Implementing diffusion-weighted MRI for body imaging in prospective multicentre trials: current considerations and future perspectives.

For body imaging, diffusion-weighted MRI may be used for tumour detection, staging, prognostic information, assessing response and follow-up. Disease detection and staging involve qualitative, subjective assessment of images, whereas for prognosis, progression or response, quantitative evaluation of the apparent diffusion coefficient (ADC) is required. Validation and qualification of ADC in multicentre trials involves examination of i) technical performance to determine biomarker bias and reproducibility and ii) biological performance to interrogate a specific aspect of biology or to forecast outcome. Unfortunately, the variety of acquisition and analysis methodologies employed at different centres make ADC values non-comparable between them. This invalidates implementation in multicentre trials and limits utility of ADC as a biomarker. This article reviews the factors contributing to ADC variability in terms of data acquisition and analysis. Hardware and software considerations are discussed when implementing standardised protocols across multi-vendor platforms together with methods for quality assurance and quality control. Processes of data collection, archiving, curation, analysis, central reading and handling incidental findings are considered in the conduct of multicentre trials. Data protection and good clinical practice are essential prerequisites. Developing international consensus of procedures is critical to successful validation if ADC is to become a useful biomarker in oncology. KEY POINTS: • Standardised acquisition/analysis allows quantification of imaging biomarkers in multicentre trials. • Establishing "precision" of the measurement in the multicentre context is essential. • A repository with traceable data of known provenance promotes further research.

Compact SAW aerosol generator.

In this work, we discuss and demonstrate the principle features of surface acoustic wave (SAW) aerosol generation, based on the properties of the fluid supply, the acoustic wave field and the acoustowetting phenomena. Furthermore, we demonstrate a compact SAW-based aerosol generator amenable to mass production fabricated using simple techniques including photolithography, computerized numerical control (CNC) milling and printed circuit board (PCB) manufacturing. Using this device, we present comprehensive experimental results exploring the complexity of the acoustic atomization process and the influence of fluid supply position and geometry, SAW power and fluid flow rate on the device functionality. These factors in turn influence the droplet size distribution, measured here, that is important for applications including liquid chromatography, pulmonary therapies, thin film deposition and olfactory displays.

A genetic-based algorithm for personalized resistance training.

Association studies have identified dozens of genetic variants linked to training responses and sport-related traits. However, no intervention studies utilizing the idea of personalised training based on athlete's genetic profile have been conducted. Here we propose an algorithm that allows achieving greater results in response to high- or low-intensity resistance training programs by predicting athlete's potential for the development of power and endurance qualities with the panel of 15 performance-associated gene polymorphisms. To develop and validate such an algorithm we performed two studies in independent cohorts of male athletes (study 1: athletes from different sports (n = 28); study 2: soccer players (n = 39)). In both studies athletes completed an eight-week high- or low-intensity resistance training program, which either matched or mismatched their individual genotype. Two variables of explosive power and aerobic fitness, as measured by the countermovement jump (CMJ) and aerobic 3-min cycle test (Aero3) were assessed pre and post 8 weeks of resistance training. In study 1, the athletes from the matched groups (i.e. high-intensity trained with power genotype or low-intensity trained with endurance genotype) significantly increased results in CMJ (P = 0.0005) and Aero3 (P = 0.0004). Whereas, athletes from the mismatched group (i.e. high-intensity trained with endurance genotype or low-intensity trained with power genotype) demonstrated non-significant improvements in CMJ (P = 0.175) and less prominent results in Aero3 (P = 0.0134). In study 2, soccer players from the matched group also demonstrated significantly greater (P < 0.0001) performance changes in both tests compared to the mismatched group. Among non- or low responders of both studies, 82% of athletes (both for CMJ and Aero3) were from the mismatched group (P < 0.0001). Our results indicate that matching the individual's genotype with the appropriate training modality leads to more effective resistance training. The developed algorithm may be used to guide individualised resistance-training interventions.

A Comparison of Stride Length and Lower Extremity Kinematics during Barefoot and Shod Running in Well Trained Distance Runners.

Stride length, hip, knee and ankle angles were compared during barefoot and shod running on a treadmill at two speeds. Nine well-trained (1500m time: 3min:59.80s ± 14.7 s) male (22 ±3 years; 73 ±9 kg; 1.79 ±0.4 m) middle distance (800 m - 5,000 m) runners performed 2 minutes of running at 3.05 m·s-1 and 4.72 m·s-1 on an treadmill. This approach allowed continuous measurement of lower extremity kinematic data and calculation of stride length. Statistical analysis using a 2X2 factorial ANOVA revealed speed to have a main effect on stride length and hip angle and footwear to have a main effect on hip angle. There was a significant speed*footwear interaction for knee and ankle angles. Compared to shod running at the lower speed (3.05 m·s-1), well trained runners have greater hip, knee and ankle angles when running barefoot. Runners undertake a high volume (~75%) of training at lower intensities and therefore knowledge of how barefoot running alters running kinematics at low and high speeds may be useful to the runner.

Assessing myeloma bone disease with whole-body diffusion-weighted imaging: comparison with x-ray skeletal survey by region and relationship with laboratory estimates of disease burden.

AIM: To estimate and compare the extent of myeloma bone disease by skeletal region using whole-body diffusion-weighted imaging (WB-DWI) and skeletal survey (SS) and record interobserver agreement, and to investigate differences in imaging assessments of disease extent and apparent diffusion coefficient (ADC) between patients with pathological high versus low disease burden. MATERIALS AND METHODS: Twenty patients with relapsed myeloma underwent WB-DWI and SS. Lesions were scored by number and size for each skeletal region by two independent observers using WB-DWI and SS. Observer scores, ADC, and ADC-defined volume of tumour-infiltrated marrow were compared between patients with high and low disease burden (assessed by serum paraproteins and marrow biopsy). RESULTS: Observer scores were higher on WB-DWI than SS in every region (p<0.05) except the skull, with greater interobserver reliability in rating the whole skeleton (WB-DWI: ICC = 0.74, 95% CI: 0.443-0.886; SS: ICC = 0.44, 95% CI: 0.002-0.730) and individual body regions. WB-DWI scores were not significantly higher in patients with high versus low disease burden (observer 1: mean ± SD: 48.8 ± 7, 38.6 ± 14.5, observer 2: mean ± SD: 37.3 ± 13.5, 30.4 ± 15.5; p = 0.06, p = 0.35). CONCLUSION: WB-DWI demonstrated more lesions than SS in all regions except the skull with greater interobserver agreement. Sensitivity is not a limiting factor when considering WB-DWI in the management pathway of patients with myeloma.

Diffusion-weighted magnetic resonance imaging for assessment of lung lesions: repeatability of the apparent diffusion coefficient measurement.

PURPOSE: To establish repeatability of apparent diffusion coefficients (ADCs) acquired from free-breathing diffusion-weighted magnetic resonance imaging (DW-MRI) in malignant lung lesions and investigate effects of lesion size, location and respiratory motion. METHODS: Thirty-six malignant lung lesions (eight patients) were examined twice (1- to 5-h interval) using T1-weighted, T2-weighted and axial single-shot echo-planar DW-MRI (b = 100, 500, 800 s/mm(2)) during free-breathing. Regions of interest around target lesions on computed b = 800 s/mm(2) images by two independent observers yielded ADC values from maps (pixel-by-pixel fitting using all b values and a mono-exponential decay model). Intra- and inter-observer repeatability was assessed per lesion, per patient and by lesion size (> or <2 cm) or location. RESULTS: ADCs were similar between observers (mean ± SD, 1.15 ± 0.28 × 10(-3) mm(2)/s, observer 1; 1.15 ± 0.29 × 10(-3) mm(2)/s, observer 2). Intra-observer coefficients of variation of the mean [median] ADC per lesion and per patient were 11% [11.4%], 5.7% [5.7%] for observer 1 and 9.2% [9.5%], 3.9% [4.7%] for observer 2 respectively; inter-observer values were 8.9% [9.3%] (per lesion) and 3.0% [3.7%] (per patient). Inter-observer coefficient of variation (CoV) was greater for lesions <2 cm (n = 20) compared with >2 cm (n = 16) (10.8% vs 6.5% ADCmean, 11.3% vs 6.7% ADCmedian) and for mid (n = 14) vs apical (n = 9) or lower zone (n = 13) lesions (13.9%, 2.7%, 3.8% respectively ADCmean; 14.2%, 2.8%, 4.7% respectively ADCmedian). CONCLUSION: Free-breathing DW-MRI of whole lung achieves good intra- and inter-observer repeatability of ADC measurements in malignant lung tumours. KEY POINTS: • Diffusion-weighted MRI of the lung can be satisfactorily acquired during free-breathing • DW-MRI demonstrates high contrast between primary and metastatic lesions and normal lung • Apparent diffusion coefficient (ADC) measurements in lung tumours are repeatable and reliable • ADC offers potential in assessing response in lung metastases in clinical trials.

Use of apparent diffusion coefficient as a response biomarker in bone: effect of developing sclerosis on quantified values.

OBJECTIVE: To investigate the effect of sclerosis on apparent diffusion coefficient measurements in bone metastases from prostate cancer undergoing treatment. MATERIALS AND METHODS: Sixteen patients underwent CT scans and MRI at baseline and 12 weeks following commencement of chemotherapy. For each patient, up to five bone metastases were selected. Hounsfield units were measured on CT and apparent diffusion coefficient (ADC) was measured on diffusion weighted MRI at both time points. Correlations between changes in apparent diffusion coefficient and Hounsfield units were investigated. RESULTS: Corresponding pre- and post-treatment apparent diffusion coefficient and Hounsfield units were available on 60 lesions from 16 patients. Overall, there was no significant correlation between changes in apparent diffusion coefficient with Hounsfield units. However, where changes in Hounsfield units increased by more than 50 %, there was a trend for an associated ADC rise. CONCLUSIONS: Increasing sclerosis of bone metastases on treatment does not significantly impede diffusion.

Measurement reproducibility of perfusion fraction and pseudodiffusion coefficient derived by intravoxel incoherent motion diffusion-weighted MR imaging in normal liver and metastases.

OBJECTIVE: To determine the measurement reproducibility of perfusion fraction f, pseudodiffusion coefficient D and diffusion coefficient D in colorectal liver metastases and normal liver. METHODS: Fourteen patients with known colorectal liver metastases were examined twice using respiratory-triggered echo-planar DW-MRI with eight b values (0 to 900 s/mm(2)) 1 h apart. Regions of interests were drawn around target metastasis and normal liver in each patient to derive ADC (all b values), ADC(high) (b values ≥ 100 s/mm(2)) and intravoxel incoherent motion (IVIM) parameters f, D and D by least squares data fitting. Short-term measurement reproducibility of median ADC, ADC(high), f, D and D values were derived from Bland-Altman analysis. RESULTS: The measurement reproducibility for ADC, ADC(high) and D was worst in colorectal liver metastases (-21 % to +25 %) compared with liver parenchyma (-6 % to +8 %). Poor measurement reproducibility was observed for the perfusion-sensitive parameters of f (-75 % to +241 %) and D (-89 % to +2,120 %) in metastases, and to a lesser extent the f (-24 % to +25 %) and D (-31 % to +59 %) of liver. CONCLUSIONS: Estimates of f and D derived from the widely used least squares IVIM fitting showed poor measurement reproducibility. Efforts should be made to improve the measurement reproducibility of perfusion-sensitive IVIM parameters.

Is predictive coding falsifiable?

Predictive-coding has justifiably become a highly influential theory in Neuroscience. However, the possibility of its unfalsifiability has been raised. We argue that if predictive-coding were unfalsifiable, it would be a problem, but there are patterns of behavioural and neuroimaging data that would stand against predictive-coding. Contra (vanilla) predictive patterns are those in which the more expected stimulus generates the largest evoked-response. However, basic formulations of predictive-coding mandate that an expected stimulus should generate little, if any, prediction error and thus little, if any, evoked-response. It has, though, been argued that contra (vanilla) predictive patterns can be obtained if precision is higher for expected stimuli. Certainly, using precision, one can increase the amplitude of an evoked-response, turning a predictive into a contra (vanilla) predictive pattern. We demonstrate that, while this is true, it does not present an absolute barrier to falsification. This is because increasing precision also reduces latency and increases the frequency of the response. These properties can be used to determine whether precision-weighting in predictive-coding justifiably explains a contra (vanilla) predictive pattern, ensuring that predictive-coding is falsifiable.

Combination of chemical suppression techniques for dual suppression of fat and silicone at diffusion-weighted MR imaging in women with breast implants.

OBJECTIVES: Silicone breast prostheses prove technically challenging when performing diffusion-weighted MR imaging in the breasts. We describe a combined fat and chemical suppression scheme to achieve dual suppression of fat and silicone, thereby improving the quality of diffusion-weighted images in women with breast implants. METHODS: MR imaging was performed at 3.0 and 1.5 T in women with silicone breast implants using short-tau inversion recovery (STIR) fat-suppressed echo-planar (EPI) diffusion-weighted MR imaging (DWI) on its own and combined with the slice-select gradient-reversal (SSGR) technique. Imaging was performed using dedicated breast imaging coils. RESULTS: Complete suppression of the fat and silicone signal was possible at 3.0 T using EPI DWI with STIR and SSGR, evaluated with dedicated breast coils. However, a residual silicone signal was still perceptible at 1.5 T using this combined approach. Nevertheless, a further reduction in silicone signal at 1.5 T could be achieved by employing thinner slice partitions and the addition of the chemical-selective fat-suppression (CHESS) technique. CONCLUSIONS: DWI using combined STIR and SSGR chemical suppression techniques is feasible to eliminate or reduce silicone signal from prosthetic breast implants. KEY POINTS: Breast magnetic resonance imaging (MRI) is frequently needed following breast implants. Unsuppressed signal from silicone creates artefacts on diffusion-weighted MR sequences. Dual fat/chemical suppression can eliminate signal from fat and silicone. STIR with slice selective gradient reversal can suppress fat and silicone signal.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

Dynamic contrast-enhanced MRI of neuroendocrine hepatic metastases: A feasibility study using a dual-input two-compartment model.

Neuroendocrine hepatic metastases exhibit various contrast uptake enhancement patterns in dynamic contrast-enhanced MRI. Using a dual-input two-compartment distributed parameter model, we analyzed the dynamic contrast-enhanced MRI datasets of seven patient study cases with the aim to relate the tumor contrast uptake patterns to parameters of tumor microvasculature. Simulation studies were also performed to provide further insights into the effects of individual microcirculatory parameter on the tumor concentration-time curves. Although the tumor contrast uptake patterns can be influenced by many parameters, initial results indicate that hepatic blood flow and the ratio of fractional vascular volume to fractional interstitial volume may potentially distinguish between the patterns of neuroendocrine hepatic metastases.

Optimising diffusion weighted MRI for imaging metastatic and myeloma bone disease and assessing reproducibility.

OBJECTIVES: To establish normal bone marrow values of apparent diffusion coefficient (ADC) over an age range, compare them with metastatic and myelomatous involvement, to establish reproducibility and to optimise b values. METHODS: The ADCs of bone marrow in 7 volunteers (mean age 29.7 years), 34 volunteers (mean age 63.3 years) and 43 patients with metastatic and myelomatous involvement (mean age 65.5 years) were measured. In 9 volunteers diffusion weighted MRI was repeated within 7 days. b values were derived to optimise contrast between normal and pathological marrow. RESULTS: The mean ADC of bone marrow in younger volunteers was significantly higher than that of older volunteers. The coefficient of reproducibility was 14.8%. The ADC mean of metastatic and myeloma bone disease was 1054 + / -456 x 10⁻6mm²s⁻¹. An ADC threshold of 655 × 10(-6) mm(2)s(-1) separated normal and abnormal marrow with a sensitivity and specificity of 90% and 93% respectively. Contrast between normal and abnormal marrow was optimal at b = 1389 smm(-2). CONCLUSION: The reproducibility of ADC measurements in bone is equivalent to published data for soft tissue with a high sensitivity and specificity for separating abnormal from age matched normal bone marrow. A b value of around 1,400 smm(-2) is optimal for imaging bone marrow.

Assessing response in bone metastases in prostate cancer with diffusion weighted MRI.

OBJECTIVES: To determine whether changes in ADC of bone metastases secondary to prostate carcinoma are significantly different in responders compared with progressors on chemotherapy. METHODS: Twenty-six patients with known bone metastases secondary to prostate carcinoma underwent diffusion-weighted MRI of the lumbar spine and pelvis at baseline and 12 weeks following chemotherapy. RECIST assessment of staging CT and PSA taken at the same time points were used to classify patients as responders, progressors or stable. ADC (from b = 0,50,100,250,500,750 smm⁻²) and ADC(slow) (from b = 100,250,500,750 smm⁻²) were calculated for up to 5 lesions per patient. RESULTS: Mean ADC/ADC(slow) in lesions from responders and progressors showed a significant increase. Although the majority of lesions demonstrated an ADC/ADC(slow) rise, some lesions in both responders and progressors demonstrated a fall in ADC beyond the limits of reproducibility. CONCLUSIONS: Mean ADC is not an appropriate measure of response in bone metastases. The heterogeneity of changes in ADC is likely to be related to the composition of bone marrow with changes that have opposing effects on ADC.

Intra-Trial Reliability and Usefulness of Isometric Mid-Thigh Pull Testing on Portable Force Plates.

The aim of this study was to assess the intra-trial reliability and usefulness of portable force plates and a customised Isometric Mid-Thigh Pull rig. Twenty males (age: 24.1 ± 2.5 years, body height: 177.7 ± 0.09 cm, body mass: 88.4 ± 17.9 kg) with weightlifting experience ± 12 months attended 1 familiarisation session and 1 testing session where 4 isometric mid-thigh pulls were performed. Maximum force, absolute peak force (PF), relative PF, allometrically scaled PF, and force (150, 200, 250 ms) were deemed reliable (ICC ≥ 0.91 and CV ≤ 9.8%) based on predetermined criteria (ICC ≥ 0.8 and CV ≤ 10%). The impulse and the rate of force development (RFD) were deemed unreliable (ICC ≤ 0.91 and CV ≥ 10 %) at all time points. Maximum force, absolute PF, relative PF to body weight and body mass, rand allometrically scaled PF, had a typical error (TE) lower than the smallest worthwhile change small effect (SWC0.2) and moderate effect (SWC0.5) and were rated as good with regard to usefulness. The TE for force at selected time points (150, 200, 250 ms) was also higher than the SWC0.2, achieving a rating of marginal, but TE was higher than SWC0.5, achieving a rating of good with regard to usefulness. Portable force plates and customised rigs can reliably determine peak force and force output at different time points and for detecting the SWC in maximum and absolute force measures, greater familiarisation may be required to establish reliability of other variables such as the impulse and the RFD.

Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans.

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R(2)* pixel maps were produced for each tumour and at each time point and changes in R(2)* induced by carbogen were determined. There was a mean reduction in R(2)* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R(2)* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R(2)* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients.

Motion artifact correction in free-breathing abdominal MRI using overlapping partial samples to recover image deformations.

This article presents a method to reconstruct liver MRI data acquired continuously during free breathing, without any external sensor or navigator measurements. When the deformations associated with k-space data are known, generalized matrix inversion reconstruction has been shown to be effective in reducing the ghosting and blurring artifacts of motion. This article describes a novel method to obtain these nonrigid deformations. A breathing model is built from a fast dynamic series: low spatial resolution images are registered and their deformations parameterized by overall superior-inferior displacement. The correct deformation for each subset of the subsequent imaging data is then found by comparing a few lines of k-space with the equivalent lines from a deformed reference image while varying the deformation over the model parameter. This procedure is known as image deformation recovery using overlapping partial samples (iDROPS). Simulations using 10 rapid dynamic studies from volunteers showed the average error in iDROPS-derived deformations within the liver to be 1.43 mm. A further four volunteers were imaged at higher spatial resolution. The complete reconstruction process using data from throughout several breathing cycles was shown to reduce blurring and ghosting in the liver. Retrospective respiratory gating was also demonstrated using the iDROPS parameterization.

Reproducibility of reference tissue quantification of dynamic contrast-enhanced data: comparison with a fixed vascular input function.

Reference tissues are currently used to analyse dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data. The assessment of tumour response to treatment with anti-cancer drugs is a particularly important application of this type of analysis and requires a measure of reproducibility to define a level above which a significant change due to therapy can be inferred. This study compares the reproducibility of such quantification strategies with that found using a published, group-averaged uptake curve. It is shown that reference tissue quantification gives poorer reproducibility for most parameters than that found using a group-averaged plasma curve (a change in K(trans) of greater than 41.8% and 16.4% would be considered significant in the two approaches, respectively), but successfully incorporates some of the variability observed in plasma kinetics between visits and provides vascular input functions that, across the group, are comparable with the group-averaged curve. This study therefore provides an indirect validation of the methodology.

Evaluation of response to treatment using DCE-MRI: the relationship between initial area under the gadolinium curve (IAUGC) and quantitative pharmacokinetic analysis.

The initial area under the gadolinium curve (IAUGC) is often used in addition to or as an alternative to parameters derived from pharmacokinetic modelling of T1-weighted dynamic contrast-enhanced (DCE) MRI data in the assessment of response to treatment of cancer. However, the physiological meaning of the IAUGC has not been rigorously defined with respect to model-based parameters. Here, simulations of DCE-MRI data were used to investigate the relationship between IAUGC and the parameters K(trans) (transfer constant), v(e) (fractional extravascular extracellular volume) and v(p) (fractional plasma volume), using two vascular input functions. It is shown that IAUGC is a mixed parameter that can display correlation with K(trans), v(e) and v(p) and ultimately has an intractable relationship with all three. Furthermore, it is demonstrated that the range over which IAUGC is taken and the nature of the vascular input function do not significantly affect this relationship.