Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals.

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer's disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aß)-positive patients showed greater 11C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased 11C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer's disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced 11C-BU99008 uptake in Aß-positive patients compared to controls, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume, although the correlations with 18F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced 11C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased 11C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aß-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong.

Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load.

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aß)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer's brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer's disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aß load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Has molecular imaging delivered to drug development?

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

Experimental validation of the hyperpolarized 129 Xe chemical shift saturation recovery technique in healthy volunteers and subjects with interstitial lung disease.

PURPOSE: To assess the sensitivity of the hyperpolarized 129 Xe chemical shift saturation recovery (CSSR) technique for noninvasive quantification of changes to lung microstructure and function in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). METHODS: Ten healthy volunteers, four subjects with SSc and four with IPF were scanned at 1.5 T. A CSSR pulse sequence was implemented using binomial-composite radiofrequency pulses to monitor 129 Xe magnetization in tissues and blood plasma (T/P) and red blood cells (RBCs). The dynamics of 129 Xe uptake into these compartments were fitted with three existing analytical models of gas diffusion to extract parameters of lung physiology. These parameters were quantitatively compared between models. RESULTS: Uptake of xenon into the pulmonary capillaries was impaired in subjects with IPF and SSc. Statistically significant septal thickening was measured by 129 Xe CSSR in IPF patients. Preliminary data suggests age-dependent alterations to septal thickness in healthy volunteers. These findings were reproduced using each of the literature models. CSSR-derived parameters were compared with gold-standard indicators of pulmonary function; diffusing capacity of carbon monoxide and pulmonary transit-time. CONCLUSIONS: CSSR with hyperpolarized 129 Xe is sensitive to pathology-induced degradation of lung structure/function and shows promise for quantification of disease severity and monitoring treatment response. Magn Reson Med 74:196-207, 2015. © 2014 Wiley Periodicals, Inc.

Fluorine magnetic resonance in vivo: a powerful tool in the study of drug distribution and metabolism.

Magnetic resonance (MR) provides an attractive non-invasive way of studying drug distribution in vivo. Widespread occurrence of fluorine in medicinal compounds, and its favourable MR properties, make it an effective probe for drug absorption, distribution, metabolism and excretion (ADME) studies. We discuss practicalities of detection and localization, and when (19)F MR would add value in a clinical trial, exemplified by deployments in oncology and psychiatry, where it is a practical way of demonstrating chronic brain accumulation directly. Limitations are emphasized to minimize failure risk, for example, inadequate sensitivity relative to tissue drug concentrations. The review anticipates increasing clinical (19)F MR as high field human scanners become widespread, and requirements to demonstrate mechanisms underlying clinical effects become more pressing.

Induced hepatic fibrosis in rats: hepatic steatosis, macromolecule content, perfusion parameters, and their correlations--preliminary MR imaging in rats.

PURPOSE: To prospectively evaluate magnetic resonance (MR) imaging for the characterization of liver fibrosis by estimating fat and extracellular matrix content and hepatic perfusion parameters in CCl(4)-treated rats. MATERIALS AND METHODS: The animal research protocol was approved by the Institutional Animal Care and Use Committee. Fifty-two rats (38 treated, 14 control) were included. A CCl(4) mixture was injected three times per week for 2-16 weeks. Fat-to-water ratios (FWRs) were calculated. Images were obtained with 12 saturation offset frequencies; magnetization transfer ratios (MTRs) were calculated. Distribution volume (DV), mean transit time (MTT), and portal fraction (PF) of blood inflow were calculated. For pairwise group comparisons, an unequal two-tailed Student t test was used. For pairwise correlations between variables, Pearson correlation coefficients were calculated. For multiple pairwise comparisons, Bonferroni correction was performed by adjusting the significance level (alpha). RESULTS: FWR and DV were correlated with CCl(4) treatment duration from 0 through 8 weeks (r = 0.658, P < .001 and r = -0.664, P < .001, respectively; alpha = .010). PF and MTT were correlated with CCl(4) treatment duration from 0 through 16 weeks (r = -0.483, P = .002 and r = 0.414, P = .008, respectively; alpha = .010). DV was inversely correlated with FWR over the same period (r = -0.581, P < .001; alpha = .007). Fibrotic rats without cirrhosis had a higher FWR and lower DV and PF (P < .001, P < .001, and P = .004, respectively; alpha = .017) than control rats, and lower MTR, DV, and MTT (P = .014, .001, and .010, respectively; alpha = .017) than cirrhotic rats. Cirrhotic rats had a higher FWR and a lower PF (P < .001, alpha = .017) than control rats. CONCLUSION: Magnetization transfer contrast is not a specific indicator of increased fibrosis in diseased liver; steatosis may influence some perfusion parameters.

Evaluation of 11C-BU99008, a PET Ligand for the Imidazoline2 Binding Site in Human Brain.

The imidazoline2 binding site (I2BS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C-BU99008 has previously been identified as a putative PET radioligand. Here, we present the first in vivo characterization of this PET radioligand in humans and assess its test-retest reproducibility. Methods: Fourteen healthy male volunteers underwent dynamic PET imaging with 11C-BU99008 and arterial sampling. Six subjects were used in a test-retest assessment, and 8 were used in a pharmacologic evaluation, undergoing a second or third heterologous competition scan with the mixed I2BS/α2-adrenoceptor drug idazoxan (n = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid (n = 4; 50 mg). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. Results: Brain uptake of 11C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment model was preferred. VT estimates were high in the striatum (105 ± 21 mL⋅cm-3), medium in the cingulate cortex (62 ± 10 mL⋅cm-3), and low in the cerebellum (41 ± 7 mL⋅cm-3). Test-retest reliability was reasonable. The uptake was dose-dependently reduced throughout the brain by pretreatment with idazoxan, with an average block across all regions of about 60% (VT, ∼30 mL⋅cm-3) at the highest dose (80 mg). The median effective dose for idazoxan was 28 mg. Uptake was not blocked by pretreatment with the monoamine oxidase inhibitor isocarboxazid. Conclusion:11C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I2BS distribution, and good test-retest reliability.

Non-invasive assessment of liver disease in rats using multiparametric magnetic resonance imaging: a feasibility study.

Non-invasive quantitation of liver disease using multiparametric magnetic resonance imaging (MRI) could refine clinical care pathways, trial design and preclinical drug development. The aim of this study was to evaluate the use of multiparametric MRI in experimental models of liver disease. Liver injury was induced in rats using 4 or 12 weeks of carbon tetrachloride (CCl4) intoxication and 4 or 8 weeks on a methionine and choline deficient (MCD) diet. Liver MRI was performed using a 7.0 Tesla small animal scanner at baseline and specified timepoints after liver injury. Multiparametric liver MRI parameters [T1 mapping, T2* mapping and proton density fat fraction (PDFF)] were correlated with gold standard histopathological measures. Mean hepatic T1 increased significantly in rats treated with CCl4 for 12 weeks compared to controls [1122±78 ms versus 959±114 ms; d=162.7, 95% CI (11.92, 313.4), P=0.038] and correlated strongly with histological collagen content (rs=0.717, P=0.037). In MCD diet-treated rats, hepatic PDFF correlated strongly with histological fat content (rs=0.819, P<0.0001), steatosis grade (rs=0.850, P<0.0001) and steatohepatitis score (rs=0.818, P<0.0001). Although there was minimal histological iron, progressive fat accumulation in MCD diet-treated livers significantly shortened T2*. In preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required.This article has an associated First Person interview with the first author of the paper.

Quantitative analysis of dynamic 18F-FDG PET/CT for measurement of lung inflammation.

BACKGROUND: An inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, is present in some patients with chronic obstructive pulmonary disease (COPD). Thoracic fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) has been proposed as a promising imaging biomarker to assess this inflammation. We sought to introduce a fully quantitative analysis method and compare this with previously published studies based on the Patlak approach using a dataset comprising 18F-FDG PET scans from COPD subjects with elevated circulating inflammatory markers (fibrinogen) and matched healthy volunteers (HV). Dynamic 18F-FDG PET scans were obtained for high-fibrinogen (>2.8 g/l) COPD subjects (N = 10) and never smoking HV (N = 10). Lungs were segmented using co-registered computed tomography images and subregions (upper, middle and lower) were semi-automatically defined. A quantitative analysis approach was developed, which corrects for the presence of air and blood in the lung (qABL method), enabling direct estimation of the metabolic rate of FDG in lung tissue. A normalised Patlak analysis approach was also performed to enable comparison with previously published results. Effect sizes (Hedge's g) were used to compare HV and COPD groups. RESULTS: The qABL method detected no difference (Hedge's g = 0.15 [-0.76 1.04]) in the tissue metabolic rate of FDG in the whole lung between HV (µ = 6.0 ± 1.9 × 10-3 ml cm-3 min-1) and COPD (µ = 5.7 ± 1.7 × 10-3 ml cm-3 min-1). However, analysis with the normalised Patlak approach detected a significant difference (Hedge's g = -1.59 [-2.57 -0.48]) in whole lung between HV (µ = 2.9 ± 0.5 × 10-3 ml cm-3 min-1) and COPD (µ = 3.9 ± 0.7 × 10-3 ml cm-3 min-1). The normalised Patlak endpoint was shown to be a composite measure influenced by air volume, blood volume and actual uptake of 18F-FDG in lung tissue. CONCLUSIONS: We have introduced a quantitative analysis method that provides a direct estimate of the metabolic rate of FDG in lung tissue. This work provides further understanding of the underlying origin of the 18F-FDG signal in the lung in disease groups and helps interpreting changes following standard or novel therapies.

Magnetic resonance imaging reveals the complementary effects of decongestant and Breathe Right Nasal Strips on internal nasal anatomy.

OBJECTIVES/HYPOTHESIS: This magnetic resonance imaging (MRI) study of 26 subjects with nasal congestion was performed to assess in the complete nasal passage both the anatomical effect of the marketed Breathe Right Nasal Strip (BRNS) relative to placebo and the potential adjunctive effect of using a decongestant in combination with the BRNS. STUDY DESIGN: Randomized, crossover study. METHODS: The study consisted of two parts, the first involving application of either the BRNS or the placebo strip in a randomized, crossover design with evaluator blinding, and repeated MRI scanning; and the second a sequential process of decongestant administration, MRI scanning, application of the BRNS, and repeated MRI. The same anatomical MRI protocol was used throughout. Nasal patency was assessed in the whole nasal passage and eight subregions (by inferior-superior, anterior-posterior division). Numerical response scores representing subjective nasal congestion were also obtained. RESULTS: Results demonstrate significant anatomical enlargement with the BRNS relative to placebo (P < .001), as well as an additive effect of using a decongestant in combination with the BRNS; both supported by a strong and significant negative correlation with the subjective nasal response measures of nasal congestion (r = -0.98, P = .002). Furthermore, analysis of the nasal subregions indicates that this adjunctive effect arises from a partially localized action of the complementary products: the BRNS acting primarily anteriorly in the nose and the decongestant mainly posteriorly. CONCLUSIONS: The BRNS alone significantly increases nasal patency and alleviates perceived nasal congestion, and additional relief of symptoms can be obtained with simultaneous use of a decongestant. LEVEL OF EVIDENCE: 1b. Laryngoscope, 126:2205-2211, 2016.

Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer.

BACKGROUND: Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access. METHODS: Patients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([(11)C]lapatinib)-PET. Less than 20 µg of [(11)C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted. RESULTS: Six patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [(11)C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [(11)C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [(11)C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib. CONCLUSIONS: Increased lapatinib uptake was observed in brain metastases but not in normal brain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01290354.

The effects of paramagnetic contrast agents on metabolite protons in aqueous solution.

The longitudinal (R1) and transverse (R2) relaxivities of the clinically used contrast agents Gd(DTPA)2-, Gd(DOTA)- and Gd(DTPA-BMA) have been determined in mixed aqueous metabolite solutions for choline, creatine and N-acetylaspartate. Measurements were performed at 1.5 T using a STEAM sequence on 25 mM metabolite solutions at pH = 7.4 and 22 degrees C. The data showed that for all the contrast agents and metabolites, R1 approximately = R2. The largest range of relaxivity values was found for Gd(DTPA)2-, where R2 = 6.8 +/- 0.3 mM(-1) s(-1) for choline and 1.5 +/- 0.4 mM(-1) s(-1) for N-acetylaspartate. Variation in relaxivity values was attributed primarily to differences between the charges of the paramagnetic agent and metabolite. The maximum potential influence of the contrast agents on in vivo metabolite signals was calculated using the measured relaxivities.

The effect of Gd-DTPA on T(1)-weighted choline signal in human brain tumours.

The influence of Gd-DTPA on T(1)-weighted (T(1)W) proton MR spectra has been investigated in 19 patients with histologically verified low (n = 13) or high-grade (n = 6) gliomas. Repeat measurements were performed on 9 patients (7 low-grade and 2 high-grade), with 28 examinations performed in total. Comparison of spectra obtained before and after 0.2 mmol/kg Gd-DTPA showed contrast agent induced broadening of the choline signal without significant signal area change. Lack of enhancement of the choline signal with the T(1)-weighted acquisitions implies that the contrast agent and the trimethylamine-containing species do not undergo significant direct interaction. Contrast agent induced changes in the choline signal observed in this and previous studies may, therefore, be attributable to T2*/susceptibility-based effects.

Recommendations for capture, validation and summarisation of data from studies using RECIST.

Response Evaluation Criteria in Solid Tumors (RECIST) is commonly used in oncology clinical trials and provides a standard approach for the assessment of treatment. However, data capture, validation and summarisation are complex. This article focuses on managing solid tumour lesion and response assessment data from capture through summarisation. Conventions for capturing lesion data, as well as considerations for data validation and summarisation, are provided. Recommendations are based on a review of data capture forms (including data items and instructions), data validation practices and algorithms for data summarisation across solid tumour studies at a single company. The intent of the authors is to share our experiences at GSK in the spirit of harmonisation by transparently describing our decisions and methods.

Phase I dose-finding study of pazopanib in hepatocellular carcinoma: evaluation of early efficacy, pharmacokinetics, and pharmacodynamics.

BACKGROUND: A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Asian patients (N = 28) were dose escalated on pazopanib (200-800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). RESULTS: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child-Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean C(max) and area under the concentration-time curve (AUC(0-6)) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and K(trans) were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C(24) and C(max) values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease. CONCLUSION: Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity.

Radiopharmaceuticals for oncology drug development: a pharmaceutical industry perspective.

Oncology remains an increasingly important focus of therapeutic development yet there remain many scientific and operational bottlenecks to deliver optimum treatments efficiently. Radiopharmaceuticals constitute a group of methodologies able to support the many stages of drug development. Methods such as [(18)F]-FDG-PET continue to have a role, evaluating early metabolic response to treatment and supporting more conventional assessments of disease response. Improvements over such tracers (for example, use of [(18)F]-FLT) in certain settings can also widen the impact radiotracers have on clinical development. New categories of tracers able to provide molecular insight into therapeutic intervention are likely grow and aim to remove the ambiguity of how effective a new drug is. It is likely that newer tracers able to define processes such as angiogenesis and apoptosis will supplement other methods in supporting early development decision-making and de-risking expensive, late-stage programs. Labeled drugs themselves also offer the ability to study localised pharmacokinetics in vivo and study issues such as therapeutic combinations. Owing to the significant cost, resource and time investment in developing novel tracers, new opportunities need to be closely matched with emerging drug development needs.

The impact of targeted training, a dedicated protocol and on-site training material in reducing observer variability of prostate and transition zone dimensions measured by transrectal ultrasonography, in multicentre multinational clinical trials of men with symptomatic benign prostatic enlargement.

OBJECTIVE: To assess the variability of a standardized protocol of transrectal ultrasonography (TRUS), with targeted training, and compare it to the variability in other multicentre clinical trials, as TRUS-estimated total prostate volume (TPV) and transition zone volume (TZV) are considered important efficacy endpoints in assessing new drug therapies for benign prostatic enlargement (BPE), but standardizing TRUS remains a challenge in such studies. PATIENTS AND METHODS: In all, 174 patients with BPE in the placebo arm of a 30-centre clinical trial were analysed at baseline, 13 and 26 weeks with TRUS, to extract TPV and TZV values. All TRUS operators received training in the standardized methods, which was supplemented at the outset by a compact disc-based video. RESULTS: The mean (sd) changes from baseline in TPV at 13 and 26 weeks were - 2.9 (8.9) and -1.9 (8.5) mL, respectively; the respective mean changes from baseline in TZV were -1.2 (6.4) and + 0.7 (7.8) mL. For TPV, 80% of the measurements had differences of + 5.2 to -13.4 mL at 13 weeks, and + 8.0 to - 10.9 mL at 26 weeks. For TZV, 80% of the differences were + 5.8 to - 7.4 at 13 weeks, and + 9.3 to -6.5 mL at 26 weeks. CONCLUSION: The performance of TRUS compared favourably with similar published multicentre studies, which we suggest relates in part to the careful implementation of the protocol. We showed that diligent implementation of a detailed protocol, supplemented by targeted training of investigators and provision of on-site training material, promoted consistent acquisition and successful derivation of key clinical trial endpoints. Quantifying the variability of such endpoints will enable us to track deployment quality for future clinical trials, and will ensure that trials are sufficiently powered to define small changes in prostate size.

On the application of chemical shift-based multipoint water-fat separation methods in balanced SSFP imaging.

Chemical shift-based multipoint water-fat separation methods have been applied in balanced steady-state free precession (bSSFP) sequences because of the high signal-to-noise-ratio (SNR) attainable. In this approach the echo formation is approximated to occur concurrently for both water and fat at an echo time (TE) equal to half the repetition time (TR/2 approximation). However, the degree to which the imaging conditions underlying the TR/2 approximation are satisfied can significantly vary in vivo depending upon the imaging region of interest (ROI) and the pixels across a field of view (FOV). The consequence of the TR/2 approximation on chemical shift-based multipoint water-fat separation was investigated. The influence of a mismatch between the pass-band profiles of water and fat (pass-band mismatch) on fat quantification was also examined. Theoretical and experimental results demonstrate that the TR/2 approximation can result in spatially dependent noise performance of multipoint water-fat separation methods, and the pass-band mismatch can render the precision of fat quantification spatially dependent. Given that local tissue characteristics in affected liver can be substantially variable, this study is of particular importance in liver imaging.

Quantitative assessment of the hepatic pharmacokinetics of the antimicrobial sitafloxacin in humans using in vivoF magnetic resonance spectroscopy.

AIMS: To measure hepatic concentrations of the fluorine-containing antimicrobial, sitafloxacin, using in vivo(19)F magnetic resonance spectroscopy (MRS). METHODS: Data were acquired from eight healthy subjects at 2, 5, 8 and 24 h following doses of 500 mg day(-1) for 5 days using a (1)H/(19)F surface coil in a 1.5T clinical MR system. Tissue water was used as a reference. RESULTS: Estimated liver concentrations at 2 h were 15.0 +/- 4.0 microg ml(-1) (mean +/- 95% CI), compared with 3.54 +/- 0.58 microg ml(-1) in plasma (n = 6), and fell below threshold concentrations (2 microg ml(-1)) by 24 h. CONCLUSIONS: (19)F MRS is able to detect and quantify sitafloxacin in the liver. There was no evidence for the hepatic retention of the drug.