Pancreatic adenocarcinoma: a pilot study of quantitative perfusion and diffusion-weighted breath-hold magnetic resonance imaging

Purpose

To confirm the feasibility of breath-hold DCE-MRI and DWI at 3T to obtain the intra-abdominal quantitative physiologic parameters, K ^trans, k _ep, and ADC, in patients with untreated pancreatic ductal adenocarcinomas.

Methods

Diffusion-weighted single-shot echo-planar imaging (DW-SS-EPI) and dynamic contrast-enhanced (DCE) MRI were used for 16 patients with newly diagnosed biopsy-proven pancreatic ductal adenocarcinomas. K ^trans, k _ep, and apparent diffusion coefficient (ADC) values of pancreatic tumors, non-tumor adjacent pancreatic parenchyma (NAP), liver metastases, and normal liver tissues were quantitated and statistically compared.

Results

Fourteen patients were able to adequately hold their breath for DCE-MRI, and 15 patients for DW-SS-EPI. Four patients had liver metastases within the 6 cm of Z axis coverage centered on the pancreatic primary tumors. K ^trans values (10^?3 min^?1) of primary pancreatic tumors, NAP, liver metastases, and normal liver tissues were 7.3 ± 4.2 (mean ± SD), 25.8 ± 14.9, 8.1 ± 5.9, and 45.1 ± 15.6, respectively, k _ep values (10^?2 min^?1) were 3.0 ± 0.9, 7.4 ± 3.1, 5.2 ± 2.0, and 12.1 ± 2.8, respectively, and ADC values (10^?3 mm²/s) were 1.3 ± 0.2, 1.6 ± 0.3, 1.1 ± 0.1, and 1.3 ± 0.1, respectively. K ^trans, k _ep, and ADC values of primary pancreatic tumors were significantly lower than those of NAP (p < 0.05), while K ^trans and k _ep values of liver metastases were significantly lower than those of normal liver tissues (p < 0.05).

Conclusions

3T breath-hold quantitative physiologic MRI is a feasible technique that can be applied to a majority of patients with pancreatic adenocarcinomas.     

Reproducibility of Static and Dynamic 18F-FDG, 18F-FLT, and 18F-FMISO MicroPET Studies in a Murine Model of HER2+ Breast Cancer

Purpose

The objective of this study is to determine the reproducibility of static 2-deoxy-2-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG), 3′-deoxy-3′-[¹⁸F]fluorothymidine (¹⁸F-FLT), and [¹⁸F]-fluoromisonidazole (¹⁸F-FMISO) microPET measurements, as well as kinetic parameters returned from analyses of dynamic ¹⁸F-FLT and ¹⁸F-FMISO data.

Procedures

HER2+ xenografts were established in nude mice. Dynamic data were acquired for 60 min, followed by a repeat injection and second scan 6 h later. Reproducibility was assessed for the percent-injected dose per gram (%ID/g) for each radiotracer, and with kinetic parameters (K ₁ –k ₄ , K _i ) for ¹⁸F-FLT and ¹⁸F-FMISO.

Results

The value needed to reflect a change in tumor physiology is given by the 95 % confidence interval (CI), which is ±14, ±5, and ±6 % for ¹⁸F-FDG (n?=?12), ¹⁸F-FLT (n?=?11), and ¹⁸F-FMISO (n?=?11) %ID/g, respectively. V _d (=K ₁ /k ₂), k ₃, and K _FLT are the most reproducible ¹⁸F-FLT (n?=?9) kinetic parameters, with 95 % CIs of ±18, ±10, and ±18 %, respectively. V _d and K _FMISO are the most reproducible ¹⁸F-FMISO kinetic parameters (n?=?7) with 95 % CIs of ±16 and ±14 %, respectively.

Conclusions

Percent-injected dose per gram measurements are reproducible and appropriate for detecting treatment-induced changes. Kinetic parameters have larger threshold values, but are potentially sufficiently reproducible to detect treatment response.     

Methodological Considerations in Quantification of 3'-Deoxy-3'-[18F]Fluorothymidine Uptake Measured with Positron Emission Tomography in Patients with Non-Small Cell Lung Cancer

Purpose

To investigate the effect of image-derived input functions (IDIF), input function corrections and volume of interest (VOI) size in quantification of [¹⁸F]FLT uptake in non-small cell lung cancer (NSCLC) patients.

Procedures

Twenty-three NSCLC patients were scanned on a HR+ scanner. IDIFs were defined over the aorta and left ventricle. Activity concentration and metabolite fraction were measured in venous blood samples. Venous blood samples at 30, 40 and 60 min after injection were used to calibrate the IDIF time–activity curves. Adaptive thresholds were used for VOI definition. Full kinetic analysis and simplified measures were performed.

Results

Non-linear regression analysis showed better fits for the irreversible model compared to the reversible model in the majority. Calibrated and metabolite corrected plus plasma-to-blood ratio corrected input function resulted in high correlations between SUV and Patlak K _i (Pearson correlation coefficients 0.86–0.96, p value?<?0.001). No significant differences in correlation between SUV and Patlak K _i were observed with variation of IDIF structure or VOI size.

Conclusions

Plasma-to-blood ratio correction, metabolite correction and calibration improved the correlation between SUV and Patlak K _i significantly, indicating the need for these corrections when K _i is used to validate semi-quantitative measures, such as SUV.     

Quantification of Tumor Hypoxic Fractions Using Positron Emission Tomography with [<Superscript>18</Superscript>F]Fluoromisonidazole ([<Superscript>18</Superscript>F]FMISO) Kinetic Analysis and Invasive Oxygen Measurements

Purpose

The purpose of this study is to use dynamic [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) positron emission tomography (PET) to compare estimates of tumor hypoxic fractions (HFs) derived by tracer kinetic modeling, tissue-to-blood ratios (TBR), and independent oxygen (pO₂) measurements.

Procedures

BALB/c mice with EMT6 subcutaneous tumors were selected for PET imaging and invasive pO₂ measurements. Data from 120-min dynamic [¹⁸F]FMISO scans were fit to two-compartment irreversible three rate constant (K ₁, k ₂, k ₃) and Patlak models (K _i). Tumor HFs were calculated and compared using K _i, k ₃, TBR, and pO₂ values. The clinical impact of each method was evaluated on [¹⁸F]FMISO scans for three non-small cell lung cancer (NSCLC) radiotherapy patients.

Results

HFs defined by TBR (≥1.2, ≥1.3, and ≥1.4) ranged from 2 to 85 % of absolute tumor volume. HFs defined by K _i (>0.004 ml min cm^?3) and k ₃ (>0.008 min^?1) varied from 9 to 85 %. HF quantification was highly dependent on metric (TBR, k ₃, or K _i) and threshold. HFs quantified on human [¹⁸F]FMISO scans varied from 38 to 67, 0 to 14, and 0.1 to 27 %, for each patient, respectively, using TBR, k ₃, and K _i metrics.

Conclusions

[¹⁸F]FMISO PET imaging metric choice and threshold impacts hypoxia quantification reliability. Our results suggest that tracer kinetic modeling has the potential to improve hypoxia quantification clinically as it may provide a stronger correlation with direct pO₂ measurements.

     

Epoprostenol treatment of acute pulmonary hypertension is associated with a paradoxical decrease in right ventricular contractility

Objective

Prostacyclins have been suggested to exert positive inotropic effects which would render them particularly suitable for the treatment of right ventricular (RV) dysfunction due to acute pulmonary hypertension (PHT). Data on this subject are controversial, however, and vary with the experimental conditions. We studied the inotropic effects of epoprostenol at clinically recommended doses in an experimental model of acute PHT.

Design and setting

Prospective laboratory investigation in a university hospital laboratory.

Subjects

Six pigs (36?±?7?kg).

Interventions

Pigs were instrumented with biventricular conductance catheters, a pulmonary artery (PA) flow probe, and a high-fidelity pulmonary pressure catheter. Incremental doses of epoprostenol (10, 15, 20, 30, 40?ng?kg^–1?min^–1) were administered in undiseased animals and after induction of acute hypoxia-induced PHT.

Measurements and results

In acute PHT epoprostenol markedly reduced RV afterload (slopes of pressure-flow relationship in the PA from 7.0?±?0.6 to 4.2?±?0.7?mmHg?min?l^–1). This was associated with a paradoxical and dose-dependent decrease in RV contractility (slope of preload-recruitable stroke-work relationship from 3.0?±?0.4 to 1.6?±?0.2?mW?s?ml^–1; slope of endsystolic pressure-volume relationship from 1.5?±?0.3 to 0.7?±?0.3?mmHg?ml^–1). Left ventricular contractility was reduced only at the highest dose. In undiseased animals epoprostenol did not affect vascular tone and produced a mild biventricular decrease in contractility.

Conclusions

Epoprostenol has no positive inotropic effects in vivo. In contrast, epoprostenol-induced pulmonary vasodilation in animals with acute PHT was associated with a paradoxical decrease in RV contractility. This effect is probably caused indirectly by the close coupling of RV contractility to RV afterload. However, data from normal animals suggest that mechanisms unrelated to vasodilation are also involved in the observed negative inotropic response to epoprostenol.     

Direct Characterization of Arterial Input Functions by Fluorescence Imaging of Exposed Carotid Artery to Facilitate Kinetic Analysis

Purpose

With the goal of facilitating tracer kinetic analysis in small-animal planar fluorescence imaging, an experimental method for characterizing tracer arterial input functions is presented. The proposed method involves exposing the common carotid arteries by surgical dissection, which can then be imaged directly during tracer injection and clearance.

Procedures

Arterial concentration curves of IRDye-700DX-carboxylate, IRDye-800CW-EGF, and IRDye-800CW conjugated to anti-EGFR Affibody are recovered from athymic female mice (n?=?12) by directly imaging exposed vessels. Images were acquired with two imaging protocols: a slow-kinetics approach (temporal resolution?=?45 s) to recover the arterial curves from two tracers simultaneously, and a fast-kinetics approach (temporal resolution?=?500 ms) to characterize the first-pass peak of a single tracer. Arterial input functions obtained by the carotid imaging technique, as well as plasma curves measured by blood sampling were fit with a biexponential pharmacokinetic model.

Results

Pharmacological fast- and slow-phase rate constants recovered with the proposed method were 0.37?±?0.26 and 0.007?±?0.001 min^?1, respectively, for the IRDye700DX-C. For the IRDye800CW-EGF, the rate constants were 0.11?±?0.13 and 0.003?±?0.002 min^?1. These rate constants did not differ significantly from those calculated previously by blood sampling, as determined by an F test; however, the between-subject variability was four times lower for arterial curves recovered using the proposed technique, compared with blood sampling.

Conclusions

The proposed technique enables the direct characterization of arterial input functions for kinetic analysis. As this method requires no additional instrumentation, it is immediately deployable in commercially available planar fluorescence imaging systems.     

Fully Automated Radiosynthesis of 2-[18F]Fludarabine for PET Imaging of Low-Grade Lymphoma

Purpose

An efficient and fully automated radiosynthesis of 2-[¹⁸F]fluoro-9-β-d-arabinofuranosyl-adenine (2-[¹⁸F]fludarabine, [¹⁸F]-5) based on a GE TRACERlab? FX-FN module has been developed.

Procedures

A 2-nitro purine derivative 3 was developed as precursor for labeling with fluorine-18. The radiosynthesis of [¹⁸F]-5 was performed in two steps in a single reactor with an intermediary purification on Sep-Pak® silica which involved the addition of a three-way valve on the original module. After hydrolysis, [¹⁸F]-5 was purified by semi-preparative high-pressure liquid chromatography (HPLC) and a quality control was established.

Results

The labeling precursor 3 was obtained in 45 % overall yield. Nucleophilic substitution with K¹⁸F/K_2.2.2 afforded protected 2-[¹⁸F]fludarabine ([¹⁸F]-4) in 73?±?4 % , radiochemical yield (decay corrected to the end of bombardment (EOB)) and based on the initial [¹⁸F]F^? activity. An aqueous ammonia/methanol solution was used for the deprotection reaction and gave the desired [¹⁸F]-5 in 67?±?3 % yield after 20 min at 70 °C based on HPLC profile.

Conclusions

The process afforded pure 2-[¹⁸F]fludarabine in 48?±?3 % yield (decay corrected to the EOB) in 85 min, with a specific activity of 310?±?72 GBq/μmol at the end of synthesis (EOS) and a radiochemical purity up to 99 %.     

Usefulness of 11C-Choline Positron Emission Tomography for Genital Chlamydial Infection Assessment in a Balb/c Murine Model

Purpose

The aim of this study is to explore the feasibility of ¹¹C-Choline PET in the assessment of the degree of inflammation in the Chlamydia muridarum genital infection model.

Procedures

Forty female Balb/c mice received 2.5 mg of medroxyprogesterone acetate i.m. 9 and 2 days prior to the infection: 21 mice were infected by C. muridarum into the vaginal vault, 12 mice were treated with inactivated chlamydiae, and 7 mice were SPG buffer-treated as negative controls. Three healthy control mice were not treated with progesterone. Mice in each category were randomly subdivided in two groups: (1) sacrificed at 5, 10, 15, and 20 days for histological analysis and (2) undergoing ¹¹C-Choline PET at days 5, 10, and 20 post-infection (20 MBq of ¹¹C-Choline, uptake time of 10 min, acquisition through a small-animal PET tomograph for 15 min).

Results

Infected animals showed a significantly higher standardized uptake value than both controls and animals inoculated with heat-inactivated chlamydiae in each PET scan (P?<?0.05). All organs of the infected animals had scores of inflammation ranging between 2 and 3 at day 5, decreasing to 1–2 at day 20.

Conclusions

This preliminary result demonstrated that ¹¹C-Choline PET can highlight a specific proliferation mechanism of inflammatory cells induced by C. muridarum, thanks to a very high sensitivity in detecting very small amounts of tracer in inflammatory cells.     

Tumor Uptake of Hollow Gold Nanospheres After Intravenous and Intra-arterial Injection: PET/CT Study in a Rabbit VX2 Liver Cancer Model

Purpose

This study was designed to investigate the intratumoral uptake of hollow gold nanospheres (HAuNS) after hepatic intra-arterial (IA) and intravenous (IV) injection in a liver tumor model.

Materials and methods

Fifteen VX2 tumor-bearing rabbits were randomized into five groups (n?=?3 in each group) that received either IV ⁶⁴Cu-labeled PEG-HAuNS (IV-PEG-HAuNS), IA ⁶⁴Cu-labeled PEG-HAuNS (IA-PEG-HAuNS), IV cyclic peptide (RGD)-conjugated ⁶⁴Cu-labeled PEG-HAuNS (IV-RGD-PEG-HAuNS), IA RGD-conjugated ⁶⁴Cu-labeled PEG-HAuNS (IA-RGD-PEG-HAuNS), or IA ⁶⁴Cu-labeled PEG-HAuNS with lipiodol (IA-PEG-HAuNS-lipiodol). The animals underwent PET/CT 1 h after injection, and uptake expressed as percentage of injected dose per gram of tissue (%ID/g) was measured in tumor and major organs. The animals were euthanized 24 h after injection, and tissues were evaluated for radioactivity.

Results

At 1 h after injection, animals in the IA-PEG-HAuNS-lipiodol group showed significantly higher tumor uptake (P?<?0.001) and higher ratios of tumor-to-normal liver uptake (P?<?0.001) than those in all other groups. The biodistribution of radioactivity 24 h after injection showed that IA delivery of PEG-HAuNS with lipiodol resulted in the highest tumor uptake (0.33 %ID/g; P?<?0.001) and tumor-to-normal liver ratio (P?<?0.001) among all delivery methods. At 24 h, the IA-RGD-PEG-HAuNS group showed higher tumor uptake than the IA-PEG-HAuNS group (0.20 vs. 0.099 %ID/g; P?<?0.001).

Conclusion

Adding iodized oil to IA-PEG-HAuNS maximizes nanoparticle delivery to hepatic tumors and therefore may be useful in targeted chemotherapy and photoablative therapy. PET/CT can be used to noninvasively monitor the biodistribution of radiolabeled HAuNS after IV or IA injection.     

An integrated approach to determine left atrial volume, mass and function in hypertrophic cardiomyopathy by two-dimensional echocardiography

Methods

The study included 25 hypertrophic cardiomyopathy (HCM) patients (15 non-obstructive and 10 obstructive) and 25 controls for assessment of left atrial (LA) volume, mass and function by two-dimensional echocardiography. Measurement included mean LA diameter (LAD), LA mass = {(mean LAD + anterior LA wall + posterior LA wall)³ ? mean LAD³} × 0.8 + 0.6, LA volume = [(8/3 π L · A1 · A2), where L is LA length, A1 and A2 are LA area in 4-chambers and 2-chambers, respectively] including maximum (V _max), minimum (V _min), and pre-atrial contraction (V _pre-A), total atrial stroke volume (TA-SV), TA emptying fraction (TA-EF), active atrial SV (AA-SV), AA-EF, passive atrial SV (PA-SV), PA-EF, atrial expansion index (AEI), and LA kinetic energy (LA-KE) = ½ × AA-SV × P × V².

Results

LAD, LA mass, V _max, V _min, and V _pre-A were significantly higher in HCM than controls. TA-SV and TA-EF were comparable in both HCM subgroups and controls. AA-SV and LA-KE were significantly higher in both HCM subgroups than controls. LA-KE was significantly higher in obstructive HCM than non-obstructive (P < 0.001). PA-EF and AEI were significantly lower in obstructive HCM than controls (P < 0.05).

Conclusion

HCM is associated with increased LA size and augmented LA pump function especially obstructive type. LA conduit and reservoir functions are impaired in obstructive HCM.     

Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa

Purpose

Emergence of multidrug-resistant strains in intensive care units has renewed interest in colistin, which often remains the only available antimicrobial agent active against resistant Pseudomonas aeruginosa. The aim of this study is to compare lung tissue deposition and antibacterial efficiency between nebulized and intravenous administration of colistin in piglets with pneumonia caused by P. aeruginosa.

Methods

In ventilated piglets, colistimethate was administered 24 h following bronchial inoculation of Pseudomonas aeruginosa (minimum inhibitory concentration of colistin = 2 μg ml^?1) either by nebulization (8 mg kg^?1 every 12 h, n = 6) or by intravenous infusion (3.2 mg kg^?1 every 8 h, n = 6). All piglets were killed 49 h after inoculation. Colistin peak lung tissue concentrations and lung bacterial burden were assessed on multiple post mortem subpleural lung specimens.

Results

Median colistin peak lung concentration following nebulization was 2.8 μg g^?1 (25–75% interquartile range = 0.8–13.7 μg g^?1). Colistin was undetected in lung tissue following intravenous infusion. In the aerosol group, peak lung tissue concentrations were significantly greater in lung segments with mild pneumonia (median = 10.0 μg g^?1, 25–75% interquartile range = 1.8–16.1 μg g^?1) than in lung segments with severe pneumonia (median = 1.2 μg g^?1, 25–75% interquartile range = 0.5–3.3 μg g^?1) (p < 0.01). After 24 h of treatment, 67% of pulmonary segments had bacterial counts <10² cfu g^?1 following nebulization and 28% following intravenous administration (p < 0.001). In control animals, 12% of lung segments had bacterial counts <10² cfu g^?1 49 h following bronchial inoculation.

Conclusion

Nebulized colistin provides rapid and efficient bacterial killing in ventilated piglets with inoculation pneumonia caused by Pseudomonas aeruginosa.     

In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter

Purpose

The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective ¹¹C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.

Procedures

For both (?)-[¹¹C]2 and (?)-[¹¹C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (?)-[¹¹C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.

Results

The resolved enantiomers (?)-2 and (?)-6 were very potent and selective for VAChT in vitro (K _i ?35-fold selectivity for VAChT vs. σ receptors); both radioligands, (?)-[¹¹C]2 and (?)-[¹¹C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (?)-[¹¹C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550?±?0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (?)-[¹¹C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (?)-[¹¹C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (?)-[¹¹C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.

Conclusions

The radioligand (?)-[¹¹C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.     

Characterization and Evaluation of 64Cu-Labeled A20FMDV2 Conjugates for Imaging the Integrin αvβ6

Purpose

The integrin α_vβ₆ is overexpressed in a variety of aggressive cancers and serves as a prognosis marker. This study describes the conjugation, radiolabeling, and in vitro and in vivo evaluation of four chelators to determine the best candidate for ⁶⁴Cu radiolabeling of A20FMDV2, an α_vβ₆ targeting peptide.

Procedures

Four chelators were conjugated onto PEG₂₈-A20FMDV2 (1): 11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid (CB-TE1A1P), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and 4,4′-((3,6,10,13,16,19-hexazazbicyclo[6.6.6]ico-sane-1,8-diylbis(aza-nediyl))bis(methylene)dibenzoic acid (BaBaSar). All peptides were radiolabeled with ⁶⁴Cu in ammonium acetate buffer at pH 6 and formulated to pH 7.2 in PBS for use. The radiotracers were evaluated using in vitro cell binding and internalization assays and serum stability assays. In vivo studies conducted include blocking, biodistribution, and small animal PET imaging. Autoradiography and histology were also conducted.

Results

All radiotracers were radiolabeled in good radiochemical purity (>95 %) under mild conditions (37–50 °C for 15 min) with high specific activity (0.58–0.60 Ci/μmol). All radiotracers demonstrated α_vβ₆-directed cell binding (>46 %) with similar internalization levels (>23 %). The radiotracers ⁶⁴Cu-CB-TE1A1P-1 and ⁶⁴Cu-BaBaSar-1 showed improved specificity for the α_vβ₆ positive tumor in vivo over ⁶⁴Cu-DOTA-1 and ⁶⁴Cu-NOTA-1 (+/? tumor uptake ratios—3.82?+/-?0.44, 3.82?±?0.41, 2.58?±?0.58, and 1.29?±?0.14, respectively). Of the four radiotracers, ⁶⁴Cu-NOTA-1 exhibited the highest liver uptake (10.83?±?0.1 % ID/g at 4 h).

Conclusions

We have successfully conjugated, radiolabeled, and assessed the four chelates CB-TE1A1P, DOTA, NOTA, and BaBaSar both in vitro and in vivo. However, the data suggests no clear “best candidate” for the ⁶⁴Cu-radiolabeling of A20FMDV2, but instead a trade-off between the different properties (e.g., stability, selectivity, pharmacokinetics, etc.) with no obvious effects of the individual chelators.     

Physical activity,daily walking,and lower limb lymphedema associate with physical function among uterine cancer survivors

Purpose

We sought to quantify the proportion of uterine cancer survivors who self-report poor physical function. We then sought to quantify the association of poor physical function with physical activity (PA), walking, and lower limb lymphedema (LLL), among women with a history of uterine cancer.

Methods

Physical function was quantified using the Medical Outcomes Study 12-Item Short-Form Health Survey (SF-12) questionnaire. PA, walking, and LLL were measured using self-report questionnaire. PA was calculated using metabolic equivalent hours per week (MET-h week^?1), and walking was calculated using blocks per day (blocks day^?1). Logistic regression estimated odds ratios (OR) and 95 % confidence intervals (95 % CI).

Results

Among the 213 uterine cancer survivors in our survey (43 % response rate), 35 % self-reported poor physical function. Compared to participants who reported <3.0 MET-h week^?1 of PA, participants who reported ≥18.0 MET-h week^?1 of PA were less likely to have poor physical function (OR 0.03, 95 % CI 0.01–0.10; P _trend ??1 of walking, participants who reported ≥12.0 blocks day^?1 of walking were less likely to have poor physical function (OR 0.07, 95 % CI 0.03–0.19; P _trend ?P?Conclusion Higher levels of PA and walking associate with a lower likelihood of reporting poor physical function. The presence of LLL associates with a higher likelihood of reporting poor physical function. These findings are hypothesis-generating and should be evaluated in future prospective studies.     

Use of a Benzimidazole Derivative BF-188 in Fluorescence Multispectral Imaging for Selective Visualization of Tau Protein Fibrils in the Alzheimer’s Disease Brain

Purpose

Selective visualization of amyloid-β and tau protein deposits will help to understand the pathophysiology of Alzheimer’s disease (AD). Here, we introduce a novel fluorescent probe that can distinguish between these two deposits by multispectral fluorescence imaging technique.

Procedures

Fluorescence spectral analysis was performed using AD brain sections stained with novel fluorescence compounds. Competitive binding assay using [³H]-PiB was performed to evaluate the binding affinity of BF-188 for synthetic amyloid-β (Aβ) and tau fibrils.

Results

In AD brain sections, BF-188 clearly stained Aβ and tau protein deposits with different fluorescence spectra. In vitro binding assays indicated that BF-188 bound to both amyloid-β and tau fibrils with high affinity (K _i ?<?10 nM). In addition, BF-188 showed an excellent blood–brain barrier permeability in mice.

Conclusion

Multispectral imaging with BF-188 could potentially be used for selective in vivo imaging of tau deposits as well as amyloid-β in the brain.     

Pilot Study of a Novel 18F-labeled FSHR Probe for Tumor Imaging

Purpose

Follicle-stimulating hormone receptor (FSHR) is overexpressed in primary and metastatic tumor. Molecular imaging of FSHR is beneficial for prognosis and therapy of cancer. FSHβ(33–53) (YTRDLVYKDPARPKIQKTCTF), denoted as FSH1, is a FSHR antagonist. In the present study, maleimide-NOTA conjugate of FSH1 (NOTA-MAL-FSH1) was designed and labeled with [¹⁸F] aluminum fluoride. The resulting tracer, ¹⁸F-Al-NOTA-MAL-FSH1, was preliminarily evaluated in PET imaging of FSHR-positive tumor.

Procedures

NOTA-MAL-FSH1 was synthesized and radiolabeled with Al¹⁸F complex. The tumor-targeting potential and pharmacokinetic profile of the ¹⁸F-labeled compound were evaluated in vitro and in vivo using a PC3 human prostate tumor model.

Results

¹⁸F-Al-NOTA-MAL-FSH1 can be efficiently produced within 30 min with a non-decay-corrected yield of 48.6?±?2.1 % and a radiochemical purity of more than 95 %. The specific activity was at least 30 GBq/μmol. The radiotracer was stable in phosphate-buffered saline and human serum for at least 2 h. The IC₅₀ values of displacement ¹⁸F-Al-NOTA-MAL-FSH1 with FSH1 were 252?±?1.12 nM. The PC3 human prostate tumor xenografts were clearly visible with high contrast after injection of ¹⁸F-Al-NOTA-MAL-FSH1 via microPET. At 30, 60 and 120 min postinjection, the tumor uptakes were 2.98?±?0.29 % injected dose (ID)/g, 2.53?±?0.20 %ID/g and 1.36?±?0.12 %ID/g, respectively. Dynamic PET scanning showed that tumor uptake reached a plateau by about 6 min. Heart peaked earlier and then cleared quickly. Biodistribution studies confirmed that the normal organs except kidney uptakes were all below 1 %ID/g at 1 h p.i. The tumor-to-blood and tumor-to-muscle ratio at 10 min, 0.5, 1, and 2 h after injection were 1.64?±?0.36, 2.97?±?0.40, 9.31?±?1.06, and 13.59?±?2.33 and 7.05?±?1.10, 10.10?±?1.48, 16.17?±?3.29, and 30.88?±?4.67, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. FSHR-binding specificity was also demonstrated by reduced tumor uptake of ¹⁸F-Al-NOTA-MAL-FSH1 after coinjection with an excess of unlabeled FSH1 peptide.

Conclusion

NOTA-MAL-FSH1 could be labeled rapidly and efficiently with ¹⁸F using one step method. Favorable preclinical data suggest that ¹⁸F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo.     

[68Ga]-Albumin-PET in the Monitoring of Left Ventricular Function in Murine Models of Ischemic and Dilated Cardiomyopathy: Comparison with Cardiac MRI

Purpose

The purpose of this study is to evaluate left ventricular functional parameters in healthy mice and in different murine models of cardiomyopathy with the novel blood pool (BP) positron emission tomography (PET) tracer [⁶⁸Ga]-albumin.

Procedures

ECG-gated microPET examinations were obtained in healthy mice, and mice with dilative (DCM) and ischemic cardiomyopathy (ICM) using the novel BP tracer [⁶⁸Ga]-albumin (Alb_BP), as well as [¹⁸F]-FDG microPET. Cine-magnetic resonance imaging (MRI) examination performed on a clinical 1.5-T MRI provided the reference standard measurements.

Results

When considering the combined group of healthy controls, DCM and ICM Alb_BP-PET significantly overestimated the magnitudes of EDV (Alb_BP, 181?±?86 μl; cine-MRI, 125?±?80 μl; P?<?0.001) and ESV (Alb_BP, 136?±?92 μl; cine-MRI, 96?±?77 μl; P?<?0.001), whereas the EF (Alb_BP, 31?±?16 %; cine-MRI, 33?±?21 %; P?=?0.910) matched closely to cine-MRI results, as did findings with [¹⁸F]-FDG. High correlations were found between the measured cardiac parameters (EDV: R?=?0.978, ESV: R?=?0.989, and LVEF: R?=?0.992).

Conclusions

Measuring left ventricular function in mice with [⁶⁸Ga]-albumin BP PET is feasible and showed a high correlation compared to cine-MRI, which was used as a reference standard.     

Automated Radiosynthesis of [18F]ML-10, a PET Radiotracer Dedicated to Apoptosis Imaging, on a TRACERLab FX-FN Module

Purpose

[¹⁸F]ML-10 is the most advanced radiopharmaceutical for the clinical imaging of the apoptosis phenomenon by PET. The preparation of this radiopharmaceutical on a commercial radiosynthesis module and the requested quality controls for its release are presented herein.

Procedures

ML-10 as reference and its mesyloxy derivative as precursor for labelling with fluorine-18 were prepared. [¹⁸F]ML-10 was synthesized via a [¹⁸F]fluorine-de-mesyloxy aliphatic nucleophilic substitution via a GE TRACERLab® FX-FN module. Quality controls were performed.

Results

The labelling precursor was obtained in a four step synthesis in 28 % overall yield affording ML-10 in two steps (88 % yield). Pure [¹⁸F]ML-10 was obtained with a decay corrected yield of 39.8 %?±?8.4 % (n?=?7) in 70 min and a specific activity of 235?±?85 GBq/μmol at the end of synthesis.

Conclusions

[¹⁸F]ML-10 was prepared on a widely available automated module and passed the quality control. A LC/MS method was developed to measure specific radioactivity.     

Inferior vena cava collapsibility to guide fluid removal in slow continuous ultrafiltration: a pilot study

Objective

To investigate whether ultrasound determination of the inferior vena cava diameter (IVCD) and its collapsibility index (IVCCI) could be used to optimize the fluid removal rate while avoiding hypotension during slow continuous ultrafiltration (SCUF).

Methods

Twenty-four consecutive patients [13 men and 11 women, mean age 72 ± 5 years; New York Heart Association (NYHA) functional classes III–IV] with acute decompensated heart failure (ADHF) and diuretic resistance were admitted to our 16-bed medical ICU. Blood pressure (BP), heart rate (HR), respiratory rate (RR), blood samples for hematocrit, creatinine, sodium, potassium, and arterial BGA plus lactate were obtained at baseline and than every 2 h from the beginning of SCUF. IVCD, assessed by M-mode subcostal echocardiography during spontaneous breathing, was evaluated before SCUF, at 12 h, and just after the cessation of the procedure. The IVCCI was calculated as follows: [(IVCD_max ? IVCD_min)/IVCD_max] × 100.

Results

Mean UF time was 20.3 ± 4.6 h with a mean volume of 287.6 ± 96.2 ml h^?1 and a total ultrafiltrate production of 5,780.8 ± 1,994.6 ml. No significant difference in MAP, HR, RR, and IVCD before and after UF was found. IVCCI increased significantly after UF (P < 0.001). Hypotension was observed only in those patients (2/24) who reached an IVCCI >30%. In all the other patients, a significant increase in IVCCI was obtained without any hemodynamic instability.

Conclusion

IVC ultrasound is a rapid, simple, and non-invasive means for bedside monitoring of intravascular volume during SCUF and may guide fluid removal velocity.