The Delphi of ORACLE: An Expert Consensus Survey for the Development of the Observational Risk Assessment of Contractures (Longitudinal Evaluation).

OBJECTIVE: Despite rising prevalence rates, no standard tool is available to identify individuals at risk of developing contractures. This study aimed to gain expert consensus on items for the development of the Observational Risk Assessment Tool for Contractures: Longitudinal Evaluation (ORACLE) for care home residents. DESIGN: A two-round, online modified Delphi study. PARTICIPANTS: Panellists were qualified healthcare professionals with a background in physiotherapy, occupational therapy, nursing, and rehabilitation medicine. MAIN OUTCOME MEASURES: In the first round, the experts were asked to rate the predesigned list of items on a Likert scale while in the second round, consensus was sought in the areas of disagreement identified in the previous round. RESULTS: The two rounds of the Delphi survey included 30 and 25 panellists, respectively. The average clinical and academic experience of the panellists was 22.2 years and 10.5 years, respectively. The panel demonstrated a high level of consensus regarding the clinical factors (10 out of 15 items); preventive care approaches (9 out of 10 items), and contextual factors (12 out of 13 items) ranging from 70% to 100%. CONCLUSION: This Delphi study determined expert consensus on items to be included in a contracture risk assessment tool (ORACLE). The items were related to factors associated with joint contractures, appropriate preventive care interventions, and potentially relevant contextual factors associated with care home settings. The promise of a risk assessment tool that includes these items has the capacity to reduce the risk of contracture development or progression and to trigger timely and appropriate referrals to help prevent further loss of function and independence.

The impact of hypoglycaemia awareness status on regional brain responses to acute hypoglycaemia in men with type 1 diabetes.

AIMS/HYPOTHESIS: Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes increases the risk of severe hypoglycaemia sixfold and can be resistant to intervention. We explored the impact of IAH on central responses to hypoglycaemia to investigate the mechanisms underlying barriers to therapeutic intervention. METHODS: We conducted [15O]water positron emission tomography studies of regional brain perfusion during euglycaemia (target 5 mmol/l), hypoglycaemia (achieved level, 2.4 mmol/l) and recovery (target 5 mmol/l) in 17 men with type 1 diabetes: eight with IAH, and nine with intact hypoglycaemia awareness (HA). RESULTS: Hypoglycaemia with HA was associated with increased activation in brain regions including the thalamus, insula, globus pallidus (GP), anterior cingulate cortex (ACC), orbital cortex, dorsolateral frontal (DLF) cortex, angular gyrus and amygdala; deactivation occurred in the temporal and parahippocampal regions. IAH was associated with reduced catecholamine and symptom responses to hypoglycaemia vs HA (incremental AUC: autonomic scores, 26.2 ± 35.5 vs 422.7 ± 237.1; neuroglycopenic scores, 34.8 ± 88.8 vs 478.9 ± 311.1; both p < 0.002). There were subtle differences (p < 0.005, k ≥ 50 voxels) in brain activation at hypoglycaemia, including early differences in the right central operculum, bilateral medial orbital (MO) cortex, and left posterior DLF cortex, with additional differences in the ACC, right GP and post- and pre-central gyri in established hypoglycaemia, and lack of deactivation in temporal regions in established hypoglycaemia. CONCLUSIONS/INTERPRETATION: Differences in activation in the post- and pre-central gyri may be expected in people with reduced subjective responses to hypoglycaemia. Alterations in the activity of regions involved in the drive to eat (operculum), emotional salience (MO cortex), aversion (GP) and recall (temporal) suggest differences in the perceived importance and urgency of responses to hypoglycaemia in IAH compared with HA, which may be key to the persistence of the condition.

Defining the optimal method for measuring baseline metabolic tumour volume in diffuse large B cell lymphoma.

PURPOSE: Metabolic tumour volume (MTV) is a promising prognostic indicator in diffuse large B cell lymphoma (DLBCL). Optimal thresholds to divide patients into 'low' versus 'high' MTV groups depend on clinical characteristics and the measurement method. The aim of this study was to compare in consecutive unselected patients with DLBCL, different software algorithms and published methods of MTV measurement using FDG PET. METHOD: Pretreatment MTV was measured on 147 patients treated at Guy's and St Thomas' Hospital. We compared 3 methods: SUV ≥2.5, SUV ≥41% of maximum SUV and SUV ≥ mean liver uptake (PERCIST) and compared 2 software programs for measuring SUV ≥2.5; in-house 'PETTRA' software and Hermes commercial software. RESULTS: There was strong correlation between MTV using the 4 methods, although derived thresholds were very different for the 41% method. Optimal cut-offs for predicting PFS ranged from 166-400cm3. All methods predicted survival with similar accuracy. 5y-PFS was 83-87% vs. 42-44% and 5y-OS was 85-89% vs. 55-58% for the low- and high-MTV groups, respectively. Interobserver variation in 50 patients showed excellent agreement, though variation was lowest using the SUV ≥ 2.5 method. The 41% method was the most complex and took the longest time. CONCLUSION: All methods predicted PFS and OS with similar accuracy, but the derived cut-off separating good from poor prognosis varied markedly depending on the method. The choice of the optimal method should rely primarily on prognostic value, but for clinical use needs to take account of ease of use and reproducibility. In this study, all methods predicted prognosis, but SUV ≥ 2.5 had the best inter-observer agreement and was easiest to apply.

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease.

See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer's disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer's disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer's disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65-79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer's disease who were prescribed amisulpride (25-75 mg daily) to treat psychosis as part of an open study (n = 28; 69-92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer's disease control group (n = 10, 78-92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer's disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer's disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer's disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood-brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing.

Therapeutic D2/3 receptor occupancies and response with low amisulpride blood concentrations in very late-onset schizophrenia-like psychosis (VLOSLP).

OBJECTIVE: Antipsychotic drug sensitivity in very late-onset schizophrenia-like psychosis (VLOSLP) is well documented, but poorly understood. This study aimed to investigate blood drug concentration, D2/3 receptor occupancy and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimer's disease (AD). METHODS: Blood drug concentration, prolactin, symptoms and extrapyramidal side-effects (EPS) were serially assessed during dose titration. [18 F]fallypride imaging was used to quantify D2/3 receptor occupancy. Average steady-state amisulpride concentration (Caverage, ng/ml) was estimated by incorporating pharmacokinetic (PK) data into an existing population PK model (25 AD participants, 20 healthy older people). RESULTS: Eight patients (target 20) were recruited (six women; 76 + - 6 years; six treatment compliant; five serially sampled; three with paired imaging data). Mean + - SD symptom reduction was 74 ± 12% (50-100 mg/day; 92.5 + -39.4 ng/ml). Mild EPS emerged at 96 ng/ml (in AD, severe EPS, 50 mg/day, 60 ng/ml). In three participants, imaged during optimal treatment (50 mg/day; 41-70 ng/ml), caudate occupancy was 44-59% (58-74% in AD across a comparable Caverage). CONCLUSIONS: Despite the small sample size, our findings are highly relevant as they suggest that, as in AD, 50 mg/day amisulpride is associated with >40% occupancy and clinically relevant responses in VLOSLP. It was not possible to fully characterise concentration-occupancy relationships in VLOSLP, and it is thus unclear whether the greater susceptibility of those with AD to emergent EPS was accounted for by increased central drug access. Further investigation of age- and diagnosis-specific threshold sensitivities is warranted, to guide amisulpride prescribing in older people, and therapeutic drug monitoring studies offer a potentially informative future approach. Copyright © 2017 John Wiley & Sons, Ltd.

Combination of baseline metabolic tumour volume and early response on PET/CT improves progression-free survival prediction in DLBCL.

BACKGROUND: The study objectives were to assess the prognostic value of quantitative PET and to test whether combining baseline metabolic tumour burden with early PET response could improve predictive power in DLBCL. METHODS: A total of 147 patients with DLBCL underwent FDG-PET/CT scans before and after two cycles of RCHOP. Quantitative parameters including metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were measured, as well as the percentage change in these parameters. Cox regression analysis was used to test the relationship between progression-free survival (PFS) and the study variables. Receiver operator characteristics (ROC) analysis determined the optimal cut-off for quantitative variables, and Kaplan-Meier survival analysis was performed. RESULTS: The median follow-up was 3.8 years. As MTV and TLG measures correlated strongly, only MTV measures were used for multivariate analysis (MVA). Baseline MTV (MTV-0) was the only statistically significant predictor of PFS on MVA. The optimal cut-off for MTV-0 was 396 cm(3). A model combing MTV-0 and Deauville score (DS) separated the population into three distinct prognostic groups: good (MTV-0 < 400; 5-year PFS > 90 %), intermediate (MTV-0 ≥ 400+ DS1-3; 5-year PFS 58.5 %) and poor (MTV-0 ≥ 400+ DS4-5; 5-year PFS 29.7 %) CONCLUSIONS: MTV-0 is an important prognostic factor in DLBCL. Combining MTV-0 and early PET/CT response improves the predictive power of interim PET and defines a poor-prognosis group in whom most of the events occur.

Kinetic analysis of hyperpolarized data with minimum a priori knowledge: Hybrid maximum entropy and nonlinear least squares method (MEM/NLS).

PURPOSE: To assess the feasibility of using a hybrid Maximum-Entropy/Nonlinear Least Squares (MEM/NLS) method for analyzing the kinetics of hyperpolarized dynamic data with minimum a priori knowledge. THEORY AND METHODS: A continuous distribution of rates obtained through the Laplace inversion of the data is used as a constraint on the NLS fitting to derive a discrete spectrum of rates. Performance of the MEM/NLS algorithm was assessed through Monte Carlo simulations and validated by fitting the longitudinal relaxation time curves of hyperpolarized [1-(13) C] pyruvate acquired at 9.4 Tesla and at three different flip angles. The method was further used to assess the kinetics of hyperpolarized pyruvate-lactate exchange acquired in vitro in whole blood and to re-analyze the previously published in vitro reaction of hyperpolarized (15) N choline with choline kinase. RESULTS: The MEM/NLS method was found to be adequate for the kinetic characterization of hyperpolarized in vitro time-series. Additional insights were obtained from experimental data in blood as well as from previously published (15) N choline experimental data. CONCLUSION: The proposed method informs on the compartmental model that best approximate the biological system observed using hyperpolarized (13) C MR especially when the metabolic pathway assessed is complex or a new hyperpolarized probe is used.

Towards a therapeutic window of D2/3 occupancy for treatment of psychosis in Alzheimer's disease, with [18F]fallypride positron emission tomography.

OBJECTIVE: Dopamine D2/3 receptor positron emission tomography tracers have guided antipsychotic prescribing in young people with schizophrenia by establishing a 'therapeutic window' of striatal D2/3 receptor occupancy. Older people, particularly those with dementia, are highly susceptible to motor side effects and may benefit from the appropriate application of imaging techniques. The study aimed to adapt [18F]fallypride imaging for use in occupancy studies in Alzheimer's disease (AD) and to investigate whether data acquisition could be made more tolerable by piloting the protocol in a small sample. METHODS: Six participants with AD (three men; 85.0 ± 5.6 years old; MMSE = 16.0 ± 2.4) were recruited prior to commencing amisulpride for the treatment of psychosis and associated agitation. [18F]fallypride binding potential (BPND ) was determined using an interrupted scanning protocol at baseline (n = 6) and after 27.0 ± 6.1 days of amisulpride (25-50 mg) treatment (n = 4). D2/3 occupancy was calculated by percentage reduction in BPND between scanning sessions. Image data were re-analysed after reducing individual sampling times to 20 min. RESULTS: The protocol was tolerated well, apart from the final (40 min) session of the post-treatment scan in one participant. Higher occupancies were achieved in the striatum (caudate 47-70%, putamen 31-58%) and thalamus (54-76%) than in the inferior temporal gyrus (27-43%). There was high agreement between occupancy values derived using longer and shorter sampling times (mean absolute difference 6.1% in the inferior temporal gyrus; <2% all other regions). CONCLUSIONS: The protocol is feasible for use in AD and represents the first step towards establishing dose-occupancy relationships across older clinical populations.

Regional cerebral blood flow and FDG uptake in asymptomatic HIV-1 men.

Despite advances in the treatment of patients with human immunodeficiency virus (HIV), HIV-associated neurocognitive disorder occurs in 15-50% of HIV-infected individuals, and may become more apparent as ageing advances. In the present study we investigated regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose uptake (rCMRglc) in medically and psychiatrically stable HIV-1-infected participants in two age-groups. Positron emission tomography (PET) and magnetic resonance imaging (MRI)-based arterial spin labeling (ASL) were used to measure rCMRglc and rCBF, respectively, in 35 HIV-infected participants and 37 HIV-negative matched controls. All participants were currently asymptomatic with undetectable HIV-1 viral loads, without medical or psychiatric comorbidity, alcohol or substance misuse, stable on medication for at least 6 months before enrolment in the study. We found significant age effects on both ASL and PET with reduced rCBF and rCMRglc in related frontal brain regions, and consistent, although small, reductions in rCBF and rCMRglc in the anterior cingulate cortex (ACC) in HIV, a finding of potential clinical significance. There was no significant interaction between HIV status and the ageing process, and no significant HIV-related changes elsewhere in the brain on PET or ASL. This is the first paper to combine evidence from ASL and PET method in HIV participants. These finding provide evidence of crossvalidity between the two techniques, both in ageing and a clinical condition (HIV).

A review of PET attenuation correction methods for PET-MR.

Despite being thirteen years since the installation of the first PET-MR system, the scanners constitute a very small proportion of the total hybrid PET systems installed. This is in stark contrast to the rapid expansion of the PET-CT scanner, which quickly established its importance in patient diagnosis within a similar timeframe. One of the main hurdles is the development of an accurate, reproducible and easy-to-use method for attenuation correction. Quantitative discrepancies in PET images between the manufacturer-provided MR methods and the more established CT- or transmission-based attenuation correction methods have led the scientific community in a continuous effort to develop a robust and accurate alternative. These can be divided into four broad categories: (i) MR-based, (ii) emission-based, (iii) atlas-based and the (iv) machine learning-based attenuation correction, which is rapidly gaining momentum. The first is based on segmenting the MR images in various tissues and allocating a predefined attenuation coefficient for each tissue. Emission-based attenuation correction methods aim in utilising the PET emission data by simultaneously reconstructing the radioactivity distribution and the attenuation image. Atlas-based attenuation correction methods aim to predict a CT or transmission image given an MR image of a new patient, by using databases containing CT or transmission images from the general population. Finally, in machine learning methods, a model that could predict the required image given the acquired MR or non-attenuation-corrected PET image is developed by exploiting the underlying features of the images. Deep learning methods are the dominant approach in this category. Compared to the more traditional machine learning, which uses structured data for building a model, deep learning makes direct use of the acquired images to identify underlying features. This up-to-date review goes through the literature of attenuation correction approaches in PET-MR after categorising them. The various approaches in each category are described and discussed. After exploring each category separately, a general overview is given of the current status and potential future approaches along with a comparison of the four outlined categories.

Factors associated with joint contractures in adults: a systematic review with narrative synthesis.

PURPOSE: The primary objective of the review was to collate the available evidence on factors associated with joint contractures in adults. METHODS: A systematic literature search was conducted on MEDLINE, CINAHL, AMED, and EMBASE. Studies that involved participants aged ≥18 and assessed joint contracture as a primary or secondary outcome were included. Two independent reviewers screened studies against the eligibility criteria, performed data extraction, and assessed the quality of evidence. A narrative synthesis by domain and sub-domain was undertaken. The protocol was registered on PROSPERO: CRD42019145079. RESULTS: Forty-seven studies were included in the review. Identified factors were broadly classified into three major domains: sociodemographic factors, physical factors, and proxies for bed confinement. Sociodemographic factors were not associated with joint contractures. Functional ability, pain, muscle weakness, physical mobility, and bed confinement provided the most consistent evidence of association with joint contractures. The evidence regarding the relationship between spasticity and joint contractures remains unclear. Other factors might be important, but there was insufficient evidence to make inferences. CONCLUSIONS: The review identified and collated evidence on factors associated with joint contractures, which can be utilised to develop effective prevention and management strategies. Implications for rehabilitationClinical interventions based on the timely identification of risks related to joint contractures in vulnerable adults have the potential to prevent or ameliorate their development or progression.Quality and consistency of care for vulnerable adults would be enhanced by developing effective joint contracture prevention and rehabilitation strategies based on the evidence presented in this review.As many vulnerable adults are located in the community or non-acute care settings, strategies should target these loci of care.Structured risk assessments that can support non-physiotherapy staff working in these loci of care to identify risks related to joint contractures would provide an important resource for risk management.

Pre-training via Transfer Learning and Pretext Learning a Convolutional Neural Network for Automated Assessments of Clinical PET Image Quality.

Positron emission tomography (PET) using a fraction of the usual injected dose would reduce the amount of radioligand needed, as well as the radiation dose to patients and staff, but would compromise reconstructed image quality. For performing the same clinical tasks with such images, a clinical (rather than numerical) image quality assessment is essential. This process can be automated with convolutional neural networks (CNNs). However, the scarcity of clinical quality readings is a challenge. We hypothesise that exploiting easily available quantitative information in pretext learning tasks or using established pre-trained networks could improve CNN performance for predicting clinical assessments with limited data. CNNs were pre-trained to predict injected dose from image patches extracted from eight real patient datasets, reconstructed using between 0.5%-100% of the available data. Transfer learning with seven different patients was used to predict three clinically-scored quality metrics ranging from 0-3: global quality rating, pattern recognition and diagnostic confidence. This was compared to pre-training via a VGG16 network at varying pre-training levels. Pre-training improved test performance for this task: the mean absolute error of 0.53 (compared to 0.87 without pre-training), was within clinical scoring uncertainty. Future work may include using the CNN for novel reconstruction methods performance assessment.

A case-control evaluation of pulmonary and extrapulmonary findings of incidental asymptomatic COVID-19 infection on FDG PET-CT.

OBJECTIVES: To describe the findings of incidental asymptomatic COVID-19 infection on FDG PET-CT using a case-control design. METHODS: Incidental pulmonary findings suspicious of asymptomatic COVID-19 infection on FDG PET-CT were classified as a confirmed (positive RT-PCR test) or suspected case (no/negative RT-PCR test). Control cases were identified using a 4:1 control:case ratio. Pulmonary findings were re-categorised by two reporters using the BSTI classification. SUV metrics in ground glass opacification (GGO)/consolidation (where present), background lung, intrathoracic nodes, liver, spleen and bone marrow were measured. RESULTS: 7/9 confirmed and 11/15 suspected cases (COVID-19 group) were re-categorised as BSTI 1 (classic/probable COVID-19) or BSTI 2 (indeterminate COVID-19); 0/96 control cases were categorised as BSTI 1. Agreement between two reporters using the BSTI classification was almost perfect (weighted κ = 0.94). SUVmax GGO/consolidation (5.1 vs 2.2; p < 0.0001) and target-to-background ratio, normalised to liver SUVmean (2.4 vs 1.0; p < 0.0001) were higher in the BSTI 1 & 2 group vs BSTI 3 (non-COVID-19) cases. SUVmax GGO/consolidation discriminated between the BSTI 1 & 2 group vs BSTI 3 (non-COVID-19) cases with high accuracy (AUC = 0.93). SUV metrics were higher (p < 0.05) in the COVID-19 group vs control cases in the lungs, intrathoracic nodes and spleen. CONCLUSION: Asymptomatic COVID-19 infection on FDG PET-CT is characterised by bilateral areas of FDG avid (intensity > x2 liver SUVmean) GGO/consolidation and can be identified with high interobserver agreement using the BSTI classification. There is generalised background inflammation within the lungs, intrathoracic nodes and spleen. ADVANCES IN KNOWLEDGE: Incidental asymptomatic COVID-19 infection on FDG PET-CT, characterised by bilateral areas of ground glass opacification and consolidation, can be identified with high reproducibility using the BSTI classification. The intensity of associated FDG uptake (>x2 liver SUVmean) provides high discriminative ability in differentiating such cases from pulmonary findings in a non-COVID-19 pattern. Asymptomatic COVID-19 infection causes a generalised background inflammation within the mid-lower zones of the lungs, hilar and central mediastinal nodal stations, and spleen on FDG PET-CT.

Test-retest repeatability and interobserver variation of healthy tissue metabolism using 18F-FDG PET/CT of the thorax among lung cancer patients.

OBJECTIVES: The aim of this study was to assess the test-retest repeatability and interobserver variation in healthy tissue (HT) metabolism using 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET/computed tomography (PET/CT) of the thorax in lung cancer patients. METHODS: A retrospective analysis was conducted in 22 patients with non-small cell lung cancer who had two PET/CT scans of the thorax performed 3 days apart with no interval treatment. The maximum, mean and peak standardized uptake values (SUVs) in different HTs were measured by a single observer for the test-retest analysis and two observers for interobserver variation. Bland-Altman plots were used to assess the repeatability and interobserver variation. Intrasubject variability was evaluated using within-subject coefficients of variation (wCV). RESULTS: The wCV of test-retest SUVmean measurements in mediastinal blood pool, bone marrow, skeletal muscles and lungs was less than 20%. The left ventricle (LV) showed higher wCV (>60%) in all SUV parameters with wide limits of repeatability. High interobserver agreement was found with wCV of less than 10% in SUVmean of all HT, but up to 22% was noted in the LV. CONCLUSION: HT metabolism is stable in a test-retest scenario and has high interobserver agreement. SUVmean was the most stable metric in organs with low FDG uptake and SUVpeak in HTs with moderate uptake. Test-retest measurements in LV were highly variable irrespective of the SUV parameters used for measurements.

Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase.

Introduction: Pegargiminase (ADI-PEG 20I) degrades arginine in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma (MPM) and NSCLC. Imaging with proliferation biomarker 3'-deoxy-3'-[18F] fluorothymidine (18F-FLT) positron emission tomography (PET)-computed tomography (CT) was performed in a phase 1 study of pegargiminase with pemetrexed and cisplatin (ADIPemCis). The aim was to determine whether FLT PET-CT predicts treatment response earlier than CT. Methods: A total of 18 patients with thoracic malignancies (10 MPM; eight NSCLC) underwent imaging. FLT PET-CT was performed at baseline (PET1), 24 hours post-pegargiminase monotherapy (PET2), post one cycle of ADIPemCis (PET3), and at end of treatment (EOT, PET4). CT was performed at baseline (CT1) and EOT (CT4). CT4 (modified) Response Evaluation Criteria in Solid Tumors (RECIST) response was compared with treatment response on PET (changes in maximum standardized uptake value [SUVmax] on European Organisation for Research and Treatment of Cancer-based criteria). Categorical responses (progression, partial response, and stable disease) for PET2, PET3, and PET4 were compared against CT using Cohen's kappa. Results: ADIPemCis treatment response resulted in 22% mean decrease in size between CT1 and CT4 and 37% mean decrease in SUVmax between PET1 and PET4. PET2 agreed with CT4 response in 62% (8 of 13) of patients (p = 0.043), although decrease in proliferation (SUVmax) did not precede decrease in size (RECIST). Partial responses on FLT PET-CT were detected in 20% (3 of 15) of participants at PET2 and 69% (9 of 13) at PET4 with good agreement between modalities in MPM at EOT. Conclusions: Early FLT imaging (PET2) agrees with EOT CT results in nearly two-thirds of patients. Both early and late FLT PET-CT provide evidence of response to ADIPemCis therapy in MPM and NSCLC. We provide first-in-human FLT PET-CT data in MPM, indicating it is comparable with modified RECIST.

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls.

BACKGROUND: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippocampus in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling; however, this has not been tested in vivo. METHODS: In this study, we investigated the relationship between hippocampal NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study; 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippocampal NMDAR availability using the PET ligand [18F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy (1H-MRS). RESULTS: A total of 33 individuals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years; mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippocampal DVR and striatal glutamate levels in people with first-episode psychosis (rho = -0.74, p < 0.001) but not in healthy controls (rho = -0.22, p = 0.44). CONCLUSION: This study show that lower relative NMDAR availability in the hippocampus may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.

From bench to bedside: The mGluR5 system in people with and without Autism Spectrum Disorder and animal model systems.

The metabotropic glutamate receptor 5 (mGluR5) is a key regulator of excitatory (E) glutamate and inhibitory (I) γ-amino butyric acid (GABA) signalling in the brain. Despite the close functional ties between mGluR5 and E/I signalling, no-one has directly examined the relationship between mGluR5 and glutamate or GABA in vivo in the human brain of autistic individuals. We measured [18F] FPEB (18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile) binding in 15 adults (6 with Autism Spectrum Disorder) using two regions of interest, the left dorsomedial prefrontal cortex and a region primarily composed of left striatum and thalamus. These two regions were mapped out using MEGA-PRESS voxels and then superimposed on reconstructed PET images. This allowed for direct comparison between mGluR5, GABA + and Glx. To better understand the molecular underpinnings of our results we used an autoradiography study of mGluR5 in three mouse models associated with ASD: Cntnap2 knockout, Shank3 knockout, and 16p11.2 deletion. Autistic individuals had significantly higher [18F] FPEB binding (t (13) = -2.86, p = 0.047) in the left striatum/thalamus region of interest as compared to controls. Within this region, there was a strong negative correlation between GABA + and mGluR5 density across the entire cohort (Pearson's correlation: r (14) = -0.763, p = 0.002). Cntnap2 KO mice had significantly higher mGlu5 receptor binding in the striatum (caudate-putamen) as compared to wild-type (WT) mice (n = 15, p = 0.03). There were no differences in mGluR5 binding for mice with the Shank3 knockout or 16p11.2 deletion. Given that Cntnap2 is associated with a specific striatal deficit of parvalbumin positive GABA interneurons and 'autistic' features, our findings suggest that an increase in mGluR5 in ASD may relate to GABAergic interneuron abnormalities.

A tumor volume and performance status model to predict outcome before treatment in diffuse large B-cell lymphoma.

Aggressive large B-cell lymphoma (LBCL) has variable outcomes. Current prognostic tools use factors for risk stratification that inadequately identify patients at high risk of refractory disease or relapse before initial treatment. A model associating 2 risk factors, total metabolic tumor volume (TMTV) >220 cm3 (determined by fluorine-18 fluorodeoxyglucose positron emission tomography coupled with computed tomography) and performance status (PS) ≥2, identified as prognostic in 301 older patients in the REMARC trial (#NCT01122472), was validated in 2174 patients of all ages treated in 2 clinical trials, PETAL (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas; N = 510) and GOYA (N = 1315), and in real-world clinics (N = 349) across Europe and the United States. Three risk categories, low (no factors), intermediate (1 risk factor), and high (2 risk factors), significantly discriminated outcome in most of the series. Patients with 2 risk factors had worse outcomes than patients with no risk factors in the PETAL, GOYA, and real-world series. Patients with intermediate risk also had significantly worse outcomes than patients with no risk factors. The TMTV/Eastern Cooperative Oncology Group-PS combination outperformed the International Prognostic Index with a positive C-index for progression-free survival and overall survival in most series. The combination of high TMTV > 220 cm3 and ECOG-PS ≥ 2 is a simple clinical model to identify aggressive LBCL risk categories before treatment. This combination addresses the unmet need to better predict before treatment initiation for aggressive LBCL the patients likely to benefit the most or not at all from therapy.