Baseline Positron Emission Tomography Scans Research Articles

Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults

Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood. To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aβ) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults. This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aβ deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aβ deposition were included. Plasma leptin levels as assessed by enzyme-linked immunosorbent assay. Baseline levels and longitudinal changes of global Aβ and AD-signature region tau deposition measured by PET scans. Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aβ deposition (β = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (β = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (β = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aβ deposition (β = 0.006; 95% CI, 0.00-0.02; P = .27). The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aβ and tau deposition.

Dissimilar Effect of P-Glycoprotein and Breast Cancer Resistance Protein Inhibition on the Distribution of Erlotinib to the Retina and Brain in Humans and Mice.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two ATP-binding cassette efflux transporters that are coexpressed at the human blood-brain barrier (BBB) and blood-retina barrier (BRB). While pharmacological inhibition of P-gp and/or BCRP results in increased brain distribution of dual P-gp/BCRP substrate drugs, such as the tyrosine kinase inhibitor erlotinib, the effect of P-gp and/or BCRP inhibition on the retinal distribution of such drugs has hardly been investigated. In this study, we used positron emission tomography (PET) imaging to assess the effect of transporter inhibition on the distribution of [11C]erlotinib to the human retina and brain. Twenty two healthy volunteers underwent two PET scans after intravenous (i.v.) injection of a microdose (<5 μg) of [11C]erlotinib, a baseline scan, and a second scan either with concurrent i.v. infusion of tariquidar to inhibit P-gp (n = 5) or after oral intake of single ascending doses of erlotinib (300 mg, 650 mg, or 1000 mg, n = 17) to saturate erlotinib transport. In addition, transport of [3H]erlotinib to the retina and brain was assessed in mice by in situ carotid perfusion under various drug transporter inhibition settings. In comparison to the baseline PET scan, coadministration of tariquidar or erlotinib led to a significant decrease of [11C]erlotinib total volume of distribution (VT) in the human retina by -25 ± 8% (p ≤ 0.05) and -41 ± 16% (p ≤ 0.001), respectively. In contrast, erlotinib intake led to a significant increase in [11C]erlotinib VT in the human brain (+20 ± 16%, p ≤ 0.001), while administration of tariquidar did not result in any significant changes. In situ carotid perfusion experiments showed that both P-gp and BCRP significantly limit the distribution of erlotinib to the mouse retina and brain but revealed a similar discordant effect at the mouse BRB and BBB following co-perfusion with tariquidar and erlotinib as in humans. Co-perfusion with prototypical inhibitors of solute carrier transporters did not reveal a significant contribution of organic cation transporters (e.g., OCTs and OCTNs) and organic anion-transporting polypeptides (e.g., OATP2B1) to the retinal and cerebral distribution of erlotinib. In conclusion, we observed a dissimilar effect after P-gp and/or BCRP inhibition on the retinal and cerebral distribution of [11C]erlotinib. The exact mechanism for this discrepancy remains unclear but may be related to the function of an unidentified erlotinib uptake carrier sensitive to tariquidar inhibition at the BRB. Our study highlights the great potential of PET to study drug distribution to the human retina and to assess the functional impact of membrane transporters on ocular drug distribution.

Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi-center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER-ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER-ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver-operating characteristic (ROC) curves. PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity.A positive amyloid PET is not necessarily associated with tau positivity.Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

Feasibility Study to Assess Canagliflozin Distribution and Sodium-Glucose Co-Transporter 2 Occupancy Using [18 F]Canagliflozin in Patients with Type 2 Diabetes.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large interindividual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [18 F]canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes. We obtained two 90-minute dynamic PET scans with diagnostic intravenous [18 F]canagliflozin administration and a full kinetic analysis in 7 patients with type 2 diabetes. Patients received 50, 100, or 300 mg oral canagliflozin (n = 2:4:1) 2.5 hours before the second scan. Canagliflozin pharmacokinetics and urinary glucose excretion were measured. The apparent SGLT2 occupancy was derived from the difference between the apparent volume of distribution of [18 F]canagliflozin in the baseline and post-drug PET scans. Individual canagliflozin area under the curve from oral dosing until 24-hours (AUCP0-24h ) varied largely (range 1,715-25,747 μg/L*hour, mean 10,580 μg/L*hour) and increased dose dependently with mean values of 4,543, 6,525, and 20,012 μg/L*hour for 50, 100, and 300 mg, respectively (P = 0.046). SGLT2 occupancy ranged between 65% and 87%, but did not correlate with canagliflozin dose, plasma exposure, or urinary glucose excretion. We report the feasibility of [18 F]canagliflozin PET imaging to determine canagliflozin kidney disposition and SGLT2 occupancy. This suggests the potential of [18 F]canagliflozin as a tool to visualize and quantify clinically SGLT2 tissue binding.

Baseline metabolic tumour burden improves risk stratification in Hodgkin lymphoma: A Children's Oncology Group study.

The Children's Oncology Group AHOD0831 study used a positron emission tomography (PET) response-adapted approach in high-risk Hodgkin lymphoma, whereby slow early responders (SERs) received more intensive therapy than rapid early responders (RERs). We explored if baseline PET-based characteristics would improve risk stratification. Of 166 patients enrolled in the COG AHOD0831 study, 94 (57%) had baseline PET scans evaluable for quantitative analysis. For these patients, total body metabolic tumour volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax ) and peak SUV (SUVpeak ) were obtained. MTV/TLG thresholds were an SUV of 2.5 (MTV2.5 /TLG2.5 ) and 40% of the tumour SUVmax (MTV40% /TLG40% ). TLG2.5 was associated with event-free survival (EFS) in the complete cohort (p= 0.04) and in RERs (p= 0.01), but not in SERs (p= 0.8). The Youden index cut-off for TLG2.5 was 1841. Four-year EFS was 92% for RER/TLG2.5 up to 1841, 60% for RER/TLG2.5 greater than 1841, 74% for SER/TLG2.5 up to 1841 and 79% for SER/TLG2.5 greater than 1841. Second EFS for RER/TLG2.5 up to 1841 was 100%. Thus, RERs with a low baseline TLG2.5 experienced excellent EFS with less intensive therapy, whereas RERs with a high baseline TLG2.5 experienced poor EFS. These findings suggest that patients with a high upfront tumour burden may benefit from intensified therapy, even if they achieve a RER.

Plasma Aβ42/40 and PET amyloid associations among late‐middle‐aged African Americans: Preliminary results from the AA‐FAIM study

AbstractBackgroundAlzheimer’s disease (AD) models of disease progression have been built largely on non‐Hispanic White samples. Availability of AD blood‐based biomarkers may improve screening for AD risk and facilitate greater diversity in research studies; little is known about these biomarkers within African Americans (AA). Here, we characterized associations between plasma Ab42/40 and Positron Emission Tomography (PET) amyloid measures in an AA sample.MethodParticipants in the African Americans Fighting Alzheimer’s in Mid‐Life (AA‐FAIM) with &gt;=1 PET scan and plasma Ab42/40 assay were included (n=34 participants; n=117 EDTA plasma samples). The ratio Ab42/40 was calculated from plasma Ab40 and Ab42 quantified by C2N Diagnostics (PrecivityAD™). PET 11C‐Pittsburgh compound B (PIB)‐derived amyloid measures included a mean cortical DVR (global PiB DVR), PET_A+ (DVR&gt;1.19) and estimated PET_A+ duration at each plasma sample. In separate models where “time” was age or PET_A+ duration at each plasma sample (outcome=plasma Ab42/40), we used mixed effects models to estimate simple slopes from time*PET_A+ status interactions. Sensitivity, specificity and related statistics were calculated for two plasma_A+ cutoffs (0.0975, West et al., 2021; 0.089, Hu et al., 2022).ResultBaseline plasma sample and baseline PET scan average(sd) ages were 61(8.6) and 65(9), respectively. Closest plasma Ab42/40 explained 47% of variability in last global PiB DVR (mean(sd)=‐0.85(0.91) years plasma‐to‐PET). Seven(20.6%) participants were PET_A+. In longitudinal analyses, simple age‐slopes for plasma Ab42/40 change were ‐0.00061(0.00024) for PET_A+ and ‐0.00057(0.00018) for PET_A‐ (age*PET_A status interaction NS; model AICc=‐792.6). In a parallel mixed effect model, simple slopes were ‐0.00093(0.00026) for PET_A+ change/year and ‐0.00039(0.00012) for PET_A‐ change/year (interaction p∼0.06; AICc=‐800.6). Figures 1 and 2 depict relationships among plasma and PET amyloid measures. Positive and negative predictive values were 50.0% and 95.5% (0.0975 cut‐off) and 68% and 83% (0.089 cut‐off; see Figure 1 for additional statistics).ConclusionPreliminary results from this small African American sample provide encouraging data regarding plasma Ab42/40’s potential to screen for PET A+ in AAs. PET A+ duration explained more variability than age in plasma Ab42/40 trajectories. The on‐going AA‐FAIM study continues the critical effort to increase representation of AA in AD research, ensuring findings are broadly applicable.

Brain amyloid load and cognitive trajectories in older individuals at risk for dementia

AbstractBackgroundMost studies have so far investigated the cognitive performances and amyloid status on brain PET scans in cognitively normal, cognitively impaired, or individuals with dementia. In this study associations between brain amyloid status and changes in cognitive performance over time in an at‐risk older general population without dementia or substantial cognitive impairment were evaluated.MethodForty‐eight individuals from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) main study participated in the 11C‐Pittsburgh compound B (PiB)‐positron emission tomography (PET) exploratory sub‐study. Participants were categorized as amyloid+ or amyloid– after baseline PET scans were assessed visually by two experienced readers. A comprehensive cognitive Neuropsychological Test Battery (NTB) was used to assess cognitive performance at baseline, 12‐ and 24‐month follow‐up. The Prospective and Retrospective Memory Questionnaire was used to measure subjective cognitive complaints (SCCs) during the study. Changes in cognitive functions during the 2‐year study were compared across baseline amyloid groups using mixed effects regression models with maximum likelihood estimation.ResultThe mean age for all participants (n=48) was 71.4 years, and 22 participants (45%) were female. At baseline, 20 participants (42%) had amyloid+ PET scans and amyloid positivity was associated with lower NTB executive function (estimate = ‐0.38, 95% CI= ‐0.70 – ‐0.05, p=0.03). Interaction terms between baseline amyloid+ status and time were significant for NTB total score (estimate=‐0.10, 95% CI= ‐0.20 – ‐0.01, p=0.04) and NTB memory score (estimate = ‐0.18, 95% CI= ‐0.34 – ‐0.03, p=0.02). No significant associations were observed between amyloid positivity and change in NTB executive function score or NTB processing speed score. Furthermore, amyloid status was not significantly related to SCCs.ConclusionResults from this study suggest that positive amyloid status is likely to reduce cognitive abilities over time. Interestingly, in this very early at‐risk stage before the onset of substantial impairment or dementia, amyloid status was related to poorer trajectories in global cognition and memory over time, but not to subjective cognitive complaints. However, future studies with larger sample sizes and longer follow up period will be needed to further investigate the impact of amyloid accumulation.

Brain target occupancy of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme, following administration of single and multiple doses to healthy volunteers

AbstractBackgroundLY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report on single dose (SD) and multiple dose (MD) clinical studies testing the effect of LY3372689 on brain OGA enzyme occupancy (EO).MethodA positron emission tomography (PET) radioligand, 18F‐LY3316612, was used to assess brain OGA EO in healthy volunteers (HV). In the SD study [NCT03944031], 0.25, 1 and 5 mg LY3372689 were evaluated across 4 cohorts (N = 4 HV per cohort). Each HV had PET scans at baseline and two post‐dose intervals. Post‐dose scans occurred at 2 and 24 hours at 0.25, 1, and 5 mg, with additional scans for 1 mg at 30 and 54 hours. The MD study [NCT04392271] consisted of 1 cohort (N = 4 HV) given 1 mg LY3372689 once daily for 14 days. Each HV had a baseline PET scan, and PET scans at 24 hours post‐dose after the 1st and 14th administration of LY3372689. Plasma pharmacokinetics was assessed in these studies.ResultIn the SD study, the mean brain OGA EO at 5 mg was 98% at 2 hours and 93% at 24 hours. At 1 mg, the mean EO was 97% at 2 hours, 81% at 24 hours, 68% at 30 hours, and 30% at 54 hours. The EO at 0.25 mg was lower at 2 hours (26%) compared to 24 hours (46%). The Emax and EC50 values were estimated to be 97% and 0.1 ng/mL, respectively. In the MD study, the OGA EO at 24 hours after the 1st and 14th administration of 1 mg LY3372689 was 84%.ConclusionPET studies in healthy volunteers demonstrated that LY3372689 can achieve high brain target occupancy of the OGA enzyme. Brain OGA EO was maintained after multiple dosing, supporting the durability of target engagement for longer clinical trials. The human PET data will be used to support LY3372869 dose selection for efficacy trials in tauopathies.

Generation and validation of a PET radiomics model that predicts survival in diffuse large B cell lymphoma treated with R-CHOP14: A SAKK 38/07 trial post-hoc analysis.

Functional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression-free (PFS), cause-specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p<0.001) and validation (AUC, 0.706; p<0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p<0.001; OS: AUC, 0.740; p<0.001) and validation (CSS: AUC, 0.763; p<0.0001; OS: AUC, 0.703; p=0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET-derived radiomics may improve the prediction of outcome in DLBCL patients.

PET-Based Quantification of Baseline Metabolic Tumor Burden Improves Risk Stratification in High-Risk Hodgkin Lymphoma: A Children's Oncology Group Study

<h3>Purpose/Objective(s)</h3> COG AHOD0831 was a multi-center, prospective study that used a response-adapted approach for patients < 22-years-old with high-risk Hodgkin lymphoma. After 2 cycles of chemotherapy, response evaluation was performed by ¹⁸F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) scan. Rapid early responders (RERs) received less intensive therapy than slow early responders (SERs). In this study, both 1^st & 2^nd event-free survival (EFS) rates were below the pre-specified targets. We explored if measures of baseline tumor burden improve risk stratification. <h3>Materials/Methods</h3> Patients from AHOD0831 were identified who had baseline PET scans that were amenable to quantitative analyses. For each patient, metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax), and peak SUV (SUVpeak) were obtained for mediastinal (m) and total body (t) disease. MTV was defined based on thresholds of SUV > 2.5 or > 40% SUVmax. TLG was defined as MTV * tumor SUVmean. EFS was assessed by Kaplan-Meier analyses. 2^nd EFS was defined as the time to a second event, reflecting rates of successful salvage after a 1^st relapse. Receiver operating characteristic analyses estimated the ability of PET parameters to predict EFS; optimized cutoff values were identified using a Youden index. <h3>Results</h3> Of 166 patients enrolled on AHOD0831, 94 (57%) had PET scans evaluable for quantitative analysis. For this subset: median age 15.5 years; 62% male; 67% white; 45% stage III, 55% stage IV; 86% bulk; 60% nodular sclerosis histology; 54% RER, 46% SER. These characteristics did not differ significantly from the complete AHOD0831 cohort. At a median follow-up of 49 months, 4-year EFS was 76% for the complete cohort (76% RERs, 75% SERs). Patients with high tMTVs and tTLGs, based on each threshold, were significantly more likely to be SERs (all <i>P</i> < 0.02). tTLG_2.5 was significantly associated with EFS, with an optimal cutoff value of 1841 to distinguish low- and high-risk groups (<i>P</i> = 0.04). tTLG_2.5 was significantly associated with EFS in RERs (<i>P</i> = 0.01) but not in SERs (<i>P</i> = 0.8). Patients were stratified by RER vs. SER and high vs. low tTLG_2.5. The best EFS was associated with RER & low tTLG_2.5, the worst EFS with RER & high tTLG_2.5, and intermediate EFS with SER regardless of tTLG_2.5 (4-year EFS: 92%, n = 25; 60%, n = 26; 79%, n = 14; 74%, n = 29, respectively). EFS was superior in patients with tTLG_2.5 ≤1841 & RER when compared to the rest of the cohort (94% vs. 71%, <i>P</i> = 0.02). For this favorable subgroup, 2^nd EFS was 100%. <h3>Conclusion</h3> RERs with a low baseline metabolic tumor burden experienced excellent EFS with less intensive therapy. Conversely, RERs with a high baseline tumor burden experienced poor EFS that was even worse than that of SERs. Thus, patients with a high metabolic tumor burden upfront may benefit from intensified therapy, even if they achieve a RER. PET-based measures of initial disease burden may contribute to risk-based treatment algorithms and improve outcomes in HL.

Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031.

Positron emission tomography (PET)-based measures of baseline total-body tumor burden may improve risk stratification in intermediate-risk Hodgkin lymphoma (HL). Evaluable patients were identified from a cohort treated homogeneously with the same combined modality regimen on the Children's Oncology Group AHOD0031 study. Eligible patients had high-quality baseline PET scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were each measured based on 15 thresholds for every patient. Univariate and multivariable Cox regression and Kaplan-Meier survival analyses assessed for an association of MTV and TLG with event-free survival (EFS). From the AHOD0031 cohort (n=1712), 86 patients were identified who (i) were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy followed by involved field radiotherapy, and (ii) had a baseline PET scan that was amenable to quantitative analysis. Based on univariate Cox regression analysis, six PET-derived parameters were significantly associated with EFS. For each of these, Kaplan-Meier analyses and the log-rank test were used to compare patients with highest tumor burden (i.e., highest 15%) to the remainder of the cohort. EFS was significantly associated with all six PET parameters (all p<.029). In a multivariable model controlling for important covariates including disease bulk and response to chemotherapy, MTV2BP was significantly associated with EFS (p=.012). Multiple baseline PET-derived volumetric parameters were associated with EFS. MTV2BP was highly associated with EFS when controlling for disease bulk and response to chemotherapy. Incorporation of baseline MTV into risk-based treatment algorithms may improve outcomes in intermediate-risk HL.

Does sodium oxybate inhibit brain dopamine release in humans? An exploratory neuroimaging study.

To establish in an exploratory neuroimaging study whether γ-hydroxybutyrate (sodium oxybate [SO]), a sedative, anti-narcoleptic drug with abuse potential, transiently inhibits striatal dopamine release in the human. Ten healthy participants (30 years; 6M, 4F) and one participant with narcolepsy received a baseline positron emission tomography scan of [C-11]raclopride, a D2/3 dopamine receptor radioligand sensitive to dopamine occupancy, followed approximately one week later by an oral sedative 3g dose of SO and two [C-11]raclopride scans (1 h, 7 h post SO). Plasma SO levels and drowsiness duration were assessed. No significant changes were detected in [C-11]raclopride binding in striatum overall 1 or 7 h after SO, but a small non-significant increase in [C-11]raclopride binding, implying decreased dopamine occupancy, was noted in limbic striatal subdivision at one hour (+6.5%; p uncorrected=0.045; +13.2%, narcolepsy participant), returning to baseline at 7 h. A positive correlation was observed between drowsiness duration and percent change in [C-11]raclopride binding in limbic striatum (r=0.73; p=0.017). We did not find evidence in this sample of human subjects of a robust striatal dopamine change, as was reported in non-human primates. Our preliminary data, requiring extension, suggest that a 3g sedative SO dose might cause slight transient inhibition of dopamine release in limbic striatum.

Prognostic Impact of Metabolic Tumor Burden in Large B-Cell Lymphoma Patients Receiving CAR T-Cell Therapy

Introduction Chimeric antigen receptor (CAR) T-cell therapy provides long-term remissions in a substantial proportion of patients with large B-cell lymphoma (LBCL) who have relapsed or are refractory (R/R) to chemoimmunotherapy. The identification of prognostic factors to identify which patients will benefit most from this therapy is crucial to improve patient selection. Even though metabolic tumor burden assessed by 18F-fluorodeoxyglucose Positron Emission Tomography (PET) has a confirmed prognostic value in the setting of chemoimmunotherapy, its predictive role after CAR T-cell therapy is not established. Methods We conducted a single-center study including all patients with R/R LBCL who received a single infusion of CD19-targeted second-generation CAR T-cells carrying a 4-1BB costimulatory domain from July 2018 to January 2020. Adverse events were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus. All patients underwent a baseline PET scan and metabolic disease evaluation after infusion. Disease response assessment was conducted according to Lugano criteria. Metabolic tumor volume (MTV) and maximum standardized uptake value (SUVmax) were measured at baseline and at 1-month after CAR T-cell infusion, and correlated with disease response and development of adverse events. To identify the optimal cut-offs for metabolic parameters we used the maximally selected log-rank statistics in the PFS analysis. Results Thirty-five consecutive patients with R/R LBCL who received CAR T-cell therapy were included in the study. Patients' baseline characteristics are summarized in Table 1. Median age at treatment was 58 years, and 74% were males. At the time of diagnosis most of them had an advanced stage of disease (86%) and were refractory to the last therapy (n=31, 88%). Best response after CAR T-cell therapy included 9 (26%) patients in complete remission (CR) and 16 (46%) in partial remission (PR). Ten (28%) patients were in progressive disease (PD) at the 1-month disease evaluation. At a median follow-up of 7.6 months, median PFS and OS were 3.4 months and 8.2 months, respectively. Regarding toxicity, eleven (31%) patients developed clinically significant CAR T-cell related toxicity, defined as grade 2 or higher CRS (n=7, 20%) and grade 2 or higher ICANS (n=6, 17%). Median baseline MTV and MTV41% were 270 cm3(IQR 87-875) and 119 cm3 (IQR 32-300), respectively. Median SUVmax was 24 (IQR 17-32). Patients who responded (CR and PR) had lower baseline MTV values compared with non-responders (median of 228 cm3 vs 645 cm3, p=0.04) (Figure 1a). No association was found between MTV41% or SUVmax and disease response. In terms of PFS, a high baseline MTV (&amp;gt;82 cm3) was associated with a lower PFS compared to patients with lower MTV values (median PFS, 2.1 months vs. 6 months; HR 3.15, p= 0.02) (Table 2 and Figure 2). Patients with high baseline MTV41% values (&amp;gt;25 cm3) also had an inferior PFS (HR 3.44, p= 0.02); no association was found between baseline SUVmax and PFS (Table 2). As per OS, there was no significant association with baseline MTV, MTV41% and SUVmax (Table 2). Regarding toxicity, there was no significant association between baseline MTV, MTV 41% and SUVmax values with grade 2 or higher CRS and ICANS events (Figure 1b). All patients underwent a 1-month post-infusion PET evaluation. Disease response at this timepoint was: CR in 8 patients (23%), PR in 17 patients (49%) and PD in 10 patients (28%). For patients in CR and PR at 1-month the probability of PFS at 6 months was 62.5% and 12.7%, respectively (HR=3.89, p=0.02). For patients in PR at the 1-month evaluation, MTV values at that timepoint were predictive for PFS; patients in PR with low (&amp;lt;35 cm3) and high 1-month MTV values had a 6m-PFS of 33% and 0%, respectively (Figure 3)(HR=4.6, p = 0.01). In these patients, SUVmax values also predicted PFS and a trend towards significance was observed for MTV41% (HR=3, p=0.07). Conclusion Metabolic tumor burden parameters measured by 18FDG-PET before and 1-month after CAR-T cell infusion identify LBCL patients who benefit most from these therapies and could aid patient selection. Disclosures Iacoboni: Novartis, Gilead, Celgene, Roche: Honoraria. Villacampa:AstraZeneca: Other: advisory role; Merck Sharp &amp; Dohme: Honoraria. Abrisqueta:AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Bosch:Hoffmann-La Roche: Research Funding. Barba:Novartis, Celgene, Gilead, Pfizer, Amgen, Roche: Honoraria.

Baseline SUVmax did not predict histological transformation in follicular lymphoma in the phase 3 GALLIUM study

AbstractA minority of patients with follicular lymphoma (FL) undergo histological transformation (HT). This retrospective analysis of 549 patients from the phase 3 GALLIUM study (NCT01332968) assessed the relationship between maximum standardized uptake value (SUVmax) at baseline on positron emission tomography (PET) and HT risk. Previously untreated patients with high tumor burden grade 1-3a FL received obinutuzumab- or rituximab-based chemotherapy induction. The relationship between baseline SUVmax (bSUVmax) and HT risk was assessed using cutoff values for SUVmax >10 and >20. Overall, 15 of 549 (2.7%) patients with baseline PET scans experienced biopsy-confirmed HT (median follow-up, 59 months). More than 65% of patients had bSUVmax > 10, with 3.3% of these experiencing HT. Only 1 of 74 (1.4%) patients with bSUVmax > 20 underwent HT. Median bSUVmax in patients with HT vs without HT was 12.4 (range, 8.1-28.0) vs 11.8 (range, 3.1-64.4), respectively; median bSUVrange (the difference between bSUVmax of the most and least 18F-fluorodeoxyglucose–avid lymphoma sites) was 8.0 (range, 1.1-23.9) vs 7.1 (range, 0.0-59.8), respectively. There was no temporal relationship between bSUVmax and HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting that there may be little benefit in rebiopsy of lesions to exclude HT based on SUVmax alone before initiating therapy in patients with high tumor burden FL.

Baseline PET-Derived Metabolic Tumor Volume Metrics Did Not Predict Outcomes in Follicular Lymphoma Patients Treated with First-Line Immunochemotherapy and Antibody Maintenance in the Phase III GALLIUM Study

Baseline PET-Derived Metabolic Tumor Volume Metrics Did Not Predict Outcomes in Follicular Lymphoma Patients Treated with First-Line Immunochemotherapy and Antibody Maintenance in the Phase III GALLIUM Study

The Impact of Staging by Positron-Emission Tomography on Overall Survival and Progression-Free Survival in Patients With LocallyAdvanced NSCLC.

We investigated the potential impact of stage migration because of positron-emission tomography (PET) scan staging on survival in the locally advanced (stage IIIA/B) NSCLC setting. In PROCLAIM, 598 patients with stage IIIA/B nonsquamous NSCLC (intent-to-treat population) were randomized to either pemetrexed plus cisplatin and concurrent thoracic radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation or etoposide plus cisplatin and concurrent thoracic radiotherapy for 2 cycles followed by a consolidation platinum-based doublet regimen for up to 2 cycles. Baseline PET scan (PET Yes versus No) was one of the stratification factors. Subgroup analyses (PET Yes versus No) of overall survival (OS) and progression-free survival (PFS) were conducted on the intent-to-treat population regardless of treatment, as the study did not show superior efficacy for either arm. Majority (491 of 598; 82.1%) of patients had a baseline PET scan staging performed. A longer median OS (PET Yes versus No: 27.2 versus 20.8; hazard ratio= 0.81, p= 0.130) and an improved median PFS (PET Yes versus No: 11.3 versus 9.2; hazard ratio= 0.73, p= 0.012) were observed for patients with PET scans compared to those with conventional staging in both treatment arms. Both a significantly improved PFS and a numerically longer OS in the PET Yes subgroup, compared to patients with conventional staging, are consistent with improved survival due to stage migration. The magnitude of differences in OS and PFS based on PET scan is a reminder of the potential for factors other than the therapeutic intervention to affect outcomes.

Baseline PET-Derived Metabolic Tumor Volume Metrics Predict Progression-Free and Overall Survival in DLBCL after First-Line Treatment: Results from the Phase 3 GOYA Study

Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomography assessment using total metabolic tumor volume (TMTV) and tumor lesion glycolysis (TLG) measurements has been found promising as an objective method to predict survival in diffuse large B-cell lymphoma (DLBCL) patients (pts). However, the methodology for PET-derived metrics is still evolving, and their predictive value is yet to be proven in large-scale, prospective, multicenter studies. We investigated the prognostic value of baseline maximum standardized uptake value (SUVmax), TMTV and TLG for progression-free survival (PFS) in a large pt cohort treated with obinutuzumab (GA101; G) or rituximab (R) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Phase 3 GOYA study (NCT01287741; Vitolo et al. J Clin Oncol 2017). Methods: Pts aged ≥18 years, with previously untreated, CD20-positive DLBCL and an International Prognostic Index (IPI) score ≥2 and low-risk pts with IPI scores of 1 (not due to age alone) or 0 (with bulky disease) were randomized 1:1 to receive 8 x 21-day cycles of G (1000mg intravenous [IV] on Days [D] 1, 8, and 15 of Cycle [C] 1 and D1, C2-8) or R (375mg/m2 IV on D1, C1-8) plus 6 or 8 cycles of CHOP. All pts had a baseline and end of treatment (EOT) PET. PET images were segmented using an automated workflow program in MIM software, applying thresholds of 1.5 x liver background and a minimum volume of 1mL to the whole body PET images. The data were analyzed for the overall population and according to germinal center B-cell-like (GCB), unclassified, and activated B-cell-like (ABC) subtypes of DLBCL. TMTV, TLG, and SUVmax were split into 4 categories/levels according to the following quartiles: Q1, Results: Of 1418 enrolled pts, 1346 had a baseline PET scan and 1334 had detectable lesions. There was no statistical difference in PFS between the treatment arms (G vs R), thus the entire cohort was analyzed as a whole. Results of the predictive value of baseline TMTV for PFS are presented in quartiles in Figure 1, and results of the predictive value of TLG for PFS are presented in quartiles in Figure 2, for the overall PET intent-to-treat population. After a median follow-up of 29 months TMTV and TLG were highly predictive of PFS when comparing Q4 vs Q1: HR=2.21, 95% CI 1.48-3.29, p Three-year PFS for pts in TMTV Q1, 2, 3 and 4 was 86% (95% CI 81-89%), 84% (95% CI 78-88%), 78% (95% CI 72-83%) and 66% (95% CI 59-71%), respectively. TMTV also showed a trend for a better prediction of PFS (Figure 3) and OS in pts with the unclassified and ABC DLBCL subtypes when compared with those with the GCB subtype. Conclusions: This large prospective study confirms baseline TMTV and TLG as predictors of PFS and OS in DLBCL after first-line immunochemotherapy, while SUVmax may not be a predictor. Furthermore, TMTV and TLG appear to be better predictors of survival for pts with the unclassified and ABC subtypes of DLBCL than for those pts with the GCB subtype. Further analyses are underway comparing these results with the predictive value of percentage change from baseline to EOT PET, Deauville score-based analysis of EOT PET, and the various molecular DLBCL subtypes. Disclosures Kostakoglu: Roche: Consultancy, Other: GOYA is sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Lale Kostakoglu and Denis Sahin, was provided by Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Sehn: Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Chua: Lundbeck: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Merck: Honoraria. Gonzalez-Barca: Gilead: Consultancy; Sandot: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Pinto: Millenium Takeda: Research Funding; Gilead: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Merck Sharp Dome: Honoraria; Celgene: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Knapp: Roche: Employment. Mattiello: Roche: Employment. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam: Roche: Employment. Sahin: Roche: Employment, Equity Ownership. Vitolo: Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria; Mundipharma: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Trněný: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Effects of Long-Term Caffeine Consumption on the Adenosine A1 Receptor in the Rat Brain: an In Vivo PET Study with [18F]CPFPX.

Caffeine, a nonselective antagonist of adenosine receptors, is the most popular psychostimulant worldwide. Recently, a protective role of moderate chronic caffeine consumption against neurodegenerative diseases such as Alzheimer's and Parkinson's disease has been discussed. Thus, aim of the present study was an in vivo investigation of effects of long-term caffeine consumption on the adenosine A1 receptor (A1AR) in the rat brain. Sixteen adult, male rats underwent five positron emission tomography (PET) scans with the highly selective A1AR radioligand [18F]CPFPX in order to determine A1AR availability. After the first baseline PET scan, the animals were assigned to two groups: Caffeine treatment and control group. The caffeine-treated animals received caffeinated tap water (30mg/kg bodyweight/day, corresponding to 4-5 cups of coffee per day in humans) for 12 weeks. Subsequently, caffeine was withdrawn and repeated PET measurements were performed on day 1, 2, 4, and 7 of caffeine withdrawal. The control animals were measured according to the same time schedule. At day 1, after 4.4h of caffeine withdrawal, a significant decrease (-34.5%, p<0.001) of whole brain A1AR availability was observed. Unlike all other investigated brain regions in caffeine-treated rats, the hypothalamus and nucleus accumbens showed no significant intraindividual differences between baseline and first withdrawal PET scan. After approximately 27h of caffeine withdrawal, the region- and group-specific effects disappeared and A1AR availability settled around baseline. The present study provides evidence that chronic caffeine consumption does not lead to persistent changes in functional availability of cerebral A1ARs which have previously been associated with neuroprotective effects of caffeine. The acute and region-specific decrease in cerebral A1AR availability directly after caffeine withdrawal is most likely caused by residual amounts of caffeine metabolites disguising an unchanged A1AR expression at this early time-point.

A Positron Emission Tomography Study of Norepinephrine Transporter Occupancy and Its Correlation with Symptom Response in Depressed Patients Treated with Quetiapine XR.

BackgroundQuetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy.MethodsIn this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7.ResultsNorepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L.ConclusionThese data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.

PET imaging evaluation of [(18)F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates.

Positron emission tomography (PET) radioligands specific to α7 nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an α7-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[(18)F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([(18)F]DBT-10), in nonhuman primates. [(18)F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [(18)F]DBT-10 PET, with measurement of [(18)F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the α7-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [(18)F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V T/f P). [(18)F]DBT-10 was produced within 90 min at high specific activities of 428 ± 436 GBq/μmol at end of synthesis. Metabolism of [(18)F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55%. Uptake of [(18)F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8 ± 3.4%. No evidence for radiolabeled [(18)F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V T/f P values were 193-376 ml/cm(3) across regions, with regional rank order of thalamus > frontal cortex > striatum > hippocampus > occipital cortex > cerebellum > pons. Dose-dependent blockade of [(18)F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V ND/f P estimate of 20 ± 16 ml/cm(3). These results demonstrate suitable kinetic properties of [(18)F]DBT-10 for in vivo quantification of α7-nAChR binding in nonhuman primates.