Influence of leg axis alignment on MRI T2* mapping of the knee in young professional soccer players.

BACKGROUND: Investigation of the association between leg axis alignment and biochemical MRI in young professional soccer players in order to identify a potential influence of the leg axis on cartilage regions at risk. METHODS: Sixteen professional soccer players (21 ± 3 years) underwent static and dynamic leg axis analysis via radiation free DIERS formetric 4 D as well as 3-T MRI examination of both knees. Quantitative T2* mapping of the knee cartilage was performed and T2* values were evaluated as 144 regions of interest. Subgroup analysis was performed in players with severe varus alignment (> 6°). RESULTS: Analysis of the leg axis geometry revealed a mean static alignment of 6.6° ± 2.5 varus and a mean dynamic alignment of 5.1° ± 2.6 varus. Quantitative T2* mapping showed significantly increased T2* values in the superficial cartilage layer compared to the deeper region (p < 0.001) as well as a significant increase in relaxation times in the femoral cartilage from anterior to intermediate to posterior (p < 0.001). Combination of both methods revealed a significant correlation for the degree of varus alignment and the femoral, posterior, deep region of the medial knee compartment (r = 0.4; p = 0.03). If severe varus alignment was present this region showed a significant increase in relaxation time compared to players with a less pronounced leg axis deviation (p = 0.003). CONCLUSION: This study demonstrates that varus alignment in young soccer players is associated with elevated T2* relaxation times in the deep cartilage layer of the medial, posterior, femoral compartment and might therefore be a contributing factor in the early pathogenesis of manifest cartilage lesions. Therefore, these findings should be considered in the development of preventive training programs.

First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis.

BACKGROUND: Guidelines recommend atezolizumab plus nab-paclitaxel (A + nP) for first-line treatment of unresectable, locally advanced, or metastatic triple-negative breast cancer expressing programmed death-ligand 1 (PD-L1) on tumor-infiltrating immune cells (IC), based on IMpassion130. We report the final overall survival (OS) and safety of that study as per the prespecified analysis plan. PATIENTS AND METHODS: Patients were randomized to nP 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) with atezolizumab 840 mg (A + nP) or placebo (P + nP; days 1 and 15), until progression or unacceptable toxicity. Coprimary endpoints were progression-free survival [intention-to-treat (ITT) and PD-L1 IC-positive populations] and OS (tested hierarchically in the ITT population and, if significant, in the PD-L1 IC-positive population). RESULTS: Each arm comprised 451 patients; 666 (73.8%) had died by the final OS analysis cut-off (median follow-up, 18.8 months; interquartile range, 8.9-34.7 months). Median OS in the ITT population was 21.0 months [95% confidence interval (CI), 19.0-23.4 months] with A + nP, and 18.7 months (95% CI, 16.9-20.8 months) with P + nP [stratified hazard ratio (HR), 0.87; 95% CI, 0.75-1.02; P = 0.077]. Exploratory analysis in the PD-L1 IC-positive population showed a median OS of 25.4 months (95% CI, 19.6-30.7 months) with A + nP (n = 185) and 17.9 months (95% CI, 13.6-20.3 months) with P + nP (n = 184; stratified HR, 0.67; 95% CI, 0.53-0.86). Safety outcomes were consistent with previous analyses and the known toxicity profiles of each agent. Immune-mediated adverse events of special interest were reported in 58.7% and 41.6% of patients treated with A + nP and P + nP, respectively. CONCLUSION: Although the OS benefit in the ITT population was not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed with A + nP in PD-L1 IC-positive patients, consistent with prior interim analyses. This combination remained safe and tolerable with longer follow-up.

Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.

BACKGROUND: In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab-paclitaxel in aTNBC. PATIENTS AND METHODS: Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. RESULTS: Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab-paclitaxel versus 5.7 months with placebo-paclitaxel]. In the PD-L1-positive population, atezolizumab-paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo-paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab-paclitaxel versus 28.3 months with placebo-paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. CONCLUSION: Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. CLINICALTRIALS.GOV: NCT03125902.

First-in-human study demonstrating the safety and clinical efficacy of novel anti-IL-17A monoclonal antibody CJM112 in moderate to severe plaque psoriasis.

BACKGROUND AND OBJECTIVE: Anti-IL-17A IgG/κ monoclonal antibody CJM112 binds both IL-17A and IL-17AF. The purpose of this First-in-Human study was to assess CJM112 effects on safety and efficacy in patients with moderate to severe plaque psoriasis. METHODS: This study had two parts: single ascending doses of 5-450 mg subcutaneous (s.c.) CJM112 (SAD) and multi-dose parallel groups of CJM112 15 mg, 50 mg and 150 mg s.c. low frequency or high frequency (MD). SAD/MD were double-blind, randomized and placebo-controlled; MD also included a secukinumab 150 mg s.c. arm as an active comparator. Patients 18-65 years with moderate to severe psoriasis were included in this study. The efficacy outcome was the change in Psoriasis Area Severity Index (PASI) from baseline to Week 4 in the SAD part of the study, and from baseline to Week 12 in the MD part. RESULTS: 96 patients were enrolled in this study (SAD, n = 42; MD, n = 54). In SAD, CJM112 doses from 15 mg and above demonstrated higher PASI responses compared with placebo at Week 12. CJM112 450 mg did not add further efficacy, but efficacy duration was prolonged compared with CJM112 150 mg. CJM112 MD resulted in a dose-dependent decrease in PASI over time to Week 12. CJM112 150 mg high frequency did not exceed the effect of CJM112 150 mg low frequency and had similar efficacy to secukinumab 150 mg. The safety profile of CJM112 was as expected for an antibody targeting IL-17A/IL-17AF. CONCLUSIONS: CJM112 had clinical efficacy in moderate to severe psoriasis and was generally safe and well tolerated in the doses tested. Additional neutralization of IL-17AF did not translate to increased clinical efficacy compared with secukinumab.

Correlation of T2* relaxation times of the retropatellar cartilage with tibial tuberosity-trochlea groove distance in professional soccer players.

The tibial tuberosity-trochlear groove (TT-TG) distance is a radiographic measurement that is used to quantify malalignment of the patellofemoral joint (PFJ) in cross-sectional imaging. There is an ongoing debate about the impact of the TT-TG-distance on lateral patellar instability and the initiating of cartilage degeneration. In this prospective study, the association of T2* relaxation times and TT-TG distances in professional soccer players was analyzed. 36 knees of 18 professional soccer players (age: 21 ± 2.8 years) were evaluated. Participants underwent knee MRI at 3 T. For qualitative image analysis, fat-saturated 2D PD-weighted Fast Spin Echo (FSE) and T1-weighted FSE sequences were used. For quantitative analysis, T2* measurements in 3D data acquisitions were performed. In a qualitative analysis there was no structural cartilage damage and no abnormalities of the patellar and trochlea shape. The highest T2* values (26.7 ± 5.9 ms) were observed in the central compartment of the patella. The mean TT-TG distance was 10 ± 4 mm (range 3-20 mm). There was no significant correlation between TT-TG distance and T2* relaxation times in all three compartments of the retropatellar cartilage. Our study shows that so long as patellar and trochlear morphology is normal, TT-TG distance alone does not affect the tissue structure of the retropatellar cartilage in professional soccer players.

Visualization of spatial and temporal temperature distributions with magnetic particle imaging for liver tumor ablation therapy.

Temperature-resolved magnetic particle imaging (MPI) represents a promising tool for medical imaging applications. In this study an approach based on a single calibration measurement was applied for highlighting the potential of MPI for monitoring of temperatures during thermal ablation of liver tumors. For this purpose, liver tissue and liver tumor phantoms embedding different superparamagnetic iron oxide nanoparticles (SPION) were prepared, locally heated up to 70 °C and recorded with MPI. Optimal temperature MPI SPIONs and a corresponding linear model for temperature calculation were determined. The temporal and spatial temperature distributions were compared with infrared (IR) camera results yielding quantitative agreements with a mean absolute deviation of 1 °C despite mismatches in boundary areas.

First magnetic particle imaging angiography in human-sized organs by employing a multimodal ex vivo pig kidney perfusion system.

OBJECTIVE: Magnetic particle imaging (MPI) is a new, fast 3D imaging technique, which is considered promising for angiographies. As available MPI scanners suffer from restricted spatial resolution and are mostly constructed for small animal imaging, no vessels within one organ have been depicted by MPI, yet. The purpose of this study was to develop an ex vivo organ perfusion system to display vessels within one organ of human size by MPI and to compare the results to an established 3D imaging technique. APPROACH: An ex vivo porcine kidney perfusion system compatible with digital subtraction angiography (DSA), magnetic resonance tomography and MPI was developed. DSA was used to exemplarily prove intact vessel structures under ex vivo perfusion in two organs. Perfusion in nine organs was displayed by the 3D imaging techniques magnetic resonance angiography (MRA) and MPI angiography. All visible vessels in MRA and MPI were counted and their number compared between both techniques. MAIN RESULTS: The ex vivo organ perfusion system allowed us to perform angiographies by DSA, MRA and MPI. With it, organs of human size could be imaged in small animal scanners, which permitted us to depict vessels within one organ by MPI for the first time. In comparison to MRA, 33% of all vessels were visible in MPI, a difference probably caused by restricted spatial resolution in MPI. SIGNIFICANCE: The presented ex vivo organ perfusion system can serve to practically evaluate MPI's potential for angiography in human-sized organs. This is especially relevant as long as available, for angiography-suited MPI scanners still suffer from size and spatial resolution restrictions.

[Development of ground-based physician-staffed emergency missions in the city of Leipzig from 2003 to 2013]. / Entwicklung bodengebundener Notarzteinsätze im Stadtgebiet Leipzig von 2003 bis 2013.

BACKGROUND: The annual number of physician-based emergency missions reported is continuously increasing. Data from large cities concerning this development over long periods is sparse. MATERIAL AND METHODS: In this retrospective study the charts of all ground-based physician-staffed emergency missions in the city of Leipzig for the first quarters of 2003 and 2013 were analyzed. Patient characteristics, injury and illness severities, mission location, hospital admission rate, as well as emergency interventions were collated. The emergency mission rate was calculated as rescue missions per 1000 inhabitants per year. RESULTS: The number of physician-staffed emergency missions increased by approximately 24% between 2003 and 2013 (6030 vs. 7470, respectively). The emergency mission rate was 48 vs. 58 in the 2 study periods. The median patient age increased from 66 to 70 years. The number of geriatric patients (age ≥ 85 years: n = 650 (11%) vs. n = 1161 (16%), p < 0.01) also increased. The corresponding number of emergency missions in nursing homes showed a fourfold (n = 175, 3% vs. n = 750, 10%, p < 0.01). The percentage of hospital admissions also increased (n = 3049, 51% vs. n = 4738, 66%, p < 0.01). A change in patient distribution to level I hospitals was noticed (n = 1742, 29% vs. n = 3436, 46%, p < 0.01). CONCLUSION: The findings suggest that the necessity for the high number of physician-staffed emergency missions should be verified, especially in the context of strained emergency healthcare resources. The basis of an optimized use of resources could be a better inclusion of alternative, especially ambulant, healthcare structures and the implementation of a structured emergency call questionnaire accompanied by a more efficient disposition of the operating resources, not least in view of the economic aspects. Taking the concentrated patient allocation to level 1 hospitals into consideration, there is a need for optimized patient distribution strategies to minimize the overload of individual institutions and thereby improve the general quality of care at the interface between preclinical and clinical emergency medicine.

Detection and Compensation of Periodic Motion in Magnetic Particle Imaging.

The temporal resolution of the tomographic imaging method magnetic particle imaging (MPI) is remarkably high. The spatial resolution is degraded for measured voltage signal with low signal-to-noise ratio, because the regularization in the image reconstruction step needs to be increased for system-matrix approaches and for deconvolution steps in x -space approaches. To improve the signal-to-noise ratio, blockwise averaging of the signal over time can be advantageous. However, since block-wise averaging decreases the temporal resolution, it prevents resolving the motion. In this paper, a framework for averaging motion-corrupted MPI raw data is proposed. The motion is considered to be periodic as it is the case for respiration and/or the heartbeat. The same state of motion is thus reached repeatedly in a time series exceeding the repetition time of the motion and can be used for averaging. As the motion process and the acquisition process are, in general, not synchronized, averaging of the captured MPI raw data corresponding to the same state of motion requires to shift the starting point of the individual frames. For high-frequency motion, a higher frame rate is potentially required. To address this issue, a binning method for using only parts of complete frames from a motion cycle is proposed that further reduces the motion artifacts in the final images. The frequency of motion is derived directly from the MPI raw data signal without the need to capture an additional navigator signal. Using a motion phantom, it is shown that the proposed method is capable of averaging experimental data with reduced motion artifacts. The methods are further validated on in-vivo data from mouse experiments to compensate the heartbeat.

Comparison of T2* relaxation times of articular cartilage of the knee in elite professional football players and age-and BMI-matched amateur athletes.

OBJECTIVE: Recent investigation has underlined the potential of quantitative MR imaging to be used as a complementary tool for the diagnosis of cartilage degeneration at an early state. The presented study analyses T2* relaxation times of articular cartilage of the knee in professional athletes and compares the results to age- and BMI (Body Mass Index)-matched healthy amateur athletes. MATERIALS AND METHODS: 22 professional football players and 22 age- and BMI-matched individuals were underwent knee Magnetic Resonance Imaging (MRI) at 3T including qualitative and quantitative analysis. Qualitative analysis included e.g. meniscal tears, joint effusion and bone edema. For quantitative analysis T2* (22 ET: 4.6-53.6ms) measurements in 3D data acquisition were performed. Deep and superficial layers of 22 predefined cartilage segments were analysed. All data sets were postprocessed using a dedicated software tool. Statistical analysis included Student t-test, confidence intervals and a random effects model. RESULTS: In both groups, T2* relaxation times were significantly higher in the superficial compared to the deep layers (p<0.001). Professional athletes had significantly higher relaxation times in eight superficial and three deep cartilage layers in the predefined cartilage segments (p<0.05). Highly significant differences were found in the weight-bearing segments of the lateral superficial femoral condyle (p<0.001). CONCLUSION: Elevated T2* values in cartilage layers of professional football players compared to amateur athletes were noted. The effects seem to predominate in superficial cartilage layers.

In vivo liver visualizations with magnetic particle imaging based on the calibration measurement approach.

Magnetic particle imaging (MPI) facilitates the rapid determination of 3D in vivo magnetic nanoparticle distributions. In this work, liver MPI following intravenous injections of ferucarbotran (Resovist®) was studied. The image reconstruction was based on a calibration measurement, the so called system function. The application of an enhanced system function sample reflecting the particle mobility and aggregation status of ferucarbotran resulted in significantly improved image reconstructions. The finding was supported by characterizations of different ferucarbotran compositions with the magnetorelaxometry and magnetic particle spectroscopy technique. For instance, similar results were obtained between ferucarbotran embedded in freeze-dried mannitol sugar and liver tissue harvested after a ferucarbotran injection. In addition, the combination of multiple shifted measurement patches for a joint reconstruction of the MPI data enlarged the field of view and increased the covering of liver MPI on magnetic resonance images noticeably.

Geometry planning and image registration in magnetic particle imaging using bimodal fiducial markers.

PURPOSE: Magnetic particle imaging (MPI) is a quantitative imaging modality that allows the distribution of superparamagnetic nanoparticles to be visualized. Compared to other imaging techniques like x-ray radiography, computed tomography (CT), and magnetic resonance imaging (MRI), MPI only provides a signal from the administered tracer, but no additional morphological information, which complicates geometry planning and the interpretation of MP images. The purpose of the authors' study was to develop bimodal fiducial markers that can be visualized by MPI and MRI in order to create MP-MR fusion images. METHODS: A certain arrangement of three bimodal fiducial markers was developed and used in a combined MRI/MPI phantom and also during in vivo experiments in order to investigate its suitability for geometry planning and image fusion. An algorithm for automated marker extraction in both MR and MP images and rigid registration was established. RESULTS: The developed bimodal fiducial markers can be visualized by MRI and MPI and allow for geometry planning as well as automated registration and fusion of MR-MP images. CONCLUSIONS: To date, exact positioning of the object to be imaged within the field of view (FOV) and the assignment of reconstructed MPI signals to corresponding morphological regions has been difficult. The developed bimodal fiducial markers and the automated image registration algorithm help to overcome these difficulties.

Increasing the sensitivity for stem cell monitoring in system-function based magnetic particle imaging.

The use of superparamagnetic iron oxide nanoparticles (SPIONs) has provided new possibilities in biophysics and biomedical imaging technologies. The magnetization dynamics of SPIONs, which can be influenced by the environment, are of central interest. In this work, different biological SPION environments are used to investigate three different calibration methods for stem cell monitoring in magnetic particle imaging. It is shown that calibrating using SPIONs immobilized via agarose gel or intracellular uptake results in superior stem cell image quality compared to mobile SPIONs in saline. This superior image quality enables more sensitive localization and identification of a significantly smaller number of magnetically labeled stem cells. The results are important for cell tracking and monitoring of future SPION based therapies such as hyperthermia based cancer therapies, targeted drug delivery, or tissue regeneration approaches where it is crucial to image a sufficiently small number of SPIONs interacting with biological matter.

Sensitivity Enhancement in Magnetic Particle Imaging by Background Subtraction.

Biomedical applications such as cell tracking and angiography require the detection of low concentrations of superparamagnetic iron oxide nanoparticles (SPIOs) for imaging purposes. Magnetic particle imaging (MPI) is a new technology which enables the quantitative and time-resolved localization of SPIO distributions. However, the minimum concentration at which the SPIOs can be reconstructed with a suitable quality still remains to be investigated. In this work we examine the background signals in raw data that were measured without any SPIOs in the scanner tube. We show that a background subtraction in combination with a frequency cutoff for the dynamic part of the background signal lowers the detection limit for SPIOs in MPI up to a factor of ten. In-vivo mouse experiments show that for early time points from when the tracer enters the vena cava a reconstructed image of sufficient quality can only be obtained when a background subtraction is performed.

Combined Preclinical Magnetic Particle Imaging and Magnetic Resonance Imaging: Initial Results in Mice.

PURPOSE: Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. MATERIALS AND METHODS: The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. RESULTS: A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. CONCLUSION: The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

Joint reconstruction of non-overlapping magnetic particle imaging focus-field data.

The focus field is a key component to enable clinical applications in magnetic particle imaging (MPI). Due to physiological constraints, the method of choice is to place the focus of a small acquisition volume at various static positions in space and acquire the full field-of-view using a multi-station approach. In the first experiments, overlapping drive-field patches were used and boundary artifacts between drive-field patches were reduced using image processing. In this work we show that artifact-free reconstruction of non-overlapping focus-field data is feasible by using a joint reconstruction algorithm. This enables maximum scanning efficiency in multi-station focus-field experiments, which is key for reaching sufficiently short acquisition times to image the human heart.

Intracellular mannose binding lectin mediates subcellular trafficking of HIV-1 gp120 in neurons.

Human immunodeficiency virus-1 (HIV-1) enters the brain early during infection and leads to severe neuronal damage and central nervous system impairment. HIV-1 envelope glycoprotein 120 (gp120), a neurotoxin, undergoes intracellular trafficking and transport across neurons; however mechanisms of gp120 trafficking in neurons are unclear. Our results show that mannose binding lectin (MBL) that binds to the N-linked mannose residues on gp120, participates in intravesicular packaging of gp120 in neuronal subcellular organelles and also in subcellular trafficking of these vesicles in neuronal cells. Perinuclear MBL:gp120 vesicular complexes were observed and MBL facilitated the subcellular trafficking of gp120 via the endoplasmic reticulum (ER) and Golgi vesicles. The functional carbohydrate recognition domain of MBL was required for perinuclear organization, distribution and subcellular trafficking of MBL:gp120 vesicular complexes. Nocodazole, an agent that depolymerizes the microtubule network, abolished the trafficking of MBL:gp120 vesicles, suggesting that these vesicular complexes were transported along the microtubule network. Live cell imaging confirmed the association of the MBL:gp120 complexes with dynamic subcellular vesicles that underwent trafficking in neuronal soma and along the neurites. Thus, our findings suggest that intracellular MBL mediates subcellular trafficking and transport of viral glycoproteins in a microtubule-dependent mechanism in the neurons.

Combining Surface Treatments with Shallow Slots to Improve the Spatial Resolution Performance of Continuous, Thick LYSO Detectors for PET.

Positron emission tomography (PET) detectors based on continuous scintillation crystals can achieve very good performance and have a number of practical advantages compared to detectors based on a pixelated array of crystals. Our goal is to develop a thick continuous detector with high energy and spatial resolution, along with high γ-photon capture efficiency. We examine the performance of two crystal blocks: a 46 × 46 × 14 mm3 and a 48 × 48 × 25 mm3 block of LYSO (Lutetium Yttrium Orthosilicate). Using Maximum Likelihood (ML) positioning based upon the light response function (LRF) in the 14 mm thick crystal, we measure a spatial resolution of 3 mm in the central region of the crystal with degradation near the edges due to reflections off the crystal sides. We also show that we can match the spatial resolution achieved using a 14 mm thick crystal by using a 25 mm thick crystal with slots cut into the gamma entrance surface to narrow the LRF. We also find that we can improve the spatial resolution performance near the detector edges by reducing the reflectivity of the crystal sides, albeit with some loss in energy resolution.