Lula Rosso

Reproducibility of 18F-FDG and 3′-Deoxy-3′-18F-Fluorothymidine PET Tumor Volume Measurements

The objective of this study was to establish the repeatability and reproducibility limits of several volume-related PET image–derived indices—namely tumor volume (TV), mean standardized uptake value, total glycolytic volume (TGV), and total proliferative volume (TPV)—relative to those of maximum standardized uptake value (SUVmax), commonly used in clinical practice. Methods: Fixed and adaptive thresholding, fuzzy C-means, and fuzzy locally adaptive Bayesian methodology were considered for TV delineation. Double-baseline 18F-FDG (17 lesions, 14 esophageal cancer patients) and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) (12 lesions, 9 breast cancer patients) PET scans, acquired at a mean interval of 4 d and before any treatment, were used for reproducibility evaluation. The repeatability of each method was evaluated for the same datasets and compared with manual delineation. Results: A negligible variability of less than 5% was measured for all segmentation approaches in comparison to manual delineation (5%–35%). SUVmax reproducibility levels were similar to others previously reported, with a mean percentage difference of 1.8% ± 16.7% and −0.9% ± 14.9% for the 18F-FDG and 18F-FLT lesions, respectively. The best TV, TGV, and TPV reproducibility limits ranged from −21% to 31% and −30% to 37% for 18F-FDG and 18F-FLT images, respectively, whereas the worst reproducibility limits ranged from −90% to 73% and −68% to 52%, respectively. Conclusion: The reproducibility of estimating TV, mean standardized uptake value, and derived TGV and TPV was found to vary among segmentation algorithms. Some differences between 18F-FDG and 18F-FLT scans were observed, mainly because of differences in overall image quality. The smaller reproducibility limits for volume-derived image indices were similar to those for SUVmax, suggesting that the use of appropriate delineation tools should allow the determination of tumor functional volumes in PET images in a repeatable and reproducible fashion.

A New Model for Prediction of Drug Distribution in Tumor and Normal Tissues: Pharmacokinetics of Temozolomide in Glioma Patients

Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules.

GAFFlipid: a General Amber Force Field for the accurate molecular dynamics simulation of phospholipid

Previous attempts to simulate phospholipid bilayers using the General Amber Force Field (GAFF) yielded many bilayer characteristics in agreement with experiment, however when using a tensionless NPT ensemble the bilayer is seen to compress to an undesirable extent resulting in low areas per lipid and high order parameters in comparison to experiment. In this work, the GAFF Lennard-Jones parameters for the simulation of acyl chains are corrected to allow the accurate and stable simulation of pure lipid bilayers. Lipid bilayers comprised of six phospholipid types were simulated for timescales approaching a quarter of a microsecond under tensionless constant pressure conditions using Graphics Processing Units. Structural properties including area per lipid, volume per lipid, bilayer thickness, order parameter and headgroup hydration show favourable agreement with available experimental values. Expanding the system size from 72 to 288 lipids and a more experimentally realistic 2 × 288 lipid bilayer stack induces little change in the observed properties. This preliminary work is intended for combination with the new AMBER Lipid11 modular force field as part of on-going attempts to create a modular phospholipid AMBER force field allowing tensionless NPT simulations of complex lipid bilayers.

[18F]-3′Deoxy-3′-Fluorothymidine Positron Emission Tomography and Breast Cancer Response to Docetaxel

Purpose: To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [18F]-3′deoxy-3′-fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer. Experimental Design: This was a prospective unblinded study in 20 patients with American Joint Committee on Cancer (AJCC) stage II–IV breast cancer unresponsive to first-line chemotherapy or progressing on previous therapy. Individuals underwent a baseline dynamic FLT-PET scan followed by a scan 2 weeks after initiating the first or second cycle of docetaxel. PET variables were compared with anatomic response midtherapy (after 3 cycles). Results: Average and maximum tumor standardized uptake values at 60 minutes (SUV60,av and SUV60,max) normalized to body surface area ranged between 1.7 and 17.0 and 5.6 and 26.9 × 10−5 m2/mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (P = 0.0003 for SUV60,av and P = 0.0002 for SUV60,max). Reduction in tumor SUV60,av was associated with target lesion size changes midtherapy (Pearson R for SUV60,av = 0.64; P = 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV60,av in responders were due, at least in part, to reduced net intracellular trapping of FLT (rate constant, Ki). Docetaxel significantly reduced Ki by 51.1% (±28.4%, P = 0.0009). Conclusion: Changes in tumor proliferation assessed by FLT-PET early after initiating docetaxel chemotherapy can predict lesion response midtherapy with good sensitivity warranting prospective trials to assess the ability to stop therapy in the event of non–FLT-PET response. Clin Cancer Res; 17(24); 7664–72. ©2011 AACR.

Structure and dynamics of phospholipid bilayers using recently developed general all-atom force fields

Two fully hydrated pure‐species phospholipids bilayers, 1,2‐dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC) and 1,2‐dioleoyl‐sn‐glycero‐3‐phosphorylcholine (DOPC), in the fluid phase and explicit solvent have been studied using molecular dynamics simulation. Atom interactions were modeled using recently developed force fields based on AMBER with full atomistic details. Several representative liquid phase properties for the structure and dynamics of lipids with different length of hydrocarbon chains and different level of saturation have been reproduced without artificially biasing the system in order to match experimental data. In particular, as the new GAFF (General Amber Force Field) has not been explicitly developed to reproduce lipid characteristics and is naturally compatible with standard AMBER nucleic acids and proteins parameters, it is here proven a promising tool to study mixed lipid–protein processes as protein activity dependence on membrane composition, permeation of solute across membranes, and other cellular processes.

Measuring endogenous changes in serotonergic neurotransmission in humans: a [11C]CUMI-101 PET challenge study.

Serotonin (5-HT) neurotransmission is implicated in cognitive and emotional processes and a number of neuropsychiatric disorders. The use of positron emission tomography (PET) to measure ligand displacement has allowed estimation of endogenous dopamine release in the human brain; however, applying this methodology to assess central 5-HT release has proved more challenging. The aim of this study was to assess the sensitivity of a highly selective 5-HT1A partial agonist radioligand [11C]CUMI-101 to changes in endogenous 5-HT levels induced by an intravenous challenge with the selective 5-HT re-uptake inhibitor (SSRI), citalopram, in healthy human participants. We studied 15 healthy participants who underwent PET scanning in conjunction with [11C]CUMI-101 after receiving an intravenous infusion of citalopram 10 mg or placebo in a double-blind, crossover, randomized design. Regional estimates of binding potential (BPND) were obtained by calculating total volumes of distribution (VT) for presynaptic dorsal raphe nucleus (DRN) and postsynaptic cortical regions. Relative to placebo, citalopram infusion significantly increased [11C]CUMI-101 BPND at postsynaptic 5-HT1A receptors in several cortical regions, but there was no change in binding at 5-HT1A autoreceptors in the DRN. Across the postsynaptic brain regions, citalopram treatment induced a mean 7% in [11C]CUMI-101 BPND (placebo 1.3 (0.2); citalopram 1.4 (0.2); paired t-test P=0.003). The observed increase in postsynaptic [11C]CUMI-101 availability identified following acute citalopram administration could be attributable to a decrease in endogenous 5-HT availability in cortical terminal regions, consistent with preclinical animal studies, in which acute administration of SSRIs decreases DRN cell firing through activation of 5-HT1A autoreceptors to reduce 5-HT levels in postsynaptic regions. We conclude that [11C]CUMI-101 may be sensitive to changes in endogenous 5-HT release in humans.

A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced α5 benzodiazepine receptors in limbic regions.

Preclinical evidence suggests the α5 subtype of the GABA-benzodiazepine receptor is involved in some of the actions of alcohol and in memory. The positron emission tomography (PET) tracer, [11C]Ro15 4513 shows relative selectivity in labelling the α5 subtype over the other GABA-benzodiazepine receptor subtypes in limbic regions of the brain. We used this tracer to investigate the distribution of α5 subtype availability in human alcohol dependence and its relationship to clinical variables. Abstinent (>6 weeks) alcohol-dependent men and healthy male controls underwent an [11C]Ro15 4513 PET scan. We report [11C]Ro15 4513 brain uptake for 8 alcohol-dependent men and 11 healthy controls. We found a significant reduction in [11C]Ro15 4513 binding in the nucleus accumbens, parahippocampal gyri, right hippocampus and amygdala in the alcohol-dependent compared with the healthy control group. Levels of [11C]Ro15 4513 binding in both hippocampi were significantly and positively associated with performance on a delayed verbal memory task in the alcohol-dependent but not the control group. We speculate that the reduced limbic [11C]Ro15 4513 binding seen here results from the effects of alcohol, though we cannot currently distinguish whether they are compensatory in nature or evidence of brain toxicity.

Quantification of ligand PET studies using a reference region with a displaceable fraction: Application to occupancy studies with 11C-DASB as an example

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

PET imaging: implications for the future of therapy monitoring with PET/CT in oncology.

Among the methods based on molecular imaging, the measure of the tracer uptake variation between a baseline and follow-up scan with the SUV and [(18)F]FDG-PET/CT is a very powerful tool for assessing response to treatment in oncology. However, the development of new targeted therapeutics and tissue pharmacokinetic evaluation of existing ones are increasingly requiring therapy monitoring with alternative tracers and indicators. In parallel, the potential predictive and prognostic value of other image-derived parameters, such as tumour volume and textural features, relating to tumoral heterogeneity, has recently emerged from several works.

Ab initio computational study of positron emission tomography ligands interacting with lipid molecule for the prediction of nonspecific binding

Nonspecific binding is a poorly understood biological phenomenon of relevance in the study of small molecules interactions in vivo and in drug development. Nonspecific binding is thought to be correlated in part to a molecules lipophilicity, typically estimated by measuring (or calculating) octanol–water partition coefficient. This is, however, a gross simplification of a complex phenomenon. In this article, we present a computational method whose aim is to help identify positron emission tomography (PET) ligands with low nonspecific binding characteristics by investigating the molecular basis of ligand–membrane interaction. We considered a set consisting of 10 well‐studied central nervous system PET radiotracers acting on a variety of molecular targets. Quantum mechanical calculations were used to estimate the strength of the interaction between each drug molecule and one phospholipid molecule commonly present in mammalian membranes. The results indicate a correlation between the computed drug–lipid interaction energy and the in vivo nonspecific distribution volume relative to the free tracer plasma concentration, calculated using standard compartmental modeling for the analysis of PET data. Significantly, the drugs whose interaction with the lipid molecule more favorably possessed, in general, a higher nonspecific binding value, whereas for the drugs taken in consideration in this study, the water‐octanol partition coefficient, log P, did not show good predictive power of the nonspecific binding. This study also illustrates how ab initio chemical methods may offer meaningful and unbiased insights for the understanding of the underlying chemical mechanisms in biological systems.