PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small ...biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.
Positron emission tomography (PET) imaging of macrophages using the translocator protein (TSPO) tracer (R)-11CPK11195 has shown the promise to image rheumatoid arthritis (RA). To further improve TSPO ...PET for RA imaging, second generation TSPO tracers 11CDPA-713 and 18FDPA-714 have recently been evaluated pre-clinically showing better imaging characteristics.
A clinical proof of concept study to evaluate 11CDPA-713 and 18FDPA-714 to visualize arthritis in RA patients.
RA patients (n = 13) with at least two active hand joints were included. PET/CT scans of the hands were obtained after injection of 18FDPA-714, 11CDPA-713 and/or (R)-11CPK11195 (max. 2 tracers pp). Standardized uptake values (SUVs) and target-to-background (T/B) ratios were determined. Imaging data of the 3 different tracers were compared by pooled post-hoc testing, and by a head to head comparison.
Clinically active arthritis was present in 110 hand joints (2-17 pp). Arthritic joints were visualized with both 11CDPA-713 and 18FDPA-714. Visual tracer uptake corresponded with clinical signs of arthritis in 80% of the joints. Mean absolute uptake in PET-positive joints was significantly higher for 11CDPA-713 than for 18FDPA-714, the latter being not significantly different from (R)-11CPK11195 uptake. Background uptake was lower for both DPA tracers compared with that of (R)-11CPK11195. Higher absolute uptake and lower background resulted in two-fold higher T/B ratios for 11CDPA-713.
11CDPA-713 and 18FDPA-714 visualize arthritic joints in active RA patients and most optimal arthritis imaging results were obtained for 11CDPA-713. Second generation TSPO macrophage PET provides new opportunities for both early diagnosis and therapy monitoring of RA.
Purpose
Multiparametric magnetic resonance imaging (mpMRI) is a well-established imaging method for localizing primary prostate cancer (PCa) and for guiding targeted prostate biopsies.
18
FDCFPyL ...positron emission tomography combined with MRI (PSMA-PET/MRI) might be of additional value to localize primary PCa. The aim of this study was to assess the diagnostic performance of
18
FDCFPyL-PET/MRI vs. mpMRI in tumour localization based on histopathology after robot-assisted radical-prostatectomy (RARP), also assessing biopsy advice for potential image-guided prostate biopsies.
Methods
Thirty prospectively included patients with intermediate to high-risk PCa underwent
18
FDCFPyL-PET/MRI and mpMRI prior to RARP. Two nuclear medicine physicians and two radiologists assessed tumour localization on
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FDCFPyL-PET/MRI and on mpMRI respectively, and gave a prostate biopsy advice (2 segments) using a 14-segment model of the prostate. The uro-pathologist evaluated the RARP specimen for clinically significant PCa (csPCa) using the same model. csPCa was defined as any PCa with Grade Group (GG) ≥ 2. The biopsy advice based on imaging was correlated with the final histology in the RARP specimen for a total-agreement analysis. An additional near-agreement correlation was performed to approximate clinical reality.
Results
Overall, 142 of 420 (33.8%) segments contained csPCa after pathologic examination. The segments recommended for targeted biopsy contained the highest GG PCa segment in 27/30 patients (90.0%) both for
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FDCFPyL-PET/MRI and mpMRI. Areas under the receiver operating characteristics curves (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the total-agreement detection of csPCa per segment using
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FDCFPyL-PET/MRI were 0.70, 50.0%, 89.9%, 71.7%, and 77.9%, respectively. These results were 0.75, 54.2%, 94.2%, 82.8%, and 80.1%, respectively, for mpMRI only.
Conclusion
Both
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FDCFPyL-PET/MRI and mpMRI were only partly able to detect csPCa on a per-segment basis. An accurate detection (90.0%) of the highest GG lesion at patient-level was observed when comparing both
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FDCFPyL-PET/MRI and mpMRI biopsy advice with the histopathology in the RARP specimen. So, despite the finding that
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FDCFPyL-PET/MRI adequately detects csPCa, it does not outperform mpMRI.
Abstract
The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates ...the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association.
We included 78 cognitively unimpaired identical twins with 18Fflutemetamol (amyloid-β)-PET, 18Fflortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis.
At the individual level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (β = −0.37, P = 0.03) and memory functioning (β = −0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = −0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (β = −0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated, 51.6%).
Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.
Coomans & Tomassen et al. test associations between amyloid-β, tau, neurodegeneration and cognitive decline within pairs of identical twins using within-pair difference models, thereby ruling out potential confounding by genetic and shared environmental factors. The results are compatible with the amyloid cascade hypothesis.
Alzheimer's disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to ...examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimer's disease. Dynamic (11)CPittsburgh compound-B (90 min) and static (18)Ffluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimer's disease and 20 healthy controls. Parametric non-displaceable binding potential images of (11)CPittsburgh compound-B and standardized uptake value ratio images of (18)Ffluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine (11)CPittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P<0.05), while we found a trend towards poorer memory performance for older patients (P=0.11). Differences between groups were assessed using a general linear model with repeated measures (gender adjusted) with age as between subjects factor, region (frontal, temporal, parietal and occipital and posterior cingulate cortices) as within subjects factor and (11)CPittsburgh compound-B binding/(18)Ffluorodeoxyglucose uptake as dependent variables. There was no main effect of age for (11)CPittsburgh compound-B or (18)Ffluorodeoxyglucose, suggesting that overall, the extent of amyloid deposition or glucose hypometabolism did not differ between groups. Regional distributions of (11)CPittsburgh compound-B binding and (18)Ffluorodeoxyglucose uptake (both P for interaction <0.05) differed between groups, however, largely due to increased (11)CPittsburgh compound-B binding and decreased (18)Ffluorodeoxyglucose uptake in the parietal cortex of younger patients (both P<0.05). Linear regression analyses showed negative associations between visuo-spatial functioning and parietal (11)CPittsburgh compound-B binding for younger patients (standardized β: -0.37) and between visuo-spatial functioning and occipital binding for older patients (standardized β: -0.39). For (18)Ffluorodeoxyglucose, associations were found between parietal uptake with visuo-spatial (standardized β: 0.55), attention (standardized β: 0.39) and executive functioning (standardized β: 0.37) in younger patients, and between posterior cingulate uptake and memory in older patients (standardized β: 0.41, all P<0.05). These in vivo findings suggest that clinical differences between younger and older patients with Alzheimer's disease are not restricted to topographical differentiation in downstream processes but may originate from distinctive distributions of early upstream events. As such, increased amyloid burden, together with metabolic dysfunction, in the parietal lobe of younger patients with Alzheimer's disease may contribute to the distinct cognitive profile in these patients.
ABC transporters protect the brain by transporting neurotoxic compounds from the brain back into the blood. P‐glycoprotein (P‐gp) is the most investigated ABC (efflux) transporter, as it is ...implicated in neurodegenerative diseases such as Alzheimer's disease. Altered function of P‐gp can be studied in vivo, using Positron Emission Tomography (PET). To date, several radiopharmaceuticals have been developed to image P‐gp function in vivo. So far, attempts to image expression levels of P‐gp using radiolabeled P‐gp inhibitors have not been successful. Improved knowledge of compound behavior toward P‐gp from in vitro studies should increase predictability of in vivo outcome.
Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood-brain barrier (BBB) ...permeability is considered desirable for increasing clinical efficacy.
We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple
and
BBB preclinical models.
osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2).
rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (
%ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth.
These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low
transporter efflux ratios and increased brain penetrance
supporting the use of
transporter assays as an early screen in drug discovery.
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