Research Highlights

Our team published on the successful reintroduction of Combidex-enhanced MRI (nano-MRI) in clinical practice in the Radboudumc. Last week the paper ‘Ultra-small superparamagnetic iron oxides for metastatic lymph node detection: back on the block’ appeared online in the journal Wiley Reviews Nanomedicine and Nanobiotechnology.


Combidex-enhanced MRI at 3 Tesla of a 53-year-old patient with recurrent prostate cancer after radical prostatectomy and radiotherapy (PSA-level 3.9 ng/ml). Twenty-seven hours after administration of Combidex benign lymph nodes have accumulated the contrast agent, becoming black on a 3D iron-sensitive MRI scan. Metastatic lymph nodes retain signal and therefore stay white. A large (7 mm) metastatic lymph node is visible on Combidex MRI as a white spherical structure in two orthogonal planes through the node (blue circles in coronal (A) and axial images (B)). A smaller metastatic white node (2-3 mm) is indicated with red circles in the coronal (C) and axial (D) reconstructions (orthogonal planes through the node of interest) of the 3D data set. The other small spherical structures are blood vessels, best appreciated when scrolling through the 3D image data set.


Rashindra Manniesing and co-workers have shown the feasibility of segmenting white matter and gray matter in 4D CT images of the brain (Scientific Reports).

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Segmentation of the cranial cavity is a fundamental first step towards automatic cranial CT analysis. Ajay Patel has developed a robust algorithm that is capable of isolating all soft tissue in the cranial cavity with a high level of accuracy despite the presence of pathology or foreign objects. The algorithm was extensively evaluated on a large clinical database of approximately 600 patients. His work has been published in Medical Image Analysis and has previously featured on AuntMinnie and SPIE Newsroom.

Hansen et al. have published a paper in Stroke entitled: "Validation of noninvasive in vivo compound ultrasound strain imaging using histologic plaque vulnerability features ‘'


Background and Purpose Carotid plaque rupture is a major cause of stroke. Key issue for risk stratification is early identification of rupture-prone plaques. A noninvasive technique, compound ultrasound strain imaging, was developed providing high-resolution radial deformation/strain images of atherosclerotic plaques. This study, a collaboration between researchers from the Medical UltraSound Imaging Center (MUSIC, department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen) and the University Medical Center Utrecht, aimed at in vivo validation of compound ultrasound strain imaging in patients by relating the measured strains to typical features of vulnerable plaques derived from histology after carotid endarterectomy.

Materials and Methods Strains were measured in 34 severely stenotic (>70%) carotid arteries at the culprit lesion site within 48 hours before carotid endarterectomy. In all cases, the lumen-wall boundary was identifiable on B-mode ultrasound, and the imaged cross-section did not move out of the imaging plane from systole to diastole. After endarterectomy, the plaques were processed using a validated histology analysis technique.

Results Locally elevated strain values were observed in regions containing predominantly components related to plaque vulnerability, whereas lower values were observed in fibrous, collagen-rich plaques. The median strain of the inner plaque layer (1 mm thickness) was significantly higher (P<0.01) for (fibro)atheromatous (n=20, strain=0.27%) than that for fibrous plaques (n=14, strain=−0.75%). Also, a significantly larger area percentage of the inner layer revealed strains above 0.5% for (fibro)atheromatous (45.30%) compared with fibrous plaques (31.59%). (Fibro)atheromatous plaques were detected with a sensitivity, specificity, positive predictive value, and negative predictive value of 75%, 86%, 88%, and 71%, respectively. Strain did not significantly correlate with fibrous cap thickness, smooth muscle cell, or macrophage concentration.

Conclusion Compound ultrasound strain imaging allows differentiating (fibro)atheromatous from fibrous carotid artery plaques.

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Click here to view a short AudioSlides presentation of Thomas van den Heuvel about the automatic detection of cerebral microbleeds in patients with traumatic brain injury. The presence of Cerebral Microbleeds (CMBs) may have prognostic value in Traumatic Brain Injury (TBI) patients. However, manually annotating CMBs in TBI patients is a time consuming task that is prone to errors, because CMBs are easily overlooked and are difficult to distinguish from blood vessels. A Computer Aided Detection system was developed that automatically detects CMBs in TBI patients. This work has been published in NeuroImage: Clinical.

Venderink et al. have published a paper in European Urology Focus entitled: Elastic Versus Rigid Image Registration in Magnetic Resonance Imaging–transrectal Ultrasound Fusion Prostate Biopsy: A Systematic Review and Meta-analysis'


Context The main difference between the available magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion platforms for prostate biopsy is the method of image registration being either rigid or elastic. As elastic registration compensates for possible deformation caused by the introduction of an ultrasound probe for example, it is expected that it would perform better than rigid registration. Objective The aim of this meta-analysis is to compare rigid with elastic registration by calculating the detection odds ratio (OR) for both subgroups. The detection OR is defined as the ratio of the odds of detecting clinically significant prostate cancer (csPCa) by MRI-TRUS fusion biopsy compared with systematic TRUS biopsy. Secondary objectives were the OR for any PCa and the OR after pooling both registration techniques. Evidence acquisition The electronic databases PubMed, Embase, and Cochrane were systematically searched for relevant studies according to the Preferred Reporting Items for Systematic Review and Meta-analysis Statement. Studies comparing MRI-TRUS fusion and systematic TRUS-guided biopsies in the same patient were included. The quality assessment of included studies was performed using the Quality Assessment of Diagnostic Accuracy Studies version 2. Evidence synthesis Eleven papers describing elastic and 10 describing rigid registration were included. Meta-analysis showed an OR of csPCa for elastic and rigid registration of 1.45 (95% confidence interval [CI]: 1.21–1.73, p < 0.0001) and 1.40 (95% CI: 1.13–1.75, p = 0.002), respectively. No significant difference was seen between the subgroups (p = 0.83). Pooling subgroups resulted in an OR of 1.43 (95% CI: 1.25–1.63, p < 0.00001). Conclusions No significant difference was identified between rigid and elastic regis-tration for MRI-TRUS fusion-guided biopsy in the detection of csPCa; however, both techniques detected more csPCa than TRUS-guided biopsy alone.

Van der Geest et al. have published a paper in The Journal Of Nuclear Medicine entitled: Liposomal treatment of experimental arthritis can be monitored non-invasively with radiolabeled anti-FAP antibodies

Rheumatoid arthritis (RA) is a chronic autoimmune disorder resulting in synovial inflammation. Fibroblast activation protein (FAP) is over‐expressed by fibroblast‐like synoviocytes in arthritic joints. Radioimmunoimaging with anti‐FAP antibodies might be used to monitor therapy response, thus enabling tailored therapy strategies and therapeutic outcomes. The aim of this study was to assess whether radiolabeled anti‐FAP antibodies can be used to monitor the efficacy of treatment with prednisolone phosphate containing long‐circulating liposomes (PLP‐LCL) in a mouse model of arthritis. Collagen‐induced arthritis (CIA) was induced in male DBA/1J mice. Mice were treated with a single injection of 10 mg/kg PLP‐LCL or empty LCL as control. Single photon emission computed tomography

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(SPECT) and computed tomography (CT) images were acquired 24 h after injection of 99mTc‐labeled succinimidyl‐hydrazinonicotinamide (S‐HYNIC)‐conjugated anti‐FAP antibody, 28H1, at 2, 5 and 9 days after treatment. Uptake of 99mTc‐HYNIC‐28H1 in all joints was quantified and correlated with macroscopic arthritis scores. Treatment of CIA with PLP‐LCL significantly suppressed joint swelling. Already at one day after treatment the macroscopic arthritis scores showed a 50% decrease. Scores further decreased to only 10% of the initial scores at 5 and 9 days post treatment. In contrast, macroscopic scores increased up to 600% in untreated mice at 9 days post injection of empty LCL. 99mTc‐HYNIC‐28H1 uptake ranged from 1.5 %ID/g in non‐inflamed joints to 22.6 %ID/g in severely inflamed joints. Uptake of radiolabeled 28H1 in inflamed joints (%ID) correlated with arthritis score (Spearman’s ρ 0.77, p<0.0001). Moreover, uptake of 99mTc‐HYNIC‐28H1 slightly increased 9 days after therapy, which was not seen macroscopically, indicating that SPECT/CT imaging might be more sensitive compared to the macroscopic arthritis scoring method. SPECT/CT imaging with 99mTc‐HYNIC‐28H1 specifically monitored response to therapy and tracer accumulation correlated with the severity of inflammation. In addition, imaging is potentially more sensitive than the macroscopic scoring method. This study showed that SPECT/CT with 99mTc‐HYNIC‐28H1 can be used to noninvasively monitor the course of CIA in mice.

Manniesing et al. have published a paper in Radiology entitled: Quantitative Dose Dependency Analysis of Whole-Brain CT Perfusion Imaging

Purpose To quantitatively assess whether decreasing total radiation dose of the image acquisition protocol has an effect on cerebral CT perfusion values in patients with acute stroke.

Materials and Methods This retrospective study was approved by the institutional ethics committee, and informed consent was waived. Twenty consecutive patients with ischemic stroke who underwent CT perfusion imaging with a 320–detector row CT scanner were included. A standard acquisition protocol was used, which was started 5 seconds after injection of a contrast agent, with a scan at 200 mAs, followed after 4 seconds by 13 scans, one every 2 seconds, at 100 mAs, and then five scans, one every 5 seconds, at 75 mAs. The total examination had an average effective dose of 5.0 mSv. For each patient, a patient-specific digital perfusion phantom was constructed to simulate the same protocol at a lower total dose (0.5–5.0 mSv, with stepped doses of 0.5 mSv). The lowest setting for which the maximum mean difference remained within 5% of the reference standard (at 5.0 mSv) was marked as the optimal setting. At the optimal setting, Pearson correlation coefficients were calculated to assess correlations with the reference values, and paired t tests were performed to compare the means.

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Results At 2.5 mSv, the maximum mean differences in values from those of the reference standard were 4.5%, 5.0%, and 1.9%, for cerebral blood flow, cerebral blood volume, and mean transit time, respectively. Pearson correlation coefficients of perfusion values for white matter and gray matter were 0.864–0.917, and all differences were significant (P < .0001). Paired t tests showed no significant differences between the reference standard and optimal settings (P = .089–.923).

Conclusion The total dose of a clinical cerebral CT perfusion protocol can be lowered to 2.5 mSv, with only minor quantitative effects on perfusion values. Dose reduction beyond this point resulted in overestimation of perfusion values.

Relationship between behavior autism and brain connections

In a mouse model for autism researchers from the Radboudumc with French colleagues found clear abnormal brain connections. In the visual cortex of mice with an autism spectrum disorder more local connections and fewer connections with other brain areas are found. The research is published in Science Advances.

The fragile X syndrome is a genetic disorder associated with intellectual disabilities. About 30% of people with this syndrome exhibit behavior that falls within the autism spectrum disorder (ASD). For example, people with ASD have problems with social contacts, communication and the processing of sensory information.

A possible cause of the autistic behavior is an abnormal wiring of the brain. How that wiring would look like is not clear. An interesting theory argues that brain regions of people with ASD have more short, local connections, while there are less connections to distal areas. There is, in short, a local ' hyper connection ' and a distant ' disconnection '.


This idea does not come out of the blue. The possibilities for contact among people generally depend on available network connections. For example, to travel efficiently in the Netherlands not only a good network of local and provincial roads is needed, but also a good highway network. To process visual information in the brain the visual cortex needs many contacts. But in addition remote contacts are important for proper understanding and interpretation of the images (for example, a car comes right at me - danger !), to link it to behavior (spring aside!).

Researchers at the Radboudumc and French colleagues have measured the actual wiring of the brain in images of mice with fragile X syndrome. Arend Heerschap, Professor of Radiology and nuclear medicine: "With two different complementary imaging modalities we have investigated various brain areas. In our Preclinical Imaging Centre (PRIME) we have a very strong MRI machine of almost 12 Tesla, which can produce very detailed images of the mouse brain. So we observed that the visual cortex of mice with fragile X syndrome indeed has less connections and contacts with other parts of the brain. " With a form of "biological Imaging ' the local connections were visualized. Heerschap: "our French colleagues have manipulated a virus so that it is possible to follow how they travel through brain fibers. In this way, it became clear that the visual cortex of fragile X syndrome mice indeed have many more local connections than usual. For the first time, we have now shown this combination in a mouse model of fragile X syndrome and ASD."


The results support the idea that anatomical differences - a different wiring of the brain in this case - are at the basis of autistic behavior characteristics. Heerschap: "people with the fragile X syndrome and ASD are often very sensitive to sensory and visual information. They concentrate often strongly on details and have less attention for the broader, comprehensive picture. This does not proof that this is a direct causal relationship, but it does stimulate further research in this direction. The MR image observations can also be used as biomarkers to guide treatments"

In Cancer Research, Sandra_Heskamp Heskamp et al. have published a technique to visualize PD-L1 expression in living tumors, paving the way for more efficient treatment of this type of cancer.


Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive antitumor activity. Patients with tumors expressing PD-L1 are most likely to respond to this treatment. However, in clinical practice it is difficult to determine whether a patient’s tumor has this expression pattern. Read more...

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Vincent Breukels et al. have published a paper in "NMR in Biomedicine": Direct dynamic measurement of intracellular and extracellular lactate in small-volume cell suspensions with (13) C hyperpolarized NMR.

Hyperpolarized (HP) (13) C NMR allows enzymatic activity to be probed in real time in live biological systems. The use of in vitro models gives excellent control of the cellular environment, crucial in the understanding cancer metabolism. The increased conversion of pyruvate-to-lactate in cancer cells, the so-called Warburg effect, is well studied with HP (13) C NMR. Unfortunately, the equally important metabolic step of lactate transport out of the cell remains undetected, because intracellular and extracellular lactate are measured as a single resonance.

Breukels et al. present a new setup for live in vitro systems with the spectral resolution to separate the intracellular and extracellular lactate resonances. Tested with suspensions of prostate cancer carcinoma cells (PC3) in combination with HP [1-(13) C]pyruvate, they show the existence of a 3-Hz chemical shift difference between intracellular and extracellular lactate. The dynamic and simultaneous detection of both lactate pools allows lactate transport to be measured directly in addition to the pyruvate-to-lactate label conversion rate. This will help discriminating different prostate cancer types as well as increase our understanding in cancer metabolism in general.

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Ewoud Smit et al. have published a paper in the American Journal of Neuroradiology entitled: Timing-Invariant CT Angiography Derived from CT Perfusion Imaging in Acute Stroke: A Diagnostic Performance Study.

Timing-invariant CT angiography (CTA) derived from CT perfusion (CTP) data may obviate a separate cranial CTA in acute stroke, thus enhancing patient safety by reducing total examination time, radiation dose, and volume of contrast material. Therefore, they assessed the diagnostic accuracy of timing-invariant CTA for detecting intracranial artery occlusion in acute ischemic stroke, to examine whether standard CTA can be omitted.

Overall, standard CTA and timing-invariant CTA provided similar high diagnostic accuracy for occlusion detection with a sensitivity of 96% and a specificity of 100% for standard CTA and a sensitivity of 98% and a specificity of 100% for timing-invariant CTA. For proximal large-vessel occlusions, the sensitivity and specificity were 100% for both techniques. They concluded that timing-invariant CTA derived from CTP data provides diagnostic accuracy similar to that of standard CTA for the detection of artery occlusions in acute stroke. To read the full article, please click here.


Prof. Arend Heerschap and dr. William Leenders have published a paper in Cancer Research entitled: IDH1 R132H mutation generates a distinct phospholipid metabolite profile in gliomas.

Many glioma patients harbor specific mutations in the isocitrate dehydrogenase gene IDH1, which associate with a relatively better prognosis. IDH1-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Since IDH1 regulates several pathways leading to lipid synthesis, they hypothesized that IDH1 mutant tumors would display an altered phospholipid metabolite profile which would impinge on tumor pathobiology. Their results provide evidence that the IDH1-R132H mutation alters phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in IDH1-mutant glioma. To read the full article, please click here.


Lung cancer, by far the most deadly cancer worldwide, usually becomes symptomatic only when it is already advanced. With low dose CT scanning, lung cancer can be detected in an early stage, when it can still be treated successfully. Bram van Ginneken has been awarded a 1.5 million Euro VICI grant, in the NWO Vernieuwingsimpuls programme, for his proposal Lung CT Screening: More for Less. The goal of this project is to automate the reading of lung screening CT scans as much as possible, using computer detection algorithms and automatic volumetric segmentation of lung nodules, as illustrated above for one lung nodule that grows over a period of three years. From this analysis the probability that a suspicious lesions represents lung cancer can be accurately estimated and appropriate work up for the patient can be determined. We will also develop an automatic computer algorithm to estimate risk for cardiovascular and chronic obstructive lung disease from lung CT screening scans. All this information can be combined by an expert system to make a personal recommendation for the screening interval: not everybody needs a yearly CT. In this way we hope it will be possible to make screening both more effective and less costly.

Hamb thesis cover.png December 4, 2012, Thomas Hambrock defended his thesis The Value of 3 Tesla Magnetic Resonance Imaging for the Detection and Aggressiveness Assessment of Prostate Cancer - From Theory to Practice. He proved that a 3 Tesla MRI is the best way to determine precisely where a tumor in the prostate is located. MRI also provides a good localization of the most aggressive part of the tumor, so that targeted biopsies can be taken. He graduated cum laude at the UMC St Radboud in Nijmegen. His thesis is dedicated to his grandfather who died of prostate cancer at the age of 63.