BACKGROUND CONTEXT: The development of muscle fat infiltration (MFI) in the neck muscles is associated with poor functional recovery following whiplash injury. Custom software and time-consuming manual segmentation of magnetic resonance imaging (MRI) is required for quantitative analysis and presents as a barrier for clinical translation. PURPOSE: The purpose of this work was to establish a qualitative MRI measure for MFI and evaluate its ability to differentiate between individuals with severe whiplash-associated disorder (WAD), mild or moderate WAD, and healthy controls. STUDY DESIGN/SETTING: This is a cross-sectional study. PATIENT SAMPLE: Thirty-one subjects with WAD and 31 age-and sex-matched controls were recruited from an ongoing randomized controlled trial. OUTCOME MEASURES: The cervical multifidus was visually identified and segmented into eighths in the axial fat/water images (C4-C7). Muscle fat infiltration was assessed on a visual scale: 0 for no or marginal MFI, 1 for light MFI, and 2 for distinct MFI. The participants with WAD were divided in two groups: mild or moderate and severe based on Neck Disability Index % scores. METHODS: The mean regional MFI was compared between the healthy controls and each of the WAD groups using the Mann-Whitney U test. Receiver operator characteristic (ROC) analyses were carried out to evaluate the validity of the qualitative method. RESULTS: Twenty (65%) patients had mild or moderate disability and 11 (35%) were considered severe. Inter- and intra-rater reliability was excellent when grading was averaged by level or when frequency of grade II was considered. Statistically significant differences (pamp;lt;.05) in regional MFI were particularly notable between the severe WAD group and healthy controls. The ROC curve, based on detection of distinct MFI, showed an area-under-the curve of 0.768 (95% confidence interval 0.59-0.94) for discrimination of WAD participants. CONCLUSIONS: These preliminary results suggest a qualitative MRI measure for MFI is reliable and valid, and may prove useful toward the classification of WAD in radiology practice. (C) 2017 Elsevier Inc. All rights reserved.

Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment.Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n = 20, or entirely fatty breasts (nondense), n = 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular molecules in situ and a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellular in vivo levels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1 was decreased in dense breasts. No differences were found in levels of IL-1, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue.Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue.

Background

Fruit has since long been advocated as a healthy source of many nutrients, however, the high content of sugars in fruit might be a concern.

Objectives

To study effects of an increased fruit intake compared with similar amount of extra calories from nuts in humans.

Methods

Thirty healthy non-obese participants were randomized to either supplement the diet with fruits or nuts, each at +7 kcal/kg bodyweight/day for two months. Major endpoints were change of hepatic fat content (HFC, by magnetic resonance imaging, MRI), basal metabolic rate (BMR, with indirect calorimetry) and cardiovascular risk markers.

Results

Weight gain was numerically similar in both groups although only statistically significant in the group randomized to nuts (fruit: from 22.15±1.61 kg/m2 to 22.30±1.7 kg/m2, p = 0.24 nuts: from 22.54±2.26 kg/m2 to 22.73±2.28 kg/m2, p = 0.045). On the other hand BMR increased in the nut group only (p = 0.028). Only the nut group reported a net increase of calories (from 2519±721 kcal/day to 2763±595 kcal/day, p = 0.035) according to 3-day food registrations. Despite an almost three-fold reported increased fructose-intake in the fruit group (from 9.1±6.0 gram/day to 25.6±9.6 gram/day, p<0.0001, nuts: from 12.4±5.7 gram/day to 6.5±5.3 gram/day, p = 0.007) there was no change of HFC. The numerical increase in fasting insulin was statistical significant only in the fruit group (from 7.73±3.1 pmol/l to 8.81±2.9 pmol/l, p = 0.018, nuts: from 7.29±2.9 pmol/l to 8.62±3.0 pmol/l, p = 0.14). Levels of vitamin C increased in both groups while α-tocopherol/cholesterol-ratio increased only in the fruit group.

Conclusions

Although BMR increased in the nut-group only this was not linked with differences in weight gain between groups which potentially could be explained by the lack of reported net caloric increase in the fruit group. In healthy non-obese individuals an increased fruit intake seems safe from cardiovascular risk perspective, including measurement of HFC by MRI.

Background and Objective: Brachytherapy is a form of radiation therapy using sealed radiation sources inserted within or in the vicinity of the tumor of, e.g., gynecological, prostate or head and neck cancers. Accurate dose calculation is a crucial part of the treatment planning. Several reviews have called for clinical software with model-based algorithms that better take into account the effects of patient individual distribution of tissues, source-channel and shielding attenuation than the commonly employed TG-43 formalism which simply map homogeneous water dose distributions onto the patient. In this paper we give a comprehensive and thorough derivation of such an algorithm based on collapsed cone point-kernel superposition, and describe details of its implementation into a commercial treatment planning system for clinical use. Methods: A brachytherapy version of the collapsed-cone algorithm using analytical raytraces of the primary photon radiation followed by successive scattering dose calculation for once and multiply scattered photons is described in detail, including derivation of the corresponding set of recursive equations for energy transport along cone axes/transport lines and the coupling to clinical source modeling. Specific implementation issues for setting up of the calculation grid, handling of intravoxel gradients and voxels partly containing non patient applicator material are given. Results: Sample runs for two clinical cases are shown, one being a gynecological application with a tungsten-shielded applicator and one a breast implant. These two cases demonstrate the impact of improved dose calculation versus TG-43 formalism. Conclusions: Use of model-based dose calculation algorithms for brachytherapy taking the three-dimensional treatment geometry into account increases the dosimetric accuracy in planning and follow up of treatments. The comprehensive description and derivations provided gives a rigid background for further clinical, educational and research applications. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Aramchol, an oral stearoyl-coenzyme-A-desaturase-1 inhibitor, has been shown to reduce hepatic fat content in patients with primary nonalcoholic fatty liver disease (NAFLD); however, its effect in patients with human immunodeficiency virus (HIV)-associated NAFLD is unknown. The aramchol for HIV-associated NAFLD and lipodystrophy (ARRIVE) trial was a double-blind, randomized, investigator-initiated, placebo-controlled trial to test the efficacy of 12 weeks of treatment with aramchol versus placebo in HIV-associated NAFLD. Fifty patients with HIV-associated NAFLD, defined by magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) amp;gt;= 5%, were randomized to receive either aramchol 600 mg daily (n = 25) or placebo (n = 25) for 12 weeks. The primary endpoint was a change in hepatic fat as measured by MRI-PDFF in colocalized regions of interest. Secondary endpoints included changes in liver stiffness using magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE), and exploratory endpoints included changes in total-body fat and muscle depots on dual-energy X-ray absorptiometry (DXA), whole-body MRI, and cardiac MRI. The mean (+/- standard deviation) of age and body mass index were 48.2 +/- 10.3 years and 30.7 +/- 4.6 kg/m(2), respectively. There was no difference in the reduction in mean MRI-PDFF between the aramchol group at -1.3% (baseline MRI-PDFF 15.6% versus end-of-treatment MRI-PDFF 14.4%, P = 0.24) and the placebo group at -1.4% (baseline MRI-PDFF 13.3% versus end-of-treatment MRI-PDFF 11.9%, P = 0.26). There was no difference in the relative decline in mean MRI-PDFF between the aramchol and placebo groups (6.8% versus 1.1%, P = 0.68). There were no differences in MRE-derived and VCTE-derived liver stiffness and whole-body (fat and muscle) composition analysis by MRI or DXA. Compared to baseline, end-of-treatment aminotransferases were lower in the aramchol group but not in the placebo arm. There were no significant adverse events. Conclusion: Aramchol, over a 12-week period, did not reduce hepatic fat or change body fat and muscle composition by using MRI-based assessment in patients with HIV-associated NAFLD (clinicaltrials.gov ID:NCT02684591).

Atlas-based segmentation is often used to segment medical image regions. For intensity-normalized data, the quality of these segmentations is highly dependent on the similarity between the atlas and the target under the used registration method. We propose a geodesic registration method for interactive atlas-based segmentation using empirical multi-scale anatomical manifolds. The method utilizes unlabeled images together with the labeled atlases to learn empirical anatomical manifolds. These manifolds are defined on distinct scales and regions and are used to propagate the labeling information from the atlases to the target along anatomical geodesics. The resulting competing segmentations from the different manifolds are then ranked according to an image-based similarity measure. We used image volumes acquired using magnetic resonance imaging from 36 subjects. The performance of the method was evaluated using a liver segmentation task. The result was then compared to the corresponding performance of direct segmentation using Dice Index statistics. The method shows a significant improvement in liver segmentation performance between the proposed method and direct segmentation. Furthermore, the standard deviation in performance decreased significantly. Using competing complementary manifolds defined over a hierarchy of region of interests gives an additional improvement in segmentation performance compared to the single manifold segmentation.

PURPOSE:

To quantitatively and qualitatively evaluate the water-signal performance of the consistent intensity inhomogeneity correction (CIIC) method to correct for intensity inhomogeneities METHODS: Water-fat volumes were acquired using 1.5 Tesla (T) and 3.0T symmetrically sampled 2-point Dixon three-dimensional MRI. Two datasets: (i) 10 muscle tissue regions of interest (ROIs) from 10 subjects acquired with both 1.5T and 3.0T whole-body MRI. (ii) Seven liver tissue ROIs from 36 patients imaged using 1.5T MRI at six time points after Gd-EOB-DTPA injection. The performance of CIIC was evaluated quantitatively by analyzing its impact on the dispersion and bias of the water image ROI intensities, and qualitatively using side-by-side image comparisons.

RESULTS:

CIIC significantly ( P1.5T≤2.3×10-4,P3.0T≤1.0×10-6) decreased the nonphysiological intensity variance while preserving the average intensity levels. The side-by-side comparisons showed improved intensity consistency ( Pint⁡≤10-6) while not introducing artifacts ( Part=0.024) nor changed appearances ( Papp≤10-6).

CONCLUSION:

CIIC improves the spatiotemporal intensity consistency in regions of a homogenous tissue type. J. Magn. Reson. Imaging 2014.

Purpose: In order to facilitate a smooth transition for brachytherapy dose calculations from the American Association of Physicists in Medicine (AAPM) Task Group No. 43 (TG-43) formalism to model-based dose calculation algorithms (MBDCAs), treatment planning systems (TPSs) using a MBDCA require a set of well-defined test case plans characterized by Monte Carlo (MC) methods. This also permits direct dose comparison to TG-43 reference data. Such test case plans should be made available for use in the software commissioning process performed by clinical end users. To this end, a hypothetical, generic high-dose rate (HDR) Ir-192 source and a virtual water phantom were designed, which can be imported into a TPS. Methods: A hypothetical, generic HDR Ir-192 source was designed based on commercially available sources as well as a virtual, cubic water phantom that can be imported into any TPS in DICOM format. The dose distribution of the generic Ir-192 source when placed at the center of the cubic phantom, and away from the center under altered scatter conditions, was evaluated using two commercial MBDCAs [Oncentra (R) Brachy with advanced collapsed-cone engine (ACE) and BrachyVision AcuRos (TM)]. Dose comparisons were performed using state-of-the-art MC codes for radiation transport, including ALGEBRA, BrachyDose, GEANT4, MCNP5, MCNP6, and pENELopE2008. The methodologies adhered to recommendations in the AAPM TG-229 report on high-energy brachytherapy source dosimetry. TG-43 dosimetry parameters, an along-away dose-rate table, and primary and scatter separated (PSS) data were obtained. The virtual water phantom of (201)(3) voxels (1 mm sides) was used to evaluate the calculated dose distributions. Two test case plans involving a single position of the generic HDR Ir-192 source in this phantom were prepared: (i) source centered in the phantom and (ii) source displaced 7 cm laterally from the center. Datasets were independently produced by different investigators. MC results were then compared against dose calculated using TG-43 and MBDCA methods. Results: TG-43 and PSS datasets were generated for the generic source, the PSS data for use with the ACE algorithm. The dose-rate constant values obtained from seven MC simulations, performed independently using different codes, were in excellent agreement, yielding an average of 1.1109 +/- 0.0004 cGy/(h U) (k = 1, Type A uncertainty). MC calculated dose-rate distributions for the two plans were also found to be in excellent agreement, with differences within type A uncertainties. Differences between commercial MBDCA and MC results were test, position, and calculation parameter dependent. On average, however, these differences were within 1% for ACUROS and 2% for ACE at clinically relevant distances. Conclusions: A hypothetical, generic HDR Ir-192 source was designed and implemented in two commercially available TPSs employing different MBDCAs. Reference dose distributions for this source were benchmarked and used for the evaluation of MBDCA calculations employing a virtual, cubic water phantom in the form of a CT DICOM image series. The implementation of a generic source of identical design in all TPSs using MBDCAs is an important step toward supporting univocal commissioning procedures and direct comparisons between TPSs. (C) 2015 American Association of Physicists in Medicine.

Background: : Venous occlusion in the skin is difficult to detect by existing measurement techniques. Our aim was to find out whether Tissue Viability Imaging (TiVi) was better at detecting venous occlusion by comparing it with results of laser Doppler flowmetry (LDF) during graded arterial and venous stasis in human forearm skin. Methods: : Arterial and venous occlusions were simulated in 10 healthy volunteers by inflating a blood pressure cuff around the upper right arm. Changes in the concentration of red blood cells (RBC) were measured using TiVi, while skin perfusion and concentration of moving red blood cells (CMBC) were measured using static indices of LDF during exsanguination and subsequent arterial occlusion, postocclusive reactive hyperaemia, and graded increasing and decreasing venous stasis. Results: : During arterial occlusion there was a significant reduction in the mean concentration of RBC from baseline, as well as in perfusion and CMBC (p less than 0.008). Venous occlusion resulted in a significant 28% increase in the concentration of RBC (p = 0.002), but no significant change in perfusion (mean change -14%) while CMBC decreased significantly by 24% (p = 0.02). With stepwise increasing occlusion pressures there was a significant rise in the TiVi index and reduction in perfusion (p = 0.008), while the reverse was seen when venous flow was gradually restored. Conclusion: : The concentration of RBC measured with TiVi changes rapidly and consistently during both total and partial arterial and venous occlusions, while the changes in perfusion, measured by LDF, were less consistent This suggests that TiVi could be a more useful, non-invasive clinical monitoring tool for detecting venous stasis in the skin than LDF.

Background: Venous congestion in skin flaps is difficult to detect. This study evaluated the ability of tissue viability imaging (TiVi) to measure changes in the concentration of red blood cells (CRBC), oxygenation, and heterogeneity during vascular provocations in a porcine fasciocutaneous flap model.

Methods: In 5 pigs, cranial gluteal artery perforator flaps were raised (8 flaps in 5 pigs). The arterial and venous blood flow was monitored with ultrasonic flow probes. CRBC, tissue oxygenation, and heterogeneity in the skin were monitored with TiVi during baseline, 50% and 100% venous occlusion, recovery, 100% arterial occlusion and final recovery, thereby simulating venous and arterial occlusion of a free fasciocutaneous flap. A laser Doppler probe was used as a reference for microvascular perfusion in the flap.

Results: During partial and complete venous occlusion, increases in CRBC were seen in different regions of the flap. They were more pronounced in the distal part. During complete arterial occlusion, CRBC decreased in all but the most distal parts of the flap. There were also increases in tissue oxygenation and heterogeneity during venous occlusion.

Conclusions: TiVi measures regional changes in CRBC in the skin of the flap during arterial and venous occlusion, as well as an increase in oxygenated hemoglobin during venous occlusion that may be the result of reduced metabolism and impaired delivery of oxygen to the tissue. TiVi may provide a promising method for measuring flap viability because it is hand-held, easy to-use, and provides spatial information on venous congestion.

BACKGROUND AND PURPOSE: Contrast-enhancing MS lesions are important markers of active inflammation in the diagnostic work-up of MS and in disease monitoring with MR imaging. Because intravenous contrast agents involve an expense and a potential risk of adverse events, it would be desirable to identify active lesions without using a contrast agent. The purpose of this study was to evaluate whether pre-contrast injection tissue-relaxation rates and proton density of MS lesions, by using a new quantitative MR imaging sequence, can identify active lesions. MATERIALS AND METHODS: Forty-four patients with a clinical suspicion of MS were studied. MR imaging with a standard clinical MS protocol and a quantitative MR imaging sequence was performed at inclusion (baseline) and after 1 year. ROIs were placed in MS lesions, classified as nonenhancing or enhancing. Longitudinal and transverse relaxation rates, as well as proton density were obtained from the quantitative MR imaging sequence. Statistical analyses of ROI values were performed by using a mixed linear model, logistic regression, and receiver operating characteristic analysis. RESULTS: Enhancing lesions had a significantly (P &lt; .001) higher mean longitudinal relaxation rate (1.22 0.36 versus 0.89 +/- 0.24), a higher mean transverse relaxation rate (9.8 +/- 2.6 versus 7.4 +/- 1.9), and a lower mean proton density (77 +/- 11.2 versus 90 +/- 8.4) than nonenhancing lesions. An area under the receiver operating characteristic curve value of 0.832 was obtained. CONCLUSIONS: Contrast-enhancing MS lesions often have proton density and relaxation times that differ from those in nonenhancing lesions, with lower proton density and shorter relaxation times in enhancing lesions compared with nonenhancing lesions.

Background and purpose Damage to the blood-brain barrier with subsequent contrast enhancement is a hallmark of glioblastoma. Non-enhancing tumor invasion into the peritumoral edema is, however, not usually visible on conventional magnetic resonance imaging. New quantitative techniques using relaxometry offer additional information about tissue properties. The aim of this study was to evaluate longitudinal relaxation R-1, transverse relaxation R-2, and proton density in the peritumoral edema in a group of patients with malignant glioma before surgery to assess whether relaxometry can detect changes not visible on conventional images. Methods In a prospective study, 24 patients with suspected malignant glioma were examined before surgery. A standard MRI protocol was used with the addition of a quantitative MR method (MAGIC), which measured R-1, R-2, and proton density. The diagnosis of malignant glioma was confirmed after biopsy/surgery. In 19 patients synthetic MR images were then created from the MAGIC scan, and ROIs were placed in the peritumoral edema to obtain the quantitative values. Dynamic susceptibility contrast perfusion was used to obtain cerebral blood volume (rCBV) data of the peritumoral edema. Voxel-based statistical analysis was performed using a mixed linear model. Results R-1, R-2, and rCBV decrease with increasing distance from the contrast-enhancing part of the tumor. There is a significant increase in R1 gradient after contrast agent injection (Pamp;lt;.0001). There is a heterogeneous pattern of relaxation values in the peritumoral edema adjacent to the contrast-enhancing part of the tumor. Conclusion Quantitative analysis with relaxometry of peritumoral edema in malignant gliomas detects tissue changes not visualized on conventional MR images. The finding of decreasing R-1 and R-2 means shorter relaxation times closer to the tumor, which could reflect tumor invasion into the peritumoral edema. However, these findings need to be validated in the future.

This paper presents a novel method for atlas-based segmentation of medical images. The method uses semi- supervised learning of a graph describing a manifold of anatom- ical variations of whole-body images, where unlabelled data are used to find a path with small deformations from the labelled atlas to the target image. The method is evaluated on 36 whole-body magnetic resonance images with manually segmented livers as ground truth. Significant improvement (p < 0.001) was obtained compared to direct atlas-based registration. 

Central obesity is the hallmark of a number of non-inheritable disorders. The advent of imaging techniques such as magnetic resonance imaging (MRI) has allowed for a fast and accurate assessment of body fat content and distribution. However, image analysis continues to be one of the major obstacles for the use of MRI in large scale studies. In this study we assess the validity of the recently proposed fat-muscle-quantitation-system (AMRA^TM Profiler) for the quantification of intra-abdominal adipose tissue (IAAT) and abdominal subcutaneous adipose tissue (ASAT) from abdominal MR images.  Abdominal MR images were acquired from 23 volunteers with a broad range of BMIs and analysed using SliceOmatic, the current gold-standard, and the AMRA^TM Profiler based on a non-rigid image registration of a library of segmented atlases. The results show that there was a highly significant correlation between the fat volumes generated by both analysis methods, (Pearson correlation r = 0.97 p<0.001), with the AMRA^TM Profiler analysis being significantly faster (~3 mins) than the conventional SliceOmatic approach (~40 mins). There was also excellent agreement between the methods for the quantification of IAAT (AMRA 4.73 ± 1.99 vs SliceOmatic 4.73 ± 1.75 litres, p=0.97). For the AMRA^TM Profiler analysis, the intra-observer coefficient of variation was 1.6 % for IAAT and 1.1 % for ASAT, the inter-observer coefficient of variation was 1.4 % for IAAT and 1.2 % for ASAT, the intra-observer correlation was 0.998 for IAAT and 0.999 for ASAT, and the inter-observer correlation was 0.999 for both IAAT and ASAT. These results indicate that precise and accurate measures of body fat content and distribution can be obtained in a fast and reliable form by the AMRA^TM Profiler, opening up the possibility of large-scale human phenotypic studies.

This paper gives a brief overview of common non-invasive techniques for body composition analysis and a more in-depth review of a body composition assessment method based on fat-referenced quantitative magnetic resonance imaging (MRI). Earlier published studies of this method are summarized, and a previously un-published validation study, based on 4.753 subjects from the UK Biobank imaging cohort, comparing the quantitative MRI method with dual-energy x-ray absorptiometry (DXA) is presented. For whole-body measurements of adipose tissue (AT) or fat and lean tissue (LT), DXA and quantitative MRI show excellent agreement with linear correlation of 0.99 and 0.97, and coefficient of variation (CV) of 4.5 % and 4.6 % for fat (computed from AT) and lean tissue respectively, but the agreement was found significantly lower for visceral adipose tissue, with a CV of more than 20 %. The additional ability of MRI to also measure muscle volumes, muscle AT infiltration and ectopic fat in combination with rapid scanning protocols and efficient image analysis tools make quantitative MRI a powerful tool for advanced body composition assessment. 

Purpose: During the first part of the 20th century, Ra-226 was the most used radionuclide for brachytherapy. Retrospective accurate dosimetry, coupled with patient follow up, is important for advancing knowledge on long-term radiation effects. The purpose of this work was to dosimetrically characterize two Ra-226 sources, commonly used in Sweden during the first half of the 20th century, for retrospective dose-effect studies. Methods: An 8 mg Ra-226 tube and a 10 mg Ra-226 needle, used at Radiumhemmet (Karolinska University Hospital, Stockholm, Sweden), from 1925 to the 1960s, were modeled in two independent Monte Carlo (MC) radiation transport codes: GEANT4 and MCNP5. Absorbed dose and collision kerma around the two sources were obtained, from which the TG-43 parameters were derived for the secular equilibrium state. Furthermore, results from this dosimetric formalism were compared with results from a MC simulation with a superficial mould constituted by five needles inside a glass casing, placed over a water phantom, trying to mimic a typical clinical setup. Calculated absorbed doses using the TG-43 formalism were also compared with previously reported measurements and calculations based on the Sievert integral. Finally, the dose rate at large distances from a Ra-226 point-like-source placed in the center of 1 m radius water sphere was calculated with GEANT4. Results: TG-43 parameters [including gL(r), F(r,theta), Lambda, and s(K)] have been uploaded in spreadsheets as additional material, and the fitting parameters of a mathematical curve that provides the dose rate between 10 and 60 cm from the source have been provided. Results from TG-43 formalism are consistent within the treatment volume with those of a MC simulation of a typical clinical scenario. Comparisons with reported measurements made with thermoluminescent dosimeters show differences up to 13% along the transverse axis of the radium needle. It has been estimated that the uncertainty associated to the absorbed dose within the treatment volume is 10%-15%, whereas uncertainty of absorbed dose to distant organs is roughly 20%-25%. Conclusions: The results provided here facilitate retrospective dosimetry studies of Ra-226 using modern treatment planning systems, which may be used to improve knowledge on long term radiation effects. It is surely important for the epidemiologic studies to be aware of the estimated uncertainty provided here before extracting their conclusions.

The aim of this work was to investigate how dose distributions calculated with the collapsed cone (CC) algorithm depend on the size of the water phantom used in deriving the point kernel for multiple scatter. A research version of the CC algorithm equipped with a set of selectable point kernels for multiple-scatter dose that had initially been derived in water phantoms of various dimensions was used. The new point kernels were generated using EGSnrc in spherical water phantoms of radii 5 cm, 7.5 cm, 10 cm, 15 cm, 20 cm, 30 cm and 50 cm. Dose distributions derived with CC in water phantoms of different dimensions and in a CT-based clinical breast geometry were compared to Monte Carlo (MC) simulations using the Geant4-based brachytherapy specific MC code Algebra. Agreement with MC within 1% was obtained when the dimensions of the phantom used to derive the multiple-scatter kernel were similar to those of the calculation phantom. Doses are overestimated at phantom edges when kernels are derived in larger phantoms and underestimated when derived in smaller phantoms (by around 2% to 7% depending on distance from source and phantom dimensions). CC agrees well with MC in the high dose region of a breast implant and is superior to TG43 in determining skin doses for all multiple-scatter point kernel sizes. Increased agreement between CC and MC is achieved when the point kernel is comparable to breast dimensions. The investigated approximation in multiple scatter dose depends on the choice of point kernel in relation to phantom size and yields a significant fraction of the total dose only at distances of several centimeters from a source/implant which correspond to volumes of low doses. The current implementation of the CC algorithm utilizes a point kernel derived in a comparatively large (radius 20 cm) water phantom. A fixed point kernel leads to predictable behaviour of the algorithm with the worst case being a source/implant located well within a patient/phantom for which low doses at phantom edges can be overestimated by 2-5 %. It would be possible to improve the situation by using a point kernel for multiple-scatter dose adapted to the patient/phantom dimensions at hand.

Background Quantitative-chemical-shift-encoded (CSE)-MRI methods have been applied to the liver. The feasibility and potential utility CSE-MRI in monitoring changes in pancreatic proton density fat fraction (PDFF) have not yet been demonstrated. Purpose To use quantitative CSE-MRI to estimate pancreatic fat changes during a weight-loss program in adults with severe obesity and nonalcoholic fatty liver disease (NAFLD). To explore the relationship of reduction in pancreatic PDFF with reductions in anthropometric indices. Study Type Prospective/longitudinal. Population Nine adults with severe obesity and NAFLD enrolled in a weight-loss program. Field Strength/Sequence CSE-MRI fat quantification techniques and multistation-volumetric fat/water separation techniques were performed at 3 T. Assessment PDFF values were recorded from parametric maps colocalized across timepoints. Statistical Tests Rates of change of log-transformed variables across time were determined (linear-regression), and their significance assessed compared with no change (Wilcoxon test). Rates of change were correlated pairwise (Spearmans correlation). Results Mean pancreatic PDFF decreased by 5.7% (range 0.7-17.7%) from 14.3 to 8.6%, hepatic PDFF by 11.4% (2.6-22.0%) from 14.8 to 3.4%, weight by 30.9 kg (17.3-64.2 kg) from 119.0 to 88.1 kg, body mass index by 11.0 kg/m(2) (6.3-19.1 kg/m(2)) from 44.1 to 32.9 kg/m(2), waist circumference (WC) by 25.2 cm (4.0-41.0 cm) from 133.1 to 107.9 cm, HC by 23.5 cm (4.5-47.0 cm) from 135.8 to 112.3 cm, visceral adipose tissue (VAT) by 2.9 L (1.7-5.7 L) from 7.1 to 4.2 L, subcutaneous adipose tissue (SCAT) by 4.0 L (2.9-7.4 L) from 15.0 to 11.0 L. Log-transformed rate of change for pancreatic PDFF was moderately correlated with log-transformed rates for hepatic PDFF, VAT, SCAT, and WC (rho = 0.5, 0.47, 0.45, and 0.48, respectively), although not statistically significant. Data Conclusion Changes in pancreatic PDFF can be estimated by quantitative CSE-MRI in adults undergoing a weight-loss surgery program. Pancreatic and hepatic PDFF and anthropometric indices decreased significantly. Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:1092-1102.

PURPOSE

To describe the distribution of MRI-derived body composition measurements in subjects with cardiovascular disease (CVD) compared to subjects without any history of CVD.

METHOD AND MATERIALS

1864 males and 2036 females with an age range from 45 to 78 years from the UK Biobank imaging study were included in the study. Visceral adipose tissue volume normalized with height² (VATi), total abdominal adipose tissue volume normalized with height² (ATATi), total lean thigh muscle volume normalized with body weight (muscle ratio) and liver proton density fat fraction (PDFF) were measured with a 2-point Dixon imaging protocol covering neck to knee and a 10-point Dixon single slice protocol positioned within the liver using a 1.5T MR-scanner (Siemens, Germany). The MR-images were analyzed using AMRA® Profiler research (AMRA, Sweden). 213 subjects with history of cardiovascular events (angina, heart attack, or stroke) (event group) were age and gender matched to subjects with high blood pressure (HBP group), and subjects without CVD (controls).Kruskal-Wallis and Mann-Whitney U tests were used to test the observed differences for each measurement and group without correction for multiple comparisons.

RESULTS

VATi in the event group was 1.73 (1.13 - 2.32) l/m² (median, 25%-75% percentile) compared to 1.68 (1.19 - 2.23) in the HBP group, and 1.30 (0.82-1.87) in the controls. ATATi in the event group was 4.31 (2.90-5.39) l/m² compared to 4.05 (3.07-5.12) in the HBP group, and 3.48 (2.48-4.61) in the controls. Muscle ratio in the event group was 0.13 (0.12 - 0.15) l/kg as well as in the HBP group, compared to 0.14 (0.12 - 0.15) in the controls. Liver PDFF in the event group was 2.88 (1.77 - 7.72) % compared to 3.44 (2.04-6.18) in the HBP group, and 2.50 (1.58 - 5.15) in the controls. Kruskal-Wallis test showed significant differences for all variables and group comparisons (p<0.007). The post hoc test showed significant differences comparing the controls to both the event group and the HBP group. These were more significant for VATi and ATATi (p<10-4) than for muscle ratio and PDFF (p<0.03). No significant differences were detected between the event group and the HBP group.

CONCLUSION

Cardiovascular disease is strongly associated with high VATi, liver fat, and ATATi, and with low muscle ratio.

CLINICAL RELEVANCE/APPLICATION

The metabolic syndrome component in CVD can be effectively described using MRI-based body composition profiling.

PURPOSE

To describe the distribution of MRI derived body composition measurements in subjects with diabetes mellitus (DM) compared to subjects without diabetes.

METHOD AND MATERIALS

3900 subjects (1864 males and 2036 females) from the UK Biobank imaging study were included in the study. The age range was 45 to 78 years. Visceral adipose tissue volume normalized with height² (VATi), total abdominal adipose tissue volume normalized with height² (ATATi), total lean thigh muscle volume normalized with body weight (muscle ratio) and liver proton density fat fraction (PDFF) were measured with a 6 minutes 2-point Dixon imaging protocol covering neck to knee and a 10-point Dixon single axial slice protocol positioned within the liver using a 1.5T MR-scanner (Siemens, Germany). The MR-images were analyzed using AMRA® Profiler research (AMRA, Sweden). 194 subjects with clinically diagnosed DM (DM group) were age and gender matched to subjects without DM (control group). For each variable and group, the median, 25%-percentile and 75%-percentile was calculated. Mann-Whitney U test was used to test the observed differences.

RESULTS

VATi in the DM group was 2.13 (1.43-2.62) l/m² (median, 25% - 75% percentile) compared to 1.32 (0.86 - 1.79) l/m² in the control group. ATATi in the DM group was 4.94 (3.86-6.19) l/m² compared to 3.40 (2.56 - 4.70) l/m² in the control group. Muscle ratio in the DM group was 0.13 (0.11 - 0.14) l/kg compared to 0.14 (0.12 - 0.15) l/kg in the control group. Liver PDFF in the DM group was 7.23 (2.68 - 13.26) % compared to 2.49 (1.53 - 4.73) % in the control group. Mann-Whitney U test detected significant differences between the DM group and the control group for all variables (p<10-5).

CONCLUSION

DM is strongly associated with high visceral fat, liver fat, and total abdominal fat, and low muscle ratio.

CLINICAL RELEVANCE/APPLICATION

Body composition profiling shows high potential to provide direct biomarkers to improve characterization and early diagnosis of DM.

Objective: The aim of the present study was to investigate the impact of increasing fraction delivery time on the outcome of hypofractionated radiation therapy for prostate cancer.

Methods: Monoexponential and biexponential repair models have been used for patients with prostate cancer to study the loss of biochemical control at 5 years for several clinically relevant irradiation times. The theoretical predictions were compared with newly reported clinical results from 4607 patients undergoing conventionally fractionated and hypofractionated prostate radiation therapy.

Results: Time-demanding irradiation techniques appear to lead to biochemical control rates that sometimes are about 10–20 percentage points below predictions that neglect intrafraction repair. This difference appears to be of the same order of magnitude as that predicted by moderately slow to slow repair taking place during the irradiation time. The impact is largest for the patient risk groups receiving doses corresponding to the steepest part of the dose–response curve. By contrast, for treatment techniques requiring irradiation times shorter than about 20 min, the impact of intrafraction repair appears to be much smaller and probably difficult to be observed in the light of other sources of uncertainty in clinical data.

Conclusion: Neglecting intrafraction repair might overestimate the effectiveness of some treatment schedules and could also influence any subsequent estimations of fractionation sensitivity for prostate tumours.

Advances in knowledge: The effect of intrafraction repair for prostate cancer should be taken into account for long irradiation sessions as might be expected from scanned beams and/or from multiple intrafraction imaging sessions to check the positioning of the patient.

Quality control of cone-beam computed tomography (CBCT) systems is an essential part of quality assurance to periodically check that quality requirements are met, reduce uncertainties and errors and reduce the likelihood of accidents and incidents. Radiation exposure levels must be measured to ensure that patient doses associated with CBCT examinations are kept as low as reasonably achievable consistent with the required diagnostic information. The main purpose of this document is to present procedures for quality control of CBCT systems used for dental, radiotherapy, interventional radiology and guided surgery applications.

The ‘Quality control in cone-beam computed tomography’ is the second of the series on quality control protocols. The European Federation of Organizations for Medical Physics (EFOMP) published the first document on ‘Quality Controls in digital mammography’ in 2015. These books are freely available online at efomp.org and can be used as both, in-depth working guides to everyday practice and an up-to-date reference sources for medical physicists engaged in quality control of medical imaging systems.

This book is the result of the experience and knowledge of an international group of leading medical physics experts and an excellent illustration of the synergy that can be achieved when every team member works at their best and collaboratively follows the whole process through its completion.

Abstract:

Background: The majority of breast cancer patients who receive radiation treatment are affected by acute radiation-induced skin changes. The assessment of these changes is usually done by subjective methods, which complicates the comparison between different treatments or patient groups. This study investigates the feasibility of new robust methods for monitoring skin microcirculation to objectively assess and quantify acute skin reactions during radiation treatment.

Material and methods: Laser Doppler flowmetry, laser speckle contrast imaging, and polarized light spectroscopy imaging were used to measure radiation-induced changes in microvascular perfusion and red blood cell concentration (RBC) in the skin of 15 patients undergoing adjuvant radiation therapy for breast cancer. Measurements were made before treatment, once a week during treatment, and directly after the last fraction.

Results: In the treated breast, perfusion and RBC concentration were increased after 1–5 fractions (2.66–13.3 Gy) compared to baseline. The largest effects were seen in the areola and the medial area. No changes in perfusion and RBC concentration were seen in the untreated breast. In contrast, Radiation Therapy Oncology Group (RTOG) scores were increased only after 2 weeks of treatment, which demonstrates the potential of the proposed methods for early assessment of skin changes. Also, there was a moderate to good correlation between the perfusion (r = 0.52) and RBC concentration (r = 0.59) and the RTOG score given a week later.

Conclusion: We conclude that radiation-induced microvascular changes in the skin can be objectively measured using novel camera-based techniques before visual changes in the skin are apparent. Objective measurement of microvascular changes in the skin may be valuable in the comparison of skin reactions between different radiation treatments and possibly in predicting acute skin effects at an earlier stage.

Mild homocysteinemia occurs surprisingly often in patients with premature vascular disease. We studied the possible enzymatic sources of this mild hyperhomocysteinemia and the control of homocysteine levels in plasma by treatment of patients with the cofactors and cosubstrates of homocysteine catabolism. We assessed homocysteine metabolism in 131 patients who had premature disease in their coronary, peripheral, or cerebrovascular circulation by using a standard oral methionine-load test. Impaired homocysteine metabolism occurred in 28 patients. We assayed levels of the primary enzymes of homocysteine catabolism in cultured skin fibroblast extracts from 15 of these 28 patients. The patients' cystathionine beta-synthase levels (3.68 +/- 2.52 nmol/h per milligram of cell protein, mean +/- SD) were markedly depressed compared with those from 31 healthy adult control subjects (7.61 +/- 4.49, P < .001). The patients' levels of 5-methyltetrahydrofolate: homocysteine methyltransferase were normal. While betaine: homocysteine methyltransferase was not expressed in skin fibroblasts, 24-hour urinary betaine and N,N-dimethylglycine measurements were consistent with normal or enhanced remethylation of homocysteine by betaine: homocysteine methyltransferase in the 13 patients tested. When treated daily with choline and betaine, pyridoxine, or folic acid, there was a normalization of the postmethionine plasma homocysteine level in 16 of 19 patients. Our results indicate that mild homocysteinemia in premature vascular disease may be caused by either a folate deficiency or deficiencies in cystathionine beta-synthase activity. It does not necessarily involve deficiencies of either 5-methyltetrahydrofolate:homocysteine methyltransferase or betaine:homocysteine methyltransferase. Effective treatment regimens are also defined.

This study investigates the impact of breathing motion on proton breast treatment plans. Twelve patients with CT datasets acquired during breath-hold-at-inhalation (BHI), breath-hold-at-exhalation (BHE) and in free-breathing (FB) were included in the study. Proton plans were designed for the left breast for BHI and subsequently recalculated for BHE or designed for FB and recalculated for the extreme breath-hold phases. The plans were compared from the point of view of their target coverage and doses to organs-at-risk. The median amplitude of breathing motion determined from the positions of the sternum was 4.7 mm (range 0.5-14.6 mm). Breathing motion led to a degradation of the dose coverage of the target (heterogeneity index increased from 4-7% to 8-11%), but the degraded values of the dosimetric parameters of interest fulfilled the clinical criteria for plan acceptance. Exhalation decreased the lung burden [average dose 3.1-4.5 Gy (RBE)], while inhalation increased it [average dose 5.8-6.8 Gy (RBE)]. The individual values depended on the field arrangement. Smaller differences were seen for the heart [average dose 0.1-0.2 Gy (RBE)] and the LAD [1.9-4.6 Gy (RBE)]. Weak correlations were generally found between changes in dosimetric parameters and respiratory motion. The differences between dosimetric parameters for various breathing phases were small and their expected clinical impact is consequently quite small. The results indicated that the dosimetric parameters of the plans corresponding to the extreme breathing phases are little affected by breathing motion, thus suggesting that this motion might have little impact for the chosen beam orientations with scanned proton beams.

Aim: The present study aimed to investigate the implications of using the analytical anisotropic algorithm (AAA) for calculation of target coverage and radiation burden of normal tissues. Most model parameters, recommendations and planning guidelines associated with a certain outcome are from the era of pencil beam convolution (PBC) calculations on relatively simple assumptions of energy transport in media. Their relevance for AAA calculations that predict more realistic dose distributions needs to be evaluated. Patients and Methods: Forty patients with left-sided breast cancer receiving 3D conformal radiation therapy were planned using PBC with a standard protocol with 50 Gy in 25 fractions according to existing re-commendations. The plans were subsequently recalculated with the AAA and relevant dose parameters were determined and compared to their PBC equivalents. Results: The majority of the AAA-based plans had a significantly worse coverage of the planning target volume and also a higher maximum dose in hotspots near sensitive structures, suggesting that these criteria could be relaxed for AAA-calculated plans. Furthermore, the AAA predicts higher volumes of the ipsilateral lung will receive doses below 25 Gy and smaller volume doses above 25 Gy. These results indicate that lung tolerance criteria might also have to be relaxed for AAA planning in order to maintain the level of normal tissue toxicity. The AAA also predicts lower doses to the heart, thus indicating that this organ might be more sensitive to radiation than thought from PBC-based calculations. Conclusion: The AAA should be preferred over the PBC algorithm for breast cancer radiotherapy as it gives more realistic dose distributions. Guidelines for plan acceptance might have to be re-evaluated to account for differences in dose predictions in order to maintain the current levels of control and complication rates. The results also suggest an increased radiosensitivity of the heart, thus indicating that a revision of the current models for cardiovascular complications may be needed.

Background Respiratory gating and proton therapy have both been proposed to reduce the cardiopulmonary burden in breast cancer radiotherapy. This study aims to investigate the additional benefit of proton radiotherapy for breast cancer with and without respiratory gating.

Material and methods Twenty left-sided patients were planned on computed tomography (CT)-datasets acquired during enhanced inspiration gating (EIG) and free-breathing (FB), using photon three-dimensional conformal radiation therapy (3D-CRT) and scanned proton beams. Ten patients received treatment to the whole breast only (WBO) and 10 were treated to the breast and the regional lymph nodes (BRN). Dosimetric parameters characterizing the coverage of target volumes and the cardiopulmonary burden were compared using a paired, two-tailed Student’s t-test.

Results Protons ensured comparable or better target coverage than photons in all patients during both EIG and FB. The heterogeneity index decreased from 12% with photons to about 5% with protons. The mean dose to the ipsilateral lung was reduced in BRN patients from 12 Gy to 7 Gy (RBE) in EIG and from 14 Gy to 6-7 Gy (RBE) in FB, while for WBO patients all values were about 5-6 Gy (RBE). The mean dose to heart decreased by a factor of four in WBO patients [from 1.1 Gy to 0.3 Gy (RBE) in EIG and from 2.1 Gy to 0.5 Gy (RBE) in FB] and 10 in BRN patients [from 2.1 Gy to 0.2 Gy (RBE) in EIG and from 3.4 Gy to 0.3 Gy (RBE) in FB]. Similarly, the mean and the near maximum dose to left anterior descending artery (LAD) were significantly lower (p<0.05) with protons in comparison with photons.

Conclusion Proton spot scanning has a high potential to reduce the irradiation of organs at risk and other normal tissues for most patients, beyond what could be achieved with EIG and photon therapy. The largest dose sparing has been seen for BRN patients, both in terms of cardiopulmonary burden and integral dose.

Purpose: To investigate the feasibility of using scanned proton beams as adjuvant radiation therapy for breast cancer. Long-term cardiopulmonary complications may worsen the quality of life and reduce the positive contribution of radiation therapy, which has been known to improve long-term control of locoregional disease as well as the long-term survival for these patients.

Materials and Methods: Ten patients with stage I-III cancer (either after mastectomy or lumpectomy, left- or right-sided) were included in the study. The patients were identified from a larger group where dose heterogeneity in the target and/or hotspots in the normal tissues qualified them for irregular surface compensator planning with photons. The patients underwent planning with 2 scanned proton beam planning techniques, single-field uniform dose and intensity-modulated proton therapy, and the results were compared with those from irregular surface compensator. All volumes of interest were delineated and reviewed by experienced radio-oncologists. The patients were prescribed 50 GyRBE in 25 fractions. Dosimetric parameters of interest were compared with a paired, 2-tailed Student t test.

Results: The proton plans showed comparable or better target coverage than the original photon plans. There were also large reductions with protons in mean doses to the heart (0.2 versus 1.3 GyRBE), left anterior descending artery (1.4 versus 6.4 GyRBE), and the ipsilateral lung (6.3 versus 7.7 GyRBE). This reduction is important from the point of view of the quality of life of the patients after radiation therapy. No significant differences were found between single-field uniform dose and intensity-modulated proton therapy plans.

Conclusion: Spot scanning technique with protons may improve target dose homogeneity and further reduce doses to the organs at risk compared with advanced photon techniques. The results from this study indicate a potential for protons as adjuvant radiation therapy in breast cancer and a further step toward the individualization of treatment based on anatomic and comorbidity characteristics.

The liver is one of the largest organs within the human body and it handles many vital tasks such as nutrient processing, toxin removal, and synthesis of important proteins. The number of people suffering from chronic liver disease is on the rise, likely due to the present ‘western’ lifestyle. As disease develops in the liver there are pathophysiological manifestations within the liver parenchyma that are both common and important to monitor. These manifestations include inflammation, fatty infiltration (steatosis), excessive scar tissue formation (fibrosis and cirrhosis), and iron loading. Importantly, as the disease progresses there is concurrent loss of liver function. Furthermore, postoperative liver function insufficiency is an important concern when planning surgical treatment of the liver, because it is associated with both morbidity and mortality. Liver function can also be hampered due to drug-induced injuries, an important aspect to consider in drug-development.

Currently, an invasive liver needle biopsy is required to determine the aetiology and to stage or grade the pathophysiological manifestations. There are important limitations with the biopsy, which include, risk of serious complications, mortality, morbidity, inter- and intra-observer variability, sampling error, and sampling variability. Cleary, it would be beneficial to be able investigate the pathophysiological manifestations accurately, non-invasively, and on regional level.

Current available laboratory liver function blood panels are typically insufficient and often only indicate damage at a late stage. Thus, it would be beneficial to have access to biomarkers that are both sensitive and responds to early changes in liver function in both clinical settings and for the pharmaceutical industry and regulatory agencies.

The main aim of this thesis was to develop and evaluate methods that can be used for a ‘non-invasive liver biopsy’ using magnetic resonance (MR). We also aimed to develop sensitive methods for measure liver function based on gadoxetate-enhanced MR imaging (MRI).

The presented work is primarily based on a prospective study on c. 100 patients suffering from chronic liver disease of varying aetiologies recruited due to elevated liver enzyme levels, without clear signs of decompensated cirrhosis. Our results show that the commonly used liver fat cut-off for diagnosing steatosis should be lowered from 5% to 3% when using MR proton-density fat fraction (PDFF). We also show that MR elastography (MRE) is superior in staging fibrosis.

Finally we presented a framework for quantifying liver function based on gadoxetate-enhanced MRI. The method is based on clinical images and a clinical approved contrast agent (gadoxetate). The framework consists of; state-of the-art image reconstruction and correction methods, a mathematical model, and a precise model parametrization method. The model was developed and validated on healthy subjects. Thereafter the model was found applicable on the chronic liver disease cohort as well as validated using gadoxetate levels in biopsy samples and blood samples. The liver function parameters correlated with clinical markers for liver function and liver fibrosis (used as a surrogate marker for liver function).

In summary, it should be possible to perform a non-invasive liver biopsy using: MRI-PDFF for liver fat and iron loading, MRE for liver fibrosis and possibly also inflammation, and measure liver function using the presented framework for analysing gadoxetate-enhanced MRI. With the exception of an MREtransducer no additional hardware is required on the MR scanner. The liver function method is likely to be useful both in a clinical setting and in pharmaceutical trials.

Estimation of liver function is important to monitor progression of chronic liver disease (CLD). A promising method is magnetic resonance imaging (MRI) combined with gadoxetate, a liver-specific contrast agent. For this method, we have previously developed a model for an average healthy human. Herein, we extended this model, by combining it with a patient-specific non-linear mixed-effects modeling framework. We validated the model by recruiting 100 patients with CLD of varying severity and etiologies. The model explained all MRI data and adequately predicted both timepoints saved for validation and gadoxetate concentrations in both plasma and biopsies. The validated model provides a new and deeper look into how the mechanisms of liver function vary across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate. These mechanisms are shared across many liver functions and can now be estimated from standard clinical images.

Author summary

Being able to accurately and reliably estimate liver function is important when monitoring the progression of patients with liver disease, as well as when identifying drug-induced liver injury during drug development. A promising method for quantifying liver function is to use magnetic resonance imaging combined with gadoxetate. Gadoxetate is a liver-specific contrast agent, which is taken up by the hepatocytes and excreted into the bile. We have previously developed a mechanistic model for gadoxetate dynamics using averaged data from healthy volunteers. In this work, we extended our model with a non-linear mixed-effects modeling framework to give patient-specific estimates of the gadoxetate transport-rates. We validated the model by recruiting 100 patients with liver disease, covering a range of severity and etiologies. All patients underwent an MRI-examination and provided both blood and liver biopsies. Our validated model provides a new and deeper look into how the mechanisms of liver function varies across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate.

Purpose

Continuous monitoring of liver fibrosis progression in patients is not feasible with the current diagnostic golden standard (needle biopsy). Recently, magnetic resonance elastography (MRE) has emerged as a promising method for such continuous monitoring. Since there are different MRE methods that could be used in a clinical setting there is a need to investigate whether measurements produced by these MRE methods are comparable. Hence, the purpose of this pilot study was to evaluate whether the measurements of the viscoelastic properties produced by 2D (stiffness) and 3D (elasticity and ‘G_abs,Elastic’) MRE are comparable.

Materials and methods

Seven patients with diffuse or suspect diffuse liver disease were examined in the same day with the two MRE methods. 2D MRE was performed using an acoustic passive transducer, with a 1.5 T GE 450 W MR system. 3D MRE was performed using an electromagnetic active transducer, with a 1.5 T Philips Achieva MR system. Finally, mean viscoelastic values were extracted from the same anatomical region for both methods by an experienced radiologist.

Results

Stiffness correlated well with the elasticity, R² = 0.96 (P < 0.001; slope = 1.08, intercept = 0.61 kPa), as well as with ‘G_abs,Elastic’ R² = 0.96 (P < 0.001; slope = 0.95, intercept = 0.28 kPa).

Conclusion

This pilot study shows that different MRE methods can produce comparable measurements of the viscoelastic properties of the liver. The existence of such comparable measurements is important, both from a clinical as well as a research perspective, since it allows for equipment-independent monitoring of disease progression.

John "Jack" Fowler has been a busy radiation biology researcher and teacher. He has written 581 papers over the last 65 plus years. He has also received nearly every honor the medical physics field can bestow. But Jack is not done. He says it is time he wrote a book. Jack's new book, Optimum overall treatment time in radiation oncology, sums up the key concepts relating to optimum fractionation in radiation therapy that have interested him all these years.

Objectives This explorative study analyses interrelationships between peripheral compounds in saliva, plasma, and muscles together with body composition variables in healthy subjects and in fibromyalgia patients (FM). There is a need to better understand the extent cytokines and chemokines are associated with body composition and which cytokines and chemokines differentiate FM from healthy controls.Methods Here, 32 female FM patients and 30 age-matched female healthy controls underwent a clinical examination that included blood sample, saliva samples, and pain threshold tests. In addition, the subjects completed a health questionnaire. From these blood and saliva samples, a panel of 68 mainly cytokines and chemokines were determined. Microdialysis of trapezius and erector spinae muscles, phosphorus-31 magnetic resonance spectroscopy of erector spinae muscle, and whole-body magnetic resonance imaging for determination of body composition (BC)-i.e., muscle volume, fat content and infiltration-were also performed.Results After standardizing BC measurements to remove the confounding effect of Body Mass Index, fat infiltration and content are generally increased, and fat-free muscle volume is decreased in FM. Mainly saliva proteins differentiated FM from controls. When including all investigated compounds and BC variables, fat infiltration and content variables were most important, followed by muscle compounds and cytokines and chemokines from saliva and plasma. Various plasma proteins correlated positively with pain intensity in FM and negatively with pain thresholds in all subjects taken together. A mix of increased plasma cytokines and chemokines correlated with an index covering fat infiltration and content in different tissues. When muscle compounds were included in the analysis, several of these were identified as the most important regressors, although many plasma and saliva proteins remained significant.Discussion Peripheral factors were important for group differentiation between FM and controls. In saliva (but not plasma), cytokines and chemokines were significantly associated with group membership as saliva compounds were increased in FM. The importance of peripheral factors for group differentiation increased when muscle compounds and body composition variables were also included. Plasma proteins were important for pain intensity and sensitivity. Cytokines and chemokines mainly from plasma were also significantly and positively associated with a fat infiltration and content index.Conclusion Our findings of associations between cytokines and chemokines and fat infiltration and content in different tissues confirm that inflammation and immune factors are secreted from adipose tissue. FM is clearly characterized by complex interactions between peripheral tissues and the peripheral and central nervous systems, including nociceptive, immune, and neuroendocrine processes.

We have investigated loop-induced structural perturbation of the stem structure in hairpins d(GAATTCXnGAATTC) (X = A, T and n = 3, 4, 5 and 6) that contain an EcoRI restriction site in close proximity to the hairpin loop. Oligonucleotides containing either a T3 or a A3 loop were not hydrolyzed by the restriction enzyme and also showed only weak binding to EcoRI in the absence of the cofactor Mg2+. In contrast, hairpins with larger loops are hydrolyzed by the enzyme at the scission site next to the loop although the substrate with a A4 loop is significantly more resistant than the oligonucleotide containing a T4 loop. The hairpin structures with 3 loop residues were found to be thermally most stable while larger hairpin loops resulted in structures with lower melting temperatures. The T-loop hairpins are thermally more stable than the hairpins containing the same number of A residues in the loop. As judged from proton NMR spectroscopy and the thermodynamic data, the base pair closest to the hairpin loop did form in all cases studied. The hairpin loops did, however, affect the conformation of the stem structure of the hairpins. From 31P and 1H NMR spectroscopy we conclude that the perturbation of the stem structure is stronger for smaller hairpin loops and that the extent of the perturbation is limited to 2-3 base pairs for hairpins with T3 or A4 loops. Our results demonstrate that hairpin loops modulate the conformation of the stem residues close to the loop and that this in turn reduces the substrate activity for DNA sequence specific proteins.

Introduction: Rotator cuff (RC) tears result in muscle atrophy and fat infiltration within the RC muscles. An estimation of muscle quality and deformation, or extensibility, is useful in selecting the most appropriate surgical procedure. We determined if noninvasive quantitative assessment of intramuscular fat using MRI could be used to predict extensibility of the supraspinatus muscle. Methods: Seventeen cadaveric shoulders were imaged to assess intramuscular fat infiltration. Extensibility and histological evaluations were then performed. Results: Quantitative fat infiltration positively correlated with histological findings and presented a positive correlation with muscle extensibility (r=0.69; P=0.002). Extensibility was not significantly different between shoulders graded with a higher fat content versus those with low fat when implementing qualitative methods. Discussion: A noninvasive prediction of whole-muscle extensibility may directly guide pre-operative planning to determine if the torn edge could efficiently cover the original footprint while aiding in postoperative evaluation of RC repair.

IntroductionThe aim of the study is to assess the administered activity levels versus visual-based image quality using visual grading regression (VGR) including an assessment of the newly stated image criteria for whole-body bone scintigraphy. Materials and methodsA total of 90 patients was included and grouped in three levels of administered activity: 400, 500 and 600 MBq. Six clinical image criteria regarding image quality was formulated by experienced nuclear medicine physicians. Visual grading was performed in all images, where three physicians rated the fulfilment of the image criteria on a four-step ordinal scale. The results were analysed using VGR. A count analysis was also made where the total number of counts in both views was registered. ResultsThe administered activity of 600 MBq gives significantly better image quality than 400 MBq in five of six criteria (Pless than005). Comparing the administered activity of 600 MBq to 500 MBq, four criteria of six show significantly better image quality (Pless than005). The administered activity of 500 MBq gives no significantly better image quality than 400 Mbq (Pless than005). The count analysis shows that none of the three levels of administrated activity fulfil the recommendations by the EANM. ConclusionThere was a significant improvement in perceived image quality using an activity level of 600 MBq compared to lower activity levels in whole-body bone scintigraphy for the gamma camera equipment end set-up used in this study. This type of visual-based grading study seems to be a valuable tool and easy to implement in the clinical environment.

Detailed aerosol knowledge is essential in numerous applications, including risk assessment in nuclear industry. Cascade impactor sampling of uranium aerosols in the breathing zone of nuclear operators was carried out at a nuclear fuel fabrication plant. Collected aerosols were evaluated using scanning electron microscopy and energy dispersive X-ray spectroscopy. Imaging revealed remarkable variations in aerosol morphology at the different workshops, and a presence of very large particles (up to ≅ 100 × 50 μm²) in the operator breathing zone. Characteristic X-ray analysis showed varying uranium weight percentages of aerosols and, frequently, traces of nitrogen, fluorine and iron. The analysis method, in combination with cascade impactor sampling, can be a powerful tool for characterization of aerosols. The uranium aerosol source term for risk assessment in nuclear fuel fabrication appears to be highly complex.

To address the problems inherent in manual methods, a novel, semi-automated tissue segmentation image analysis technique has been developed. The purpose of this study was to demonstrate the feasibility and describe preliminary observations of applying this technique to quantify and monitor longitudinal changes in abdominal adipose tissue and thigh muscle volume in obese adults during weight loss. Abdominal adipose tissue and thigh muscle volume decreased during weight loss. As a proportion of body weight, adipose tissue volumes decreased during weight loss. By comparison, as a proportion of body weight, thigh muscle volume increased.

Introduction/aims: Fat-referenced magnetic resonance imaging (MRI) has emerged as a promising volumetric technique for measuring muscular volume and fat in neuromuscular disorders, but the experience in inflammatory myopathies remains limited. Therefore, this work aimed at describing how sporadic inclusion body myositis (sIBM) manifests on standardized volumetric fat-referenced MRI muscle measurements, including within-scanner repeatability, natural progression rate, and relationship to clinical parameters. Methods: Ten sIBM patients underwent whole-leg Dixon MRI at baseline (test-retest) and after 12 months. The lean muscle volume (LMV), muscle fat fraction (MFF), and muscle fat infiltration (MFI) of the quadriceps, hamstrings, adductors, medial gastrocnemius, and tibialis anterior were computed. Clinical assessments of IBM Functional Rating Scale (IBMFRS) and knee extension strength were also performed. The baseline test-retest MRI measurements were used to estimate the within-subject standard deviation (s(w)). 12-month changes were derived for all parameters. Results: The MRI measurements showed high repeatability in all muscles; s(w) ranged from 2.7 to 18.0 mL for LMV, 0.7-1.3 percentage points (pp) for MFF, and 0.2-0.7 pp for MFI. Over 12 months, average LMV decreased by 7.4% while MFF and MFI increased by 3.8 pp and 1.8 pp, respectively. Mean IBMFRS decreased by 2.4 and mean knee extension strength decreased by 32.8 N. Discussion: The MRI measurements showed high repeatability and 12-month changes consistent with muscle atrophy and fat replacement as well as a decrease in both muscle strength and IBMFRS. Our findings suggest that fat-referenced MRI measurements are suitable for assessing disease progression and treatment response in inflammatory myopathies.

High dose-rate (HDR) brachytherapy is a kind of radiotherapy used to treat, among others, prostate cancer. When applied to prostate cancer a radioactive source is moved through catheters implanted into the prostate. For each patient a treatment plan is constructed that decide for example catheter placement and dwell time distribution, that is where to stop the radioactive source and for how long.

Mathematical optimization methods has been used to find quality plans with respect to dwell time distribution, however few optimization approaches regarding catheter placement have been studied. In this article we present an integrated optimization model that optimize catheter placement and dwell time distribution simultaneously. Our results show that integrating the two decisions yields greatly improved plans, from 15% to 94% improvement.

Since the presented model is computationally demanding to solve we also present three heuristics: tabu search, variable neighbourhood search and genetic algorithm. Of these variable neighbourhood search is clearly the best, outperforming a state-of-the-art optimization software (CPLEX) and the two other heuristics.

Background: Steatosis is routinely assessed histologically in clinical practice and research. Automated image analysis can reduce the effort of quantifying steatosis. Since reproducibility is essential for practical use, we have evaluated different analysis methods in terms of their agreement with stereological point counting (SPC) performed by a hepatologist. Methods: The evaluation was based on a large and representative data set of 970 histological images from human patients with different liver diseases. Three of the evaluated methods were built on previously published approaches. One method incorporated a new approach to improve the robustness to image variability. Results: The new method showed the strongest agreement with the expert. At 20x resolution, it reproduced steatosis area fractions with a mean absolute error of 0.011 for absent or mild steatosis and 0.036 for moderate or severe steatosis. At 10x resolution, it was more accurate than and twice as fast as all other methods at 20x resolution. When compared with SPC performed by two additional human observers, its error was substantially lower than one and only slightly above the other observer. Conclusions: The results suggest that the new method can be a suitable automated replacement for SPC. Before further improvements can be verified, it is necessary to thoroughly assess the variability of SPC between human observers.

Objective: The GE FASTlab radiosynthesis module is routinely used for the production of [¹⁸F]FDG, utilizing the commercially available phosphate cassettes. Because of the observation of a white precipitate in the product vial before the product expiry time, we re-examined the quality of the produced [¹⁸F]FDG solution.

Methods: Phosphate buffered [¹⁸F]FDG solution was synthesized on the FASTlab and analyzed at both National Taiwan University Hospital (NTUH) of Taiwan and Royal Brisbane and Women’s Hospital (RBWH) of Australia. In addition to the standard product quality control (QC), the concentration of aluminum (Al³⁺) as probable cause of the precipitations in the [¹⁸F]FDG solution was analyzed by inductively coupled plasma mass spectrometry (ICP-MS at RBWH) and inductively coupled plasma optical emission spectrometry (ICP-OES at NTUH), and using three semi-quantitative methods at NTUH, Advantec^® Alumi Check Test Strip, Quantofix^® Aluminum Test Strip and MColortest™ Aluminum Test kit.

Results: The precipitates were observed in the [¹⁸F]FDG solution within 24 (NTUH) and 6 (RBWH) hours after the end of synthesis in 38–100 % of the batches, dependent on the batch of the FASTlab cassettes. Addition of metal-free HCl_(aq) to aliquots of [¹⁸F]FDG containing precipitate, followed by ICP-MS analysis revealed Al³⁺ concentrations of 70–80 ppm. Al³⁺ concentrations of 10–12 ppm were detected in [¹⁸F]FDG batches that did not show any precipitation. In contrast, less than 5 ppm of the residual Al³⁺ was detected by semi-quantitative methods in all batches.

Conclusion: The US (USP), British (BP), European (EP) and Japanese (JP) pharmacopeias demand that [¹⁸F]FDG for injection should be clear and particulate free within the given shelf-life/expiration time. To avoid Al-phosphate precipitation within the product expiry time, FASTlab citrate cassettes, rather than phosphate cassettes, should be used for [¹⁸F]FDG production. Although testing for Al³⁺ is not listed in the [¹⁸F]FDG monographs of the USP, BP and EP, residual Al³⁺ levels should be considered in the interests of patient safety.

Background and purpose: Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS. Methods: Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing-remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study. Results: In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results. Conclusions: This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity.

OBJECTIVE: Insulin causes capillary recruitment in muscle and adipose tissue, but the metabolic and microvascular effects of insulin in the skin have not been studied in detail. The aim of this study was to measure glucose metabolism and microvascular blood flow in the skin during local insulin delivery and after an oral glucose load.

METHODS: Microdialysis catheters were inserted intracutanously in human subjects. In eight subjects two microdialysis catheters were inserted, one perfused with insulin and one with control solution. First the local effects of insulin was studied, followed by a systemic provocation by an oral glucose load. Additionally, as control experiment, six subjects did not recieve local delivery of insulin or the oral glucose load. During microdialysis the local blood flow was measured by urea clearance and by laser speckle contrast imaging (LSCI).

RESULTS: Within 15 minutes of local insulin delivery, microvascular blood flow in the skin increased (urea clearance: P=.047, LSCI: P=.002) paralleled by increases in pyruvate (P=.01) and lactate (P=.04), indicating an increase in glucose uptake. An oral glucose load increased urea clearance from the catheters, indicating an increase in skin perfusion, although no perfusion changes were detected with LSCI. The concentration of glucose, pyruvate and lactate increased in the skin after the oral glucose load.

CONCLUSION: Insulin has metabolic and vasodilatory effects in the skin both when given locally and after systemic delivery through an oral glucose load.

Experimental and computational studies on the formation of aryl azides from the corresponding diazonium salts support a stepwise mechanism via acyclic zwitterionic intermediates. The low energy barriers associated with both transition structures are compatible with very fast and efficient processes, thus making this method suitable for the chemical synthesis of radiolabelled aryl azides.

Advanced model-based iterative reconstruction algorithms in quantitative computed tomography (CT) perform automatic segmentation of tissues to estimate material properties of the imaged object. Compared with conventional methods, these algorithms may improve quality of reconstructed images and accuracy of radiation treatment planning. Automatic segmentation of tissues is, however, a difficult task. The aim of this work was to develop and evaluate an algorithm that automatically segments tissues in CT images of the male pelvis. The newly developed algorithm (MK2014) combines histogram matching, thresholding, region growing, deformable model and atlas-based registration techniques for the segmentation of bones, adipose tissue, prostate and muscles in CT images. Visual inspection of segmented images showed that the algorithm performed well for the five analysed images. The tissues were identified and outlined with accuracy sufficient for the dual-energy iterative reconstruction algorithm whose aim is to improve the accuracy of radiation treatment planning in brachytherapy of the prostate.