare" in 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography (18F-FLT PET). We determined the magnitude of the 18F-FLT flare in non-small cell lung cancer (NSCLC) patients treated with the antifolate pemetrexed in relation to clinical outcome. METHOD: Twenty-one patients with advanced/metastatic non-small cell lung cancer (NSCLC) scheduled to receive palliative pemetrexed ± platinum-based chemotherapy underwent 18F-FLT PET at baseline and 4 h after initiating single-agent pemetrexed. Plasma deoxyuridine (dUrd) levels and thymidine kinase 1 (TK1) activity were measured before each scan. Patients were then treated with the combination therapy. The 18F-FLT PET variables were compared to RECIST 1.1 and overall survival (OS). RESULTS: Nineteen patients had evaluable PET scans at both time points. A total of 32% (6/19) of patients showed 18F-FLT flares (>20% change in SUVmax-wsum). At the lesion level, only one patient had an FLT flare in all the lesions above (test-retest borders). The remaining had varied uptake. An 18F-FLT flare occurred in all lesions in 1 patient, while another patient had an 18F-FLT reduction in all lesions; 17 patients showed varied lesion uptake. All patients showed global TS inhibition reflected in plasma dUrd levels (p < 0.001) and 18F-FLT flares of TS-responsive normal tissues including small bowel and bone marrow (p = 0.004 each). Notably, 83% (5/6) of patients who exhibited 18F-FLT flares were also RECIST responders with a median OS of 31 m, unlike patients who did not exhibit 18F-FLT flares (15 m). Baseline plasma TK1 was prognostic of survival but its activity remained unchanged following treatment. CONCLUSIONS: The better radiological response and longer survival observed in patients with an 18F-FLT flare suggest the efficacy of the tracer as an indicator of the early therapeutic response to pemetrexed in NSCLC.

The reliability of glomerular filtration rate measured from plasma clearance: a multi-centre study of 1,878 healthy potential renal transplant donors.

PURPOSE: The objective of the study was to undertake a clinical audit of departmental performance in the measurement of glomerular filtration rate (GFR) using the coefficient of variation (CV) of extracellular fluid volume (ECFV) as the benchmark. ECFV is held within narrow limits in healthy subjects, narrower than GFR, and should therefore have a low CV. METHODS: Fifteen departments participated in this retrospective study of healthy renal transplant donors. Data were analysed separately for men (n ranged from 28 to 115 per centre; total = 819) and women (n = 28-146; 1,059). All centres used the slope-intercept method with blood sample numbers ranging from two to five. Subjects did not fast prior to GFR measurement. GFR was scaled to body surface area (BSA) and corrected for the single compartment assumption. GFR scaled to ECFV was calculated as the terminal slope rate constant and corrected for the single compartment assumption. ECFV/BSA was calculated as the ratio of GFR/BSA to GFR/ECFV. RESULTS: The departmental CVs of ECFV/BSA and GFR/BSA ranged from 8.3 to 25.8% and 12.8 to 21.9%, respectively, in men, and from 9.6 to 21.1% and 14.8 to 23.7%, respectively, in women. Both CVs correlated strongly between men and women from the same centre, suggesting department-specific systematic errors. GFR/BSA was higher in men in 14 of 15 centres, whereas GFR/ECFV was higher in women in 14 of 15 centres. Both correlated strongly between men and women, suggesting regional variation in GFR. CONCLUSION: The CV of ECFV/BSA in normal subjects is a useful indicator of the technical robustness with which GFR is measured and, in this study, indicated a wide variation in departmental performance.

Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling.

UNLABELLED: Aim. The aim of this study was to investigate the influence of age, gender, obesity and scaling on glomerular filtration rate (GFR) and extracellular fluid volume (ECV) in healthy subjects. METHODS: This is a retrospective multi-centre study of 1878 healthy prospective kidney transplant donors (819 men) from 15 centres. Age and body mass index (BMI) were not significantly different between men and women. Slope-intercept GFR was measured (using Cr-51-EDTA in 14 centres; Tc-99m-DTPA in one) and scaled to body surface area (BSA) and lean body mass (LBM), both estimated from height and weight. GFR was also expressed as the slope rate constant, with one-compartment correction (GFR/ECV). ECV was measured as the ratio, GFR to GFR/ECV. RESULTS: ECV was age independent but GFR declined with age, at a significantly faster rate in women than men. GFR/BSA was higher in men but GFR/ECV and GFR/LBM were higher in women. Young women (<30 years) had higher GFR than young men but the reverse was recorded in the elderly (>65 years). There was no difference in GFR between obese (BMI>30 kg/m2) and non-obese men. Obese women, however, had lower GFR than non-obese women and negative correlations were observed between GFR and both BMI and %fat. The decline in GFR with age was no faster in obese versus non-obese subjects. ECV/BSA was higher in men but ECV/LBM was higher in women. ECV/weight was almost gender independent, suggesting that fat-free mass in women contains more extracellular water. BSA is therefore a misleading scaling variable. CONCLUSION: There are several significant differences in GFR and ECV between healthy men and women.

Prevalence of Depressive Symptoms in a Memory Clinic Cohort: A Retrospective Study.

BACKGROUND: Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimer's disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date. OBJECTIVE: To examine the prevalence, features, and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging. METHODS: We included 300 patients from a single-center memory clinic cohort that received diagnostic biomarker evaluation with amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence. RESULTS: One hundred forty-two (47%) patients had a history of significant depressive symptoms ('D+'). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients. CONCLUSION: Approximately half of patients who meet appropriate use criteria for amyloid PET have a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET.

A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer's disease.

Background: Alzheimer's disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care. Methods: We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called "Alzheimer's Predictive Vector" (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO). Results: The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer's related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype. Conclusions: This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis.

Alzheimer's disease is the most common cause of dementia, impacting memory, thinking and behaviour. It can be challenging to diagnose Alzheimer's disease which can lead to suboptimal patient care. During the development of Alzheimer's disease the brain shrinks and the cells within it die. One method that can be used to assess brain function is magnetic resonance imaging, which uses magnetic fields and radio waves to produce images of the brain. In this study, we develop a method that uses magnetic resonance imaging data to identify differences in the brain between people with and without Alzheimer's disease, including before obvious shrinkage of the brain occurs. This method could be used to help diagnose patients with Alzheimer's Disease.

Evaluating cognitive profiles of patients undergoing clinical amyloid-PET imaging.

Episodic memory impairment and brain amyloid-beta are two of the main hallmarks of Alzheimer's Disease. In the clinical setting, these are often evaluated through neuropsychological testing and amyloid PET imaging, respectively. The use of amyloid PET in clinical practice is only indicated in patients with substantial diagnostic uncertainty due to atypical clinical presentation, multiple comorbidities and/or early age of onset. The relationship between amyloid-beta and cognition has been previously investigated, but no study has examined how neuropsychological features relate to the presence of amyloid pathology in the clinical population that meets the appropriate use criteria for amyloid PET imaging. In this study, we evaluated a clinical cohort of patients (n = 107) who presented at the Imperial Memory Clinic and were referred for clinical amyloid PET and neuropsychological assessment as part of their diagnostic workup. We compared the cognitive performance of amyloid-positive patients (Aß-pos, n = 47) with that of stable amyloid-negative (stableAß-neg, n = 26) and progressive amyloid-negative (progAß-neg, n = 34) patients. The amyloid-positive group performed significantly worse than both amyloid-negative groups in the visuospatial and working memory domains. Episodic memory performance, however, effectively differentiated the amyloid-positive group from the stable but not the progressive amyloid-negative group. On affective questionnaires, the stable amyloid-negative group reported significantly higher levels of depression than the amyloid-positive group. In our clinical cohort, visuospatial dysfunction and working memory impairment were better indicators of amyloid positivity than episodic memory dysfunction. These findings highlight the limited value of isolated cognitive scores in patients with atypical clinical presentation, comorbidities and/or early age of onset.

Insights into schizophrenia using positron emission tomography: building the evidence and refining the focus.

Schizophrenia involves dysregulation in dopaminergic transmission. Studies show heightened presynaptic striatal dopaminergic function and elevated striatal D(2)/D(3) receptor density in the brain. Cognitive impairments result from hypostimulation of D(1) receptors and are associated with dysfunction in the prefrontal cortex. Here we discuss relevant positron emissions tomography (PET) studies and provide future directions.

Using amyloid PET imaging to diagnose Alzheimer's disease in patients with multiple sclerosis.

BACKGROUND: Cognitive dysfunction affects 40-60% of individuals with multiple sclerosis (MS). The neuropsychological profile commonly consists of a subcortical pattern of deficits, although a proportion of patients have a severe progressive cortical dementia. However, patients with MS can be affected by other neurodegenerative diseases, such as Alzheimer's disease (AD). Little is known about the co-existence of these two conditions but distinguishing dementia due to MS alone from a coexisting neurodegenerative disease is challenging. Amyloid PET imaging has allowed improved AD diagnosis, especially in patients with atypical presentations or multiple possible causes of cognitive impairment. Amyloid PET demonstrates increased cortical signal in AD, whereas reductions in subcortical uptake are associated with demyelination. To the authors knowledge, there are no reports of clinical Amyloid PET use in MS patients with dementia. METHODS: Here, three MS patients presenting to the Cognitive Neurology Clinic with progressive cognitive impairment are described. Due to lack of diagnostic clarity from standard investigations, they underwent Amyloid PET Imaging with 18F-florbetapir according to established appropriate use criteria and after review by a multidisciplinary team. RESULTS: Two patients were diagnosed with AD based on positive Amyloid PET imaging and were subsequently started on cholinesterase inhibitor treatment. The other patient had a negative scan, leading to further investigations and identification of another potential cause of worsening cognitive impairment. CONCLUSIONS: The experience from this case series suggests that Amyloid PET Imaging may be of diagnostic value in selected patients with MS and dementia. In these individuals, it may provide diagnostic clarity and assist with therapeutic decisions.

Monitoring Response to Transarterial Chemoembolization in Hepatocellular Carcinoma Using 18F-Fluorothymidine PET.

Accurate disease monitoring is essential after transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) because of the potential for profound adverse events and large variations in survival outcome. Posttreatment changes on conventional imaging can confound determination of residual or recurrent disease, magnifying the clinical challenge. On the basis of increased expression of thymidylate synthase (TYMS), thymidine kinase 1 (TK-1), and equilibrative nucleoside transporter 1 (SLC29A1) in HCC compared with liver tissue, we conducted a proof-of-concept study evaluating the efficacy of 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET to assess response to TACE. Because previous PET studies in HCC have been hampered by high background liver signal, we investigated whether a temporal-intensity voxel clustering (kinetic spatial filtering, or KSF) improved lesion detection. Methods: A tissue microarray was built from 36 HCC samples and from matching surrounding cirrhotic tissue and was stained for TK-1 A prospective study was conducted; 18 patients with a diagnosis of HCC by the criteria of the American Association for the Study of Liver Diseases who were eligible for treatment with TACE were enrolled. The patients underwent baseline conventional imaging and dynamic 18F-FLT PET with KSF followed by TACE. Imaging was repeated 6-8 wk after TACE. The PET parameters were compared with modified enhancement-based RECIST. Results: Cancer Genome Atlas analysis revealed increased RNA expression of TYMS, TK-1, and SLC29A1 in HCC. TK-1 protein expression was significantly higher in HCC (P < 0.05). The sensitivity of 18F-FLT PET for baseline HCC detection was 73% (SUVmax, 9.7 ± 3.0; tumor to liver ratio, 1.2 ± 0.3). Application of KSF did not improve lesion detection. Lesion response after TACE by modified RECIST was 58% (14 patients with 24 lesions). A 30% reduction in mean 18F-FLT PET uptake was observed after TACE, correlating with an observed PET response of 60% (15/25). A significant and profound reduction in the radiotracer delivery parameter K1 after TACE was observed. Conclusion:18F-FLT PET can differentiate HCC from surrounding cirrhotic tissue, with PET parameters correlating with TACE response. KSF did not improve visualization of tumor lesions. These findings warrant further investigation.

Systematic Evaluation of Kinetics and Distribution of Muscle and Lymph Node Activation Measured by 18F-FDG- and 11C-PBR28-PET/CT Imaging, and Whole Blood and Muscle Transcriptomics After Immunization of Healthy Humans With Adjuvanted and Unadjuvanted Vaccines.

Systems vaccinology has been applied to detect signatures of human vaccine induced immunity but its ability, together with high definition in vivo clinical imaging is not established to predict vaccine reactogenicity. Within two European Commission funded high impact programs, BIOVACSAFE and ADITEC, we applied high resolution positron emission tomography/computed tomography (PET/CT) scanning using tissue-specific and non-specific radioligands together with transcriptomic analysis of muscle biopsies in a clinical model systematically and prospectively comparing vaccine-induced immune/inflammatory responses. 109 male participants received a single immunization with licensed preparations of either AS04-adjuvanted hepatitis B virus vaccine (AHBVV); MF59C-adjuvanted (ATIV) or unadjuvanted seasonal trivalent influenza vaccine (STIV); or alum-OMV-meningococcal B protein vaccine (4CMenB), followed by a PET/CT scan (n = 54) or an injection site muscle biopsy (n = 45). Characteristic kinetics was observed with a localized intramuscular focus associated with increased tissue glycolysis at the site of immunization detected by 18F-fluorodeoxyglucose (FDG) PET/CT, peaking after 1-3 days and strongest and most prolonged after 4CMenB, which correlated with clinical experience. Draining lymph node activation peaked between days 3-5 and was most prominent after ATIV. Well defined uptake of the immune cell-binding radioligand 11C-PBR28 was observed in muscle lesions and draining lymph nodes. Kinetics of muscle gene expression module upregulation reflected those seen previously in preclinical models with a very early (~6hrs) upregulation of monocyte-, TLR- and cytokine/chemokine-associated modules after AHBVV, in contrast to a response on day 3 after ATIV, which was bracketed by whole blood responses on day 1 as antigen presenting, inflammatory and innate immune cells trafficked to the site of immunization, and on day 5 associated with activated CD4+ T cells. These observations confirm the use of PET/CT, including potentially tissue-, cell-, or cytokine/chemokine-specific radioligands, is a safe and ethical quantitative technique to compare candidate vaccine formulations and could be safely combined with biopsy to guide efficient collection of samples for integrated whole blood and tissue systems vaccinology in small-scale but intensive human clinical models of immunization and to accelerate clinical development and optimisation of vaccine candidates, adjuvants, and formulations.

Quantitative evaluation of beta-amyloid brain PET imaging in dementia: a comparison between two commercial software packages and the clinical report.

OBJECTIVE: To compare commercially available image analysis tools Hermes BRASS and Siemens Syngo.VIA with clinical assessment in 18F-Florbetapir PET scans. METHODS: 225 scans were reported by clinicians and quantified using two software packages. Scans were classified into Type A (typical features) or non-Type A (atypical features) for both positive and negative scans. For BRASS, scans with z-score ≥ 2 in 2 ≥ region of interest were classed positive. For Syngo.VIA a positive scan was indicated when mean cortical standardized uptake value ratio (mcSUVR) ≥ 1.17. RESULTS: 81% scans were Type A, and 19% scans were non-Type A. The sensitivity of BRASS and Syngo.VIA for Type A scans was 98.8 and 96.3%, specificity was 73 and 92%, respectively. Sensitivity for non-Type A scans was 95.8 and 79.2%, specificity was 36.8 and 57.9%, respectively.A third threshold of identifiable levels of plaque (1.08 ≤ mcSUVR ≤ 1.17) was recommended for Syngo.VIA to increase detection of false negative scans.The false positive rate of BRASS significantly decreased when an alternative positive threshold value of mcSUVR ≥ 1.18.Introduction of alternative criteria did not improve prediction outcome for non-Type A scans. More complex solutions are recommended. CONCLUSION: Hermes criteria for a positive scan leads to a high sensitivity but a low specificity. Siemens Syngo.VIA criteria gives a high sensitivity and specificity and agrees better with the clinical report. Alternative thresholds and classifications may help to improve agreement with the clinical report. ADVANCES IN KNOWLEDGE: Software packages may assist with clinical reporting of more difficult to interpret cases that require a more experienced read.

Clinical 18F-FDG and amyloid brain positron emission tomography/CT in the investigation of cognitive impairment: where are we now?

The number of people living with dementia is increasing, but as yet there remains no cure or disease-modifying treatment. This review aims to help readers understand the role of 18F-FDG PET/CT imaging in the investigation of cognitive impairment and how the advent of amyloid PET/CT imaging may hold the key to radically changing management of the most common form of dementia - Alzheimer's disease. The indications for 18F-FDG PET/CT and amyloid PET/CT imaging in cognitive impairment are outlined. Additionally, the mechanisms of action, technique, patient preparation and acquisition parameters for both are detailed. We conclude by providing a framework for interpreting 18F-FDG PET/CT and amyloid PET/CT imaging in the more common conditions that lead to cognitive impairment conditions with tips on avoiding pitfalls in interpretation.