Incorporating radiomics into clinical trials: expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers.

Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. KEY POINTS: • Data-driven processes like radiomics risk false discoveries due to high-dimensionality of the dataset compared to sample size, making adequate diversity of the data, cross-validation and external validation essential to mitigate the risks of spurious associations and overfitting. • Use of radiomic signatures within clinical trials requires multistep standardisation of image acquisition, image analysis and data mining processes. • Biological correlation may be established after clinical validation but is not mandatory.

A New Class of Smart Gadolinium Contrast Agent for Tissue pH Probing Using Magnetic Resonance Imaging.

: Detecting tissue pH in vivo is extremely vital for medical diagnosis and formulation of treatment decisions. To this end, many investigations have been carried out to develop an accurate and efficient method of in vivo pH measurement. Most of the techniques developed so far suffer from inadequate accuracy, due to poor sensitivity at low concentration of the target or nonspecific interactions within the tissue matrix. To overcome these issues, we describe herein the development of a simple, yet reliable, way to estimate pH with high precision using a Gd(III)-DOTA-silyl-based acid-labile group as a pH-sensitive contrast agent with Magnetic Resonance Imaging (MRI). With this method, a change in T1 weighted image intensity of the newly developed pH-sensitive contrast is directly linked to the proton concentration in the media. As a result, we were able estimate the pH of the target with 95% reliability.

In vivo quantification of the [(11)C]DASB binding in the normal canine brain using positron emission tomography.

BACKGROUND: [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB) is currently the mostly used radiotracer for positron emission tomography (PET) quantitative studies of the serotonin transporter (SERT) in the human brain but has never been validated in dogs. The first objective was therefore to evaluate normal [(11)C]DASB distribution in different brain regions of healthy dogs using PET. The second objective was to provide less invasive and more convenient alternative methods to the arterial sampling-based kinetic analysis. RESULTS: A dynamic acquisition of the brain was performed during 90 min. The PET images were coregistered with the magnetic resonance images taken prior to the study in order to manually drawn 20 regions of interest (ROIs). The highest radioactivity concentration of [(11)C]DASB was observed in the hypothalamus, raphe nuclei and thalamus and lowest levels in the parietal cortex, occipital cortex and cerebellum. The regional radioactivity in those 20 ROIs was quantified using the multilinear reference tissue model 2 (MRTM2) and a semi-quantitative method. The values showed least variability between 40 and 60 min and this time interval was set as the optimal time interval for [(11)C]DASB quantification in the canine brain. The correlation (R(2)) between the MRTM2 and the semi-quantitative method using the data between 40 and 60 min was 99.3% (two-tailed p-value < 0.01). CONCLUSIONS: The reference tissue models and semi-quantitative method provide a more convenient alternative to invasive arterial sampling models in the evaluation of the SERT of the normal canine brain. The optimal time interval for static scanning is set at 40 to 60 min after tracer injection.

MR pulse wave velocity increases with age faster in the thoracic aorta than in the abdominal aorta.

PURPOSE: To assess the difference between thoracic and abdominal aortic pulse wave velocity (PWV) in apparently healthy subjects including young adults to elderly subjects. MATERIALS AND METHODS: We performed PWV and distensibility measurements and analysis of thoracic and abdominal aortic segments in 96 apparently normal subjects aged 20-80 years with magnetic resonance (MR). Both unadjusted correlation and General Linear Model (GLM) analysis of log-transformed PWV (thoracic and abdominal aorta) and distensibility (four aortic cross-sections) were performed. RESULTS: Both thoracic and abdominal PWV values and distensibility values increased with age. In unadjusted analyses the correlation between the ln(thoracic PWV) and age (r = 0.71; P < 0.001) was stronger than between ln(abdominal PWV) and age (r = 0.50; P < 0.001). In GLM analysis, the only determinant of thoracic and abdominal PWV was age (F = 42.5 and F = 14.8, respectively; both P < 0.001). Similarly, correlation between ln(distensibility) and age was strong (r = -0.79, r = -0.67, r = -0.71, and r = -0.65 for ascending, descending, diaphragmatic, and low abdominal aorta, respectively; all P < 0.001). In GLM analysis, age was the major determinant for distensibility of the ascending aorta (F = 81.7; P < 0.001), descending aorta (F = 42.2; P < 0.001), diaphragmatic aorta (F = 39.2; P < 0.001), and low abdominal aorta (F = 32.8; P < 0.001). CONCLUSION: The thoracic aorta is less stiff than the abdominal aorta in young and middle-aged subjects, and stiffens more rapidly with age than the abdominal aorta, resulting in a stiffer thoracic than abdominal aorta at older age.

Establishing cooperation in a mixed-motive social dilemma. An fMRI study investigating the role of social value orientation and dispositional trust.

When people are confronted with social dilemmas, their decision-making strategies tend to be associated with individual social preferences; prosocials have an intrinsic willingness to cooperate, while proselfs need extrinsic motivators signaling personal gain. In this study, the biological roots for the proselfs/prosocials concept are explored by investigating the neural correlates of cooperative versus defect decisions when participants engage in a series of one-shot, anonymous prisoner's dilemma situations. Our data are in line with previous studies showing that prosocials activate several social cognition regions of the brain more than proselfs (here: medial prefrontal cortex, temporo-parietal junction, and precuneus BA 7 (Brodmann area 7), and that dispositional trust positively affects prosocials' decisions to cooperate. At the neural level, however, dispositional trust appears to exert a greater marginal effect on brain activity of proselfs in three social cognition regions, which does not translate into an increase in cooperation. An event-related analysis shows that cooperating prosocials show significantly more activation in the precuneus (BA 7) than proselfs. Based on previous research, we interpret this result to be consistent with prosocials' enhanced tendency to infer the intentions of others in social dilemma games, and the importance of establishing norm congruence when they decide to cooperate.

Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells.

OBJECTIVES: Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. RESULTS: First, we demonstrated that TNF(ΔARE) mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF(ΔARE) mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. CONCLUSIONS: These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.

A decade of experience with deep brain stimulation for patients with refractory medial temporal lobe epilepsy.

In this study, we present long-term results from patients with medial temporal lobe (MTL) epilepsy treated with deep brain stimulation (DBS). Since 2001, 11 patients (8M) with refractory MTL epilepsy underwent MTL DBS. When unilateral DBS failed to decrease seizures by > 90%, a switch to bilateral MTL DBS was proposed. After a mean follow-up of 8.5 years (range: 67-120 months), 6/11 patients had a ≥ 90% seizure frequency reduction with 3/6 seizure-free for > 3 years; three patients had a 40%-70% reduction and two had a < 30% reduction. In 3/5 patients switching to bilateral DBS further improved outcome. Uni- or bilateral MTL DBS did not affect neuropsychological functioning. This open study with an extended long-term follow-up demonstrates maintained efficacy of DBS for MTL epilepsy. In more than half of the patients, a seizure frequency reduction of at least 90% was reached. Bilateral MTL DBS may herald superior efficacy in unilateral MTL epilepsy.

Deep brain stimulation in patients with refractory temporal lobe epilepsy.

PURPOSE: This pilot study prospectively evaluated the efficacy of long-term deep brain stimulation (DBS) in medial temporal lobe (MTL) structures in patients with MTL epilepsy. METHODS: Twelve consecutive patients with refractory MTL epilepsy were included in this study. The protocol included invasive video-EEG monitoring for ictal-onset localization and evaluation for subsequent stimulation of the ictal-onset zone. Side effects and changes in seizure frequency were carefully monitored. RESULTS: Ten of 12 patients underwent long-term MTL DBS. Two of 12 patients underwent selective amygdalohippocampectomy. After mean follow-up of 31 months (range, 12-52 months), one of 10 stimulated patients are seizure free (>1 year), one of 10 patients had a >90% reduction in seizure frequency; five of 10 patients had a seizure-frequency reduction of > or =50%; two of 10 patients had a seizure-frequency reduction of 30-49%; and one of 10 patients was a nonresponder. None of the patients reported side effects. In one patient, MRI showed asymptomatic intracranial hemorrhages along the trajectory of the DBS electrodes. None of the patients showed changes in clinical neurological testing. Patients who underwent selective amygdalohippocampectomy are seizure-free (>1 year), AEDs are unchanged, and no side effects have occurred. CONCLUSIONS: This open pilot study demonstrates the potential efficacy of long-term DBS in MTL structures that should now be further confirmed by multicenter randomized controlled trials.