Day-to-Day Test–Retest Variability of CBF, CMRO2, and OEF Measurements Using Dynamic 15O PET Studies

Contains fulltext : 169592.pdf (publisher's version ) (Open Access)PURPOSE: We assessed test-retest variability of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) measurements derived from dynamic (15)O positron emission tomography (PET) scans. PROCEDURES: In seven healthy volunteers, complete test-retest (15)O PET studies were obtained; test-retest variability and left-to-right ratios of CBF, CBV, OEF, and CMRO(2) in arterial flow territories were calculated. RESULTS: Whole-brain test-retest coefficients of variation for CBF, CBV, CMRO(2), and OEF were 8.8%, 13.8%, 5.3%, and 9.3%, respectively. Test-retest variability of CBV left-to-right ratios was <7.4% across all territories. Corresponding values for CBF, CMRO(2), and OEF were better, i.e., <4.5%, <4.0%, and <1.4%, respectively. CONCLUSIONS: The test-retest variability of CMRO(2) measurements derived from dynamic (15)O PET scans is comparable to within-session test-retest variability derived from steady-state (15)O PET scans. Excellent regional test-retest variability was observed for CBF, CMRO(2), and OEF. Variability of absolute CBF and OEF measurements is probably affected by physiological day-to-day variability of CBF

Head-to-head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

Purpose P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects. Methods: Three non-human primates underwent 4 PET scans: 2 with (R)[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed. Results At baseline, [18F]MC225 VT values were higher, and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After inhibition, VT values of the 2 tracers were similar; however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers. Conclusion [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-humanprimates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT

Improved detection of diffuse glioma infiltration with imaging combinations: a diagnostic accuracy study

Background Surgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/FLAIR-weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration. Methods We included 20 consecutive adults with newly-diagnosed non-enhancing (seven diffuse astrocytomas, IDH-mutant; one oligodendroglioma, IDH-mutant and1p/19q-codeleted; one glioblastoma IDH-wildtype) or enhancing glioma (glioblastoma, nine IDH-wildtype and two IDH-mutant). Standardized pre-operative imaging (T1-, T2-, FLAIR-weighted and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multi-region stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by two neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis. Results A total of 174 biopsies were obtained (63 from nine non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of Apparent Diffusion Coefficient (ADC) with [18F]FET PET (AUC, 95%CI: 0.89,0.79-0.99) detected tumor better than T1G MRI (0.56,0.39-0.72;P<.001) and [18F]FET PET (0.76,0.66-0.86;P=0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65-0.98) compared to 0.69 (0.56-0.81;P=0.019) for [18F]FET PET. Conclusion and relevance Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy

Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer:study protocol of the INDIBLADE trial

Introduction: Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. Methods: The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. Discussion: This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. Clinical Trial Registration: The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).</p

FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0

The aim of this guideline is to provide a minimum standard for the acquisition and interpretation of PET and PET/CT scans with [18F]-fluorodeoxyglucose (FDG). This guideline will therefore address general information about [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) and is provided to help the physician and physicist to assist to carrying out, interpret, and document quantitative FDG PET/CT examinations, but will concentrate on the optimisation of diagnostic quality and quantitative information

Spatial concordance of DNA methylation classification in diffuse glioma

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. RESULTS: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. CONCLUSION: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists

18F-FDG PET during stereotactic body radiotherapy for stage I lung tumours cannot predict outcome: a pilot study

(18)F-Fluorodeoxyglucose positron emission tomography (FDG PET) has been used to assess metabolic response several months after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer. However, whether a metabolic response can be observed already during treatment and thus can be used to predict treatment outcome is undetermined. Ten medically inoperable patients with FDG PET-positive lung tumours were included. SBRT consisted of three fractions of 20 Gy delivered at the 80% isodose at days 1, 6 and 11. FDG PET was performed before, on day 6 immediately prior to administration of the second fraction of SBRT and 12 weeks after completion of SBRT. Tumour metabolism was assessed semi-quantitatively using the maximum standardized uptake value (SUV(max)) and SUV(70%). After the first fraction, median SUV(max) increased from 6.7 to 8.1 (p = 0.07) and median SUV(70%) increased from 5.7 to 7.1 (p = 0.05). At 12 weeks, both median SUV(max) and median SUV(70%) decreased by 63% to 3.1 (p = 0.008) and to 2.5 (p = 0.008), respectively. SUV increased during treatment, possibly due to radiation-induced inflammation. Therefore, it is unlikely that (18)F-FDG PET during SBRT will predict treatment success

Direct comparison of [11C] choline and [18F] FET PET to detect glioma infiltration: a diagnostic accuracy study in eight patients

Background Positron emission tomography (PET) is increasingly used to guide local treatment in glioma. The purpose of this study was a direct comparison of two potential tracers for detecting glioma infiltration, O-(2-[18F]-fluoroethyl)-l-tyrosine ([18F] FET) and [11C] choline. Methods Eight consecutive patients with newly diagnosed diffuse glioma underwent dynamic [11C] choline and [18F] FET PET scans. Preceding craniotomy, multiple stereotactic biopsies were obtained from regions inside and outside PET abnormalities. Biopsies were assessed independently for tumour presence by two neuropathologists. Imaging measurements were derived at the biopsy locations from 10 to 40 min [11C] choline and 20–40, 40–60 and 60–90 min [18F] FET intervals, as standardized uptake value (SUV) and tumour-to-brain ratio (TBR). Diagnostic accuracies of both tracers were compared using receiver operating characteristic analysis and generalized linear mixed modelling with consensus histopathological assessment as reference. Results Of the 74 biopsies, 54 (73%) contained tumour. [11C] choline SUV and [18F] FET SUV and TBR at all intervals were higher in tumour than in normal samples. For [18F] FET, the diagnostic accuracy of TBR was higher than that of SUV for intervals 40–60 min (area under the curve: 0.88 versus 0.81, p = 0.026) and 60–90 min (0.90 versus 0.81, p = 0.047). The diagnostic accuracy of [18F] FET TBR 60–90 min was higher than that of [11C] choline SUV 20–40 min (0.87 versus 0.67, p = 0.005). Conclusions [18F] FET was more accurate than [11C] choline for detecting glioma infiltration. Highest accuracy was found for [18F] FET TBR for the interval 60–90 min post-injection

Neurobiological basis and risk factors of persistent fatigue and concentration problems after COVID-19: study protocol for a prospective case–control study (VeCosCO)

Introduction: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints. To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [18F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI. / Methods and analysis: This is a prospective case–control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [18F]DPA-714 PET, and brain functioning and structure using (f)MRI. / Ethics and dissemination: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population