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1.
  • Franceschini, N., et al. (författare)
  • GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
  • 2018
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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2.
  • de Jong, R. S., et al. (författare)
  • 4MOST : Project overview and information for the First Call for Proposals
  • 2019
  • Ingår i: The Messenger. - : European Southern Observatory. - 0722-6691. ; 175, s. 3-11
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • We introduce the 4-metre Multi-Object Spectroscopic Telescope (4MOST), a new high-multiplex, wide-field spectroscopic survey facility under development for the four-metre-class Visible and Infrared Survey Telescope for Astronomy (VISTA) at Paranal. Its key specifications are: a large field of view (FoV) of 4.2 square degrees and a high multiplex capability, with 1624 fibres feeding two low-resolution spectrographs (R = λ/Δλ ~ 6500), and 812 fibres transferring light to the high-resolution spectrograph (R ~ 20 000). After a description of the instrument and its expected performance, a short overview is given of its operational scheme and planned 4MOST Consortium science; these aspects are covered in more detail in other articles in this edition of The Messenger. Finally, the processes, schedules, and policies concerning the selection of ESO Community Surveys are presented, commencing with a singular opportunity to submit Letters of Intent for Public Surveys during the first five years of 4MOST operations.
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4.
  • Joshi, Peter K, et al. (författare)
  • Directional dominance on stature and cognition in diverse human populations
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
  • Tidskriftsartikel (refereegranskat)abstract
    • Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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5.
  • Shungin, Dmitry, et al. (författare)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • Tidskriftsartikel (refereegranskat)abstract
    • Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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6.
  • Franceschini, N, et al. (författare)
  • GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
  • 2018
  • Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 5141-
  • Tidskriftsartikel (refereegranskat)abstract
    • Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
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7.
  • Adamus-Górka, Magdalena, 1977- (författare)
  • Improved dose response modeling for normal tissue damage and therapy optimization
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The present thesis is focused on the development and application of dose response models for radiation therapy. Radiobiological models of tissue response to radiation are an integral part of the radiotherapeutic process and a powerful tool to optimize tumor control and minimize damage to healthy tissues for use in clinical trials. Ideally, the models could work as a historical control arm of a clinical trial eliminating the need to randomize patents to suboptimal therapies. In the thesis overview part, some of the basic properties of the dose response relation are reviewed and the most common radiobiological dose-response models are compared with regard to their ability to describe experimental dose response data for rat spinal cord using the maximum likelihood method. For vascular damage the relative seriality model was clearly superior to the other models, whereas for white matter necrosis all models were quite good except possibly the inverse tumor and critical element models. The radiation sensitivity, seriality and steepness of the dose-response relation of the spinal cord is found to vary considerably along its length. The cervical region is more radiation sensitive, more parallel, expressing much steeper dose-response relation and more volume dependent probability of inducing radiation myelitis than the thoracic part. The higher number of functional subunits (FSUs) consistent with a higher amount of white matter close to the brain may be responsible for these phenomena. With strongly heterogeneous dose delivery and due to the random location of FSUs, the effective size of the FSU and the mean dose deposited in it are of key importance and the radiation sensitivity distribution of the FSU may be an even better descriptor for the response of the organ. An individual optimization of a radiation treatment has the potential to increase the therapeutic window and improve cure for a subgroup of patients.
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8.
  • Alevronta, Eleftheria, et al. (författare)
  • Dose-response relationships for an atomized symptom of fecal incontinence after gynecological radiotherapy.
  • 2013
  • Ingår i: Acta oncologica (Stockholm, Sweden). - : Taylor & Francis. - 1651-226X .- 0284-186X. ; 52:4, s. 719-26
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose. The aim of this study was to investigate what bowel organ and delivered dose levels are most relevant for the development of 'emptying of all stools into clothing without forewarning' so that the related dose-responses could be derived as an aid in avoiding this distressing symptom in the future. Material and methods. Of the 77 gynecological cancer survivors treated with radiotherapy (RT) for gynecological cancer, 13 developed the symptom. The survivors were treated between 1991 and 2003. The anal-sphincter region, the rectum, the sigmoid and the small intestines were all delineated and the dose-volume histograms were exported for each patient. The dose-volume parameters were estimated fitting the data to the Relative Seriality (RS), the Lyman and the generalized Equivalent Uniform Dose (gEUD) model. Results. The dose-response parameters for all three models and four organs at risk (OARs) were estimated. The data from the sigmoid fits the studied models best: D50 was 58.8 and 59.5 Gy (RS, Lyman), γ50 was 1.60 and 1.57 (RS, Lyman), s was 0.32, n was 0.13 and a was 7.7 (RS, Lyman, gEUD). The estimated volume parameters indicate that the investigated OARs behave serially for this endpoint. Our results for the three models studied indicate that they have the same predictive power (similar LL values) for the symptom as a function of the dose for all investigated OARs. Conclusions. In our study, the anal-sphincter region and sigmoid fit our data best, but all OARs were found to have steep dose-responses for 'emptying of all stools into clothing without forewarning' and thus, the outcome can be predicted with an NTCP model. In addition, the dose to the four studied OARs may be considered when minimizing the risk of the symptom.
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9.
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10.
  • Gaulton, Kyle J, et al. (författare)
  • Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
  • 2015
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
  • Tidskriftsartikel (refereegranskat)abstract
    • We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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11.
  • Gilmore, G., et al. (författare)
  • The Gaia-ESO Public Spectroscopic Survey : Motivation, implementation, GIRAFFE data processing, analysis, and final data products star
  • 2022
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 666
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. The Gaia-ESO Public Spectroscopic Survey is an ambitious project designed to obtain astrophysical parameters and elemental abundances for 100 000 stars, including large representative samples of the stellar populations in the Galaxy, and a well-defined sample of 60 (plus 20 archive) open clusters. We provide internally consistent results calibrated on benchmark stars and star clusters, extending across a very wide range of abundances and ages. This provides a legacy data set of intrinsic value, and equally a large wide-ranging dataset that is of value for the homogenisation of other and future stellar surveys and Gaia's astrophysical parameters. Aims. This article provides an overview of the survey methodology, the scientific aims, and the implementation, including a description of the data processing for the GIRAFFE spectra. A companion paper introduces the survey results. Methods. Gaia-ESO aspires to quantify both random and systematic contributions to measurement uncertainties. Thus, all available spectroscopic analysis techniques are utilised, each spectrum being analysed by up to several different analysis pipelines, with considerable effort being made to homogenise and calibrate the resulting parameters. We describe here the sequence of activities up to delivery of processed data products to the ESO Science Archive Facility for open use. Results. The Gaia-ESO Survey obtained 202 000 spectra of 115 000 stars using 340 allocated VLT nights between December 2011 and January 2018 from GIRAFFE and UVES. Conclusions. The full consistently reduced final data set of spectra was released through the ESO Science Archive Facility in late 2020, with the full astrophysical parameters sets following in 2022. A companion article reviews the survey implementation, scientific highlights, the open cluster survey, and data products.
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12.
  • Lanzafame, A. C., et al. (författare)
  • Gaia-ESO Survey: Analysis of pre-main sequence stellar spectra
  • 2015
  • Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 576
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. The Gaia-ESO Public Spectroscopic Survey is obtaining high-quality spectroscopy of some 100 000 Milky Way stars using the FLAMES spectrograph at the VLT, down to V = 19 mag, systematically covering all the main components of the Milky Way and providing the first homogeneous overview of the distributions of kinematics and chemical element abundances in the Galaxy. Observations of young open clusters, in particular, are giving new insights into their initial structure, kinematics, and their subsequent evolution. Aims. This paper describes the analysis of UVES and GIRAFFE spectra acquired in the fields of young clusters whose population includes pre-main sequence (PMS) stars. The analysis is applied to all stars in such fields, regardless of any prior information on membership, and provides fundamental stellar atmospheric parameters, elemental abundances, and PMS-specific parameters such as veiling, accretion, and chromospheric activity. Methods. When feasible,different methods were used to derive raw parameters (e. g. line equivalent widths) fundamental atmospheric parameters and derived parameters (e. g. abundances). To derive some of these parameters, we used methods that have been extensively used in the past and new ones developed in the context of the Gaia-ESO survey enterprise. The internal precision of these quantities was estimated by inter-comparing the results obtained by these different methods, while the accuracy was estimated by comparison with independent external data, such as effective temperature and surface gravity derived from angular diameter measurements, on a sample of benchmarks stars. A validation procedure based on these comparisons was applied to discard spurious or doubtful results and produce recommended parameters. Specific strategies were implemented to resolve problems of fast rotation, accretion signatures, chromospheric activity, and veiling. Results. The analysis carried out on spectra acquired in young cluster fields during the first 18 months of observations, up to June 2013, is presented in preparation of the first release of advanced data products. These include targets in the fields of the rho Oph, Cha I, NGC2264, gamma Vel, and NGC 2547 clusters. Stellar parameters obtained with the higher resolution and larger wavelength coverage from UVES are reproduced with comparable accuracy and precision using the smaller wavelength range and lower resolution of the GIRAFFE setup adopted for young stars, which allows us to provide stellar parameters with confidence for the much larger GIRAFFE sample. Precisions are estimated to be approximate to 120 K rms in T-eff, approximate to 0.3 dex rms in log g, and approximate to 0.15 dex rms in [Fe/H] for the UVES and GIRAFFE setups.
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13.
  • Smiljanic, R., et al. (författare)
  • The Gaia-ESO Survey: The analysis of high-resolution UVES spectra of FGK-type stars
  • 2014
  • Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 570
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. The ongoing Gaia-ESO Public Spectroscopic Survey is using FLAMES at the VLT to obtain high-quality medium-resolution Giraffe spectra for about 10(5) stars and high-resolution UVES spectra for about 5000 stars. With UVES, the Survey has already observed 1447 FGK-type stars. Aims. These UVES spectra are analyzed in parallel by several state-of-the-art methodologies. Our aim is to present how these analyses were implemented, to discuss their results, and to describe how a final recommended parameter scale is defined. We also discuss the precision (method-to-method dispersion) and accuracy (biases with respect to the reference values) of the final parameters. These results are part of the Gaia-ESO second internal release and will be part of its first public release of advanced data products. Methods. The final parameter scale is tied to the scale defined by the Gaia benchmark stars, a set of stars with fundamental atmospheric parameters. In addition, a set of open and globular clusters is used to evaluate the physical soundness of the results. Each of the implemented methodologies is judged against the benchmark stars to define weights in three different regions of the parameter space. The final recommended results are the weighted medians of those from the individual methods. Results. The recommended results successfully reproduce the atmospheric parameters of the benchmark stars and the expected T-eff-log g relation of the calibrating clusters. Atmospheric parameters and abundances have been determined for 1301 FGK-type stars observed with UVES. The median of the method-to-method dispersion of the atmospheric parameters is 55K for T-eff, 0.13dex for log g and 0.07 dex for [Fe/H]. Systematic biases are estimated to be between 50-100 K for T-eff, 0.10-0.25 dex for log g and 0.05-0.10 dex for [Fe/H]. Abundances for 24 elements were derived: C, N, O, Na, Mg, Al, Si, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ba, Nd, and Eu. The typical method-to-method dispersion of the abundances varies between 0.10 and 0.20 dex. Conclusions. The Gaia-ESO sample of high-resolution spectra of FGK-type stars will be among the largest of its kind analyzed in a homogeneous way. The extensive list of elemental abundances derived in these stars will enable significant advances in the areas of stellar evolution and Milky Way formation and evolution.
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14.
  • Adamus-Gorka, Magdalena, et al. (författare)
  • An “Effective functional subunit size” model for the dose response of rat spinal cord paralysis
  • 2007
  • Ingår i: 13th International Congress of Radiation Research, San Fransisco, USA, July 8-12, 2007.
  • Konferensbidrag (populärvet., debatt m.m.)abstract
    • Background: Radiobiological models for normal tissue complication probability (NTCP) are more and more commonly used in order to estimate the clinical outcome of radiation therapy. A normal tissue complication probability model to be considered a good and reliable one should fulfill the following two requirements: (a) it should predict the sigmoid shape of the dose-response curve as well as possible and (b) it should duly handle the volume effect. In the work from 2005 (IJROBP 61(3):892-900, 2005) P. van Luijk et al. suggest that none of the existing NTCP models is able to describe the volume effects present in the rat spinal cord during irradiation with small proton beams and they indicate the need for developing such new models.Methods: We have used the experimental data from H. Bijl et al. (IJROBP 52(1):205-211, 2002) to try explaining the change in the fifty percent effective dose (ED50) for different field sizes. We initiated this study to evaluate whether the induction of white matter necrosis in rat spinal cord after irradiation with small proton beams could be explained independent of used NTCP model. We therefore introduced a new concept of effective FSU dose, where a convolution of the original dose distribution with a function describing the effective size of a single FSU results in the average doses in a functional subunit. Such procedure allows determining the ED50 in an FSU of a certain size, within the irradiation field. We have also looked at non uniform dose distributions to see whether using a similar method we can explain the so called “bath and shower experiments” (IJROBP 57(1): 274-281, 2003).Results: Using the least square method to compare the effective doses for different sizes of functional subunits with the experimental data we observe the best fit for about 8 mm length. It seems that this length could be understood as an effective size of functional subunits in rat spinal cord, explaining what is otherwise interpreted as a volume effect. For the non uniform dose distributions an effective FSU length of 5 mm gives the optimal fit with the Probit dose-response model.Conclusions: The concept of an effective FSU length seems to explain at least part of the effects seen when small portions of the rat spinal cord are irradiated. The most likely FSU length for the shower and bath experiments is 5 mm according to these calculations.
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15.
  • Adamus-Gorka, Magdalena, et al. (författare)
  • Determination of the dose-response relations of thoracic and cervical myelopathy after external beam radiation therapy
  • 2007
  • Ingår i: 9th Biennial ESTRO Meeting on Physics and Radiation Technology for Clinical Radiotherapy, Barcelona, Spain, 9-13 September 2007.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • Following our previous experience, the relative seriality modelwas fitted to two different sets of clinical data for radiation myelitis concerning thoracic spinal cord after radiation treatment of 43 patients with lung carcinoma and cervical spinal cord after treating 248 patients for malignant disease of head and neck.Individual treatment data were suitably fitted by the relative seriality model. The estimated radiobiological parameters of the model indicate that the probability of inducing this complication after radiation therapy is volume dependent only for the cervical part of spinal cord, whereas for the thoracic part no volume effect could be observed.Two different statistical methods applied to the patient material showed that the radiobiological model and the estimated parameters can be used to closely predict the complication rates observed.
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17.
  • Ahlberg, Alexander, et al. (författare)
  • ESOPHAGEAL STRICTURE AFTER RADIOTHERAPY IN PATIENTS WITH HEAD AND NECK CANCER : EXPERIENCE OF A SINGLE INSTITUTION OVER 2 TREATMENT PERIODS
  • 2010
  • Ingår i: Head and Neck. - : Wiley. - 1043-3074 .- 1097-0347. ; 32:4, s. 452-461
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Risk factors for development of a stricture of the upper esophagus after radiotherapy for head and neck cancer are poorly defined. Methods. This was a retrospective case-control study of patients diagnosed and treated for esophageal stricture after radiotherapy for head and neck cancer. Results. The incidence of esophageal stricture after external beam radiation therapy (EBRT) was 3.3%. Seventy patients with stricture and 66 patients without stricture were identified. A multivariate analysis showed that there was increased risk of stricture in receiving enteral feeding during EBRT or in receiving a mean dose of >45 By to the upper esophagus. Conclusions. Enteral feeding during EBRT is strongly associated with the development of stricture of the esophagus, as is a mean dose of >45 Gy to the upper esophagus. Treatment of the stricture with Savary-Gilliard bougienage or through scope balloon dilatation is safe and successful but often has to be repeated.
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18.
  • Alevronta, Eleftheria, et al. (författare)
  • Dose-response relations for stricture in the proximal oesophagus from head and neck radiotherapy
  • 2010
  • Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 97:1, s. 54-59
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose: Determination of the dose-response relations for oesophageal stricture after radiotherapy of the head and neck. Material and methods: In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5 cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992-2000 and 2001-2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model. Results: For the treatment period 1992-2005, the mean doses were 49.8 and 33.4 Gy, respectively, for the cases and the controls. For the period 1992-2000, the mean doses for the cases and the controls were 49.9 and 45.9 Gy and for the period 2001-2005 were 49.8 and 21.4 Gy. For the period 2001-2005 the best estimates of the dose-response parameters are D-50 = 61.5 Gy (52.9-84.9 Gy), gamma = 1.4 (0.8-2.6) and s = 0.1 (0.01-0.3). Conclusions: Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001-2005. However, no dose response relation was found for the complete material.
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20.
  • Anderlind, Eva, et al. (författare)
  • Will haptic feedback speed up medical imaging? An application to radiation treatment planning
  • 2008
  • Ingår i: Acta Oncologica. - OSLO, Norge : Taylor & Francis. - 0284-186X .- 1651-226X. ; 47:1, s. 32-37
  • Tidskriftsartikel (refereegranskat)abstract
    • Haptic technology enables us to incorporate the sense of touch into computer applications, providing an additional input/output channel. The purpose of this study was to examine if haptic feedback can help physicians and other practitioners to interact with medical imaging and treatment planning systems. A haptic application for outlining target areas (a key task in radiation therapy treatment planning) was implemented and then evaluated via a controlled experiment with ten subjects. Even though the sample size was small, and the application only a prototype, results showed that haptic feedback can significantly increase (p0.05) the speed of outlining target volumes and organs at risk. No significant differences were found regarding precision or perceived usability. This promising result warrants further development of a full haptic application for this task. Improvements to the usability of the application as well as to the forces generated have been implemented and an experiment with more subjects is planned.
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21.
  • Andisheh, Bahram, 1967-, et al. (författare)
  • Clinical and radiobiological advantages of single-dose stereotactic light-ion radiation therapy for large intracranial arteriovenous malformations. Technical note
  • 2009
  • Ingår i: Journal of Neurosurgery. - : Journal of Neurosurgery Publishing Group (JNSPG). - 0022-3085 .- 1933-0693. ; 111:5, s. 919-926
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECT:Radiation treatment of large arteriovenous malformations (AVMs) remains difficult and not very effective, even though seemingly promising methods such as staged volume treatments have been proposed by some radiation treatment centers. In symptomatic patients harboring large intracranial AVMs not amenable to embolization or resection, single-session high-dose stereotactic radiation therapy is a viable option, and the special characteristics of high-ionization-density light-ion beams offer several treatment advantages over photon and proton beams. These advantages include a more favorable depth-dose distribution in tissue, an almost negligible lateral scatter of the beam, a sharper penumbra, a steep dose falloff beyond the Bragg peak, and a higher probability of vascular response due to high ionization density and associated induction of endothelial cell proliferation and/or apoptosis. Carbon ions were recently shown to be an effective treatment for skull-base tumors. Bearing that in mind, the authors postulate that the unique physical and biological characteristics of light-ion beams should convey considerable clinical advantages in the treatment of large AVMs. In the present meta-analysis the authors present a comparison between light-ion beam therapy and more conventional modalities of radiation treatment with respect to these lesions.METHODS:Dose-volume histograms and data on peripheral radiation doses for treatment of large AVMs were collected from various radiation treatment centers. Dose-response parameters were then derived by applying a maximum likelihood fitting of a binomial model to these data. The present binomial model was needed because the effective number of crucial blood vessels in AVMs (the number of vessels that must be obliterated to effect a cure, such as large fistulous nidus vessels) is low, making the Poisson model less suitable. In this study the authors also focused on radiobiological differences between various radiation treatments.RESULTS:Light-ion Bragg-peak dose delivery has the precision required for treating very large AVMs as well as for delivering extremely sharp, focused beams to irregular lesions. Stereotactic light-ion radiosurgery resulted in better angiographically defined obliteration rates, less white-matter necrosis, lower complication rates, and more favorable clinical outcomes. In addition, in patients treated by He ion beams, a sharper dose-response gradient was observed, probably due to a more homogeneous radiosensitivity of the AVM nidus to light-ion beam radiation than that seen when low-ionization-density radiation modalities, such as photons and protons, are used.CONCLUSIONS:Bragg-peak radiosurgery can be recommended for most large and irregular AVMs and for the treatment of lesions located in front of or adjacent to sensitive and functionally important brain structures. The unique physical and biological characteristics of light-ion beams are of considerable advantage for the treatment of AVMs: the densely ionizing beams of light ions create a better dose and biological effect distribution than conventional radiation modalities such as photons and protons. Using light ions, greater flexibility can be achieved while avoiding healthy critical structures such as diencephalic and brainstem nuclei and tracts. Treatment with the light ion He or Li is more suitable for AVMs
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22.
  • Brahme, Anders, et al. (författare)
  • A systems biology approach to radiation therapy optimization
  • 2010
  • Ingår i: Radiation and Environmental Biophysics. - : Springer Science and Business Media LLC. - 0301-634X .- 1432-2099. ; 49:2, s. 111-124
  • Tidskriftsartikel (refereegranskat)abstract
    • During the last 20 years, the field of cellular and not least molecular radiation biology has been developed substantially and can today describe the response of heterogeneous tumors and organized normal tissues to radiation therapy quite well. An increased understanding of the sub-cellular and molecular response is leading to a more general systems biological approach to radiation therapy and treatment optimization. It is interesting that most of the characteristics of the tissue infrastructure, such as the vascular system and the degree of hypoxia, have to be considered to get an accurate description of tumor and normal tissue responses to ionizing radiation. In the limited space available, only a brief description of some of the most important concepts and processes is possible, starting from the key functional genomics pathways of the cell that are not only responsible for tumor development but also responsible for the response of the cells to radiation therapy. The key mechanisms for cellular damage and damage repair are described. It is further more discussed how these processes can be brought to inactivate the tumor without severely damaging surrounding normal tissues using suitable radiation modalities like intensity-modulated radiation therapy (IMRT) or light ions. The use of such methods may lead to a truly scientific approach to radiation therapy optimization, particularly when invivo predictive assays of radiation responsiveness becomes clinically available at a larger scale. Brief examples of the efficiency of IMRT are also given showing how sensitive normal tissues can be spared at the same time as highly curative doses are delivered to a tumor that is often radiation resistant and located near organs at risk. This new approach maximizes the probability to eradicate the tumor, while at the same time, adverse reactions in sensitive normal tissues are as far as possible minimized using IMRT with photons and light ions.
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23.
  • Costa Ferreira, Brigida, et al. (författare)
  • The impact of different dose-response parameters on biologically optimized IMRT in breast cancer.
  • 2008
  • Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 53:10, s. 2733-52
  • Tidskriftsartikel (refereegranskat)abstract
    • The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I-II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P(+)), the biologically effective uniform dose (D), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P(+) between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven-beam plan, the differences in P(+) are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose-response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients. However, the jump from generalized to individualized radiation therapy may significantly increase the therapeutic window for patients with extreme radio sensitivity or radioresistance, provided that these are identified. Even for radiosensitive patients a simple treatment technique is sufficient to maximize the outcome, since no significant benefits were obtained with a more complex technique using seven intensity-modulated beams portals.
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24.
  • de Jong, Roelof S., et al. (författare)
  • 4MOST-4-metre Multi-Object Spectroscopic Telescope
  • 2014
  • Ingår i: Ground-based and Airborne Instrumentation for Astronomy V. - : SPIE. - 0277-786X .- 1996-756X. ; 9147
  • Konferensbidrag (refereegranskat)abstract
    • 4MOST is a wide-field, high-multiplex spectroscopic survey facility under development for the VISTA telescope of the European Southern Observatory (ESO). Its main science drivers are in the fields of galactic archeology, high-energy physics, galaxy evolution and cosmology. 4MOST will in particular provide the spectroscopic complements to the large area surveys coming from space missions like Gaia, eROSITA, Euclid, and PLATO and from ground-based facilities like VISTA, VST, DES, LSST and SKA. The 4MOST baseline concept features a 2.5 degree diameter field-of-view with similar to 2400 fibres in the focal surface that are configured by a fibre positioner based on the tilting spine principle. The fibres feed two types of spectrographs; similar to 1600 fibres go to two spectrographs with resolution R> 5000 (lambda similar to 390-930 nm) and similar to 800 fibres to a spectrograph with R> 18,000 (lambda similar to 392-437 nm & 515-572 nm & 605-675 nm). Both types of spectrographs are fixed-configuration, three-channel spectrographs. 4MOST will have an unique operations concept in which 5 year public surveys from both the consortium and the ESO community will be combined and observed in parallel during each exposure, resulting in more than 25 million spectra of targets spread over a large fraction of the southern sky. The 4MOST Facility Simulator (4FS) was developed to demonstrate the feasibility of this observing concept. 4MOST has been accepted for implementation by ESO with operations expected to start by the end of 2020. This paper provides a top-level overview of the 4MOST facility, while other papers in these proceedings provide more detailed descriptions of the instrument concept[1], the instrument requirements development[2], the systems engineering implementation[3], the instrument model[4], the fibre positioner concepts[5], the fibre feed[6], and the spectrographs[7].
  •  
25.
  • Fernández-Varea, José M., et al. (författare)
  • Limitations (and merits) of PENELOPE as a track-structure code
  • 2012
  • Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 88:1-2, s. 66-70
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To outline the limitations of PENELOPE (acronym of PENetration and Energy LOss of Positrons and Electrons) as a track-structure code, and to comment on modifications that enable its fruitful use in certain microdosimetry and nanodosimetry applications.Methods: Attention is paid to the way in which inelastic collisions of electrons are modelled and to the ensuing implications for microdosimetry analysis.Results: Inelastic mean free paths and collision stopping powers calculated with PENELOPE and two well-known optical-data models are compared. An ad hoc modification of PENELOPE is summarized where ionization and excitation of liquid water by electron impact is simulated using tables of realistic differential and total cross sections.Conclusions: PENELOPE can be employed advantageously in some track-structure applications provided that the default model for inelastic interactions of electrons is replaced by suitable tables of differential and total cross sections.
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26.
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27.
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28.
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29.
  • Mavroidis, Panayiotis, et al. (författare)
  • Comparing the Expected Effectiveness of Helical Tomotherapy and MLC-Based IMRT Using Biological Measures
  • 2007
  • Ingår i: Proceedings in 49th AAPM Annual Meeting, Minneapolis, Minnesota, USA, July 22-26, 2007.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • Purpose: Presently, the radiobiological parameters of the different tumours and normal tissues are typically not taken into account during dose prescription and optimization of a treatment plan. In this study, to investigate a more comprehensive treatment plan evaluation, the biologically effective uniform dose () is applied together with the complication-free tumour control probability (P+).Material and Methods: Three different cancer types at different anatomical sites were investigated: head & neck, lung and prostate cancers. For each cancer type, a linac MLC-based step-and-shoot IMRT plan and a Helical Tomotherapy plan were developed. By using as the common prescription point of the treatment plans and plotting the tissue response probabilities vs. for a range of prescription doses, a number of plan trials can be compared based on radiobiological measures.Results: The applied plan evaluation method shows that in the head & neck cancer case the HT treatment gives better results than the MLC-based IMRT (P+ of 62.2% and 46.0%, to the internal target volume (ITV) of 72.3Gy and 70.7Gy, respectively). In the lung cancer and prostate cancer cases, the MLC-based IMRT plans are better. For the lung cancer case, the HT and MLC-based IMRT plans give a P+ of 66.9% and 72.9%, to the ITV of 64.0Gy and 66.9Gy, respectively. Similarly, for the prostate cancer case, the two radiation modalities give a P+ of 68.7% and 72.2%, to the ITV of 86.0Gy and 85.9Gy, respectively.Discussion and Conclusions: Both MLC based-IMRT and HT can encompass the often large ITV required while they minimize the volume of the organs at risk receiving high dose. There may exist clinical cases, which may look dosimetrically similar but in radiobiological terms may be quite different. In such situations, traditional dose based evaluation tools can be complemented by the use of P+ − diagrams to compare treatment plans.
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30.
  • Mavroidis, Panayiotis, et al. (författare)
  • Comparison of the helical tomotherapy and MLC-based IMRT radiation modalities in treating brain and cranio-spinal tumors.
  • 2009
  • Ingår i: Technology in Cancer Research & Treatment. - : SAGE Publications. - 1533-0346 .- 1533-0338. ; 8:1, s. 3-14
  • Tidskriftsartikel (refereegranskat)abstract
    • The investigation of the clinical efficacy and effectiveness of Intensity Modulated Radiotherapy (IMRT) using Multileaf Collimators (MLC) and Helical Tomotherapy (HT) has been an issue of increasing interest over the past few years. In order to assess the suitability of a treatment plan, dosimetric criteria such as dose-volume histograms (DVH), maximum, minimum, mean, and standard deviation of the dose distribution are typically used. Nevertheless, the radiobiological parameters of the different tumors and normal tissues are often not taken into account. The use of the biologically effective uniform dose (D=) together with the complication-free tumor control probability (P(+)) were applied to evaluate the two radiation modalities. Two different clinical cases of brain and cranio-spinal axis cancers have been investigated by developing a linac MLC-based step-and-shoot IMRT plan and a Helical Tomotherapy plan. The treatment plans of the MLC-based IMRT were developed on the Philips treatment planning station using the Pinnacle 7.6 software release while the dedicated Tomotherapy treatment planning station was used for the HT plan. With the use of the P(+) index and the D(=) concept as the common prescription point, the different treatment plans were compared based on radiobiological measures. The tissue response probabilities were plotted against D(=) for a range of prescription doses. The applied plan evaluation method shows that in the brain cancer, the HT treatment gives slightly better results than the MLC-based IMRT in terms of optimum expected clinical outcome (P(+) of 66.1% and 63.5% for a D(=) to the PTV of 63.0 Gy and 62.0 Gy, respectively). In the cranio-spinal axis cancer, the HT plan is significantly better compared to the MLC-based IMRT plan over the clinically useful dose prescription range (P(+) of 84.1% and 28.3% for a D(=) to the PTV of 50.6 Gy and 44.0 Gy, respectively). If a higher than 5% risk for complications could be allowed, the complication-free tumor control could be increased by almost 30% compared to the initial dose prescription. In comparison to MLC based-IMRT, HT can better encompass the often large PTV while minimizing the volume of the OARs receiving high dose. A radiobiological treatment plan evaluation can provide a closer association of the delivered treatment with the clinical outcome by taking into account the dose-response relations of the irradiated tumors and normal tissues. The use of P - (D=) diagrams can complement the traditional tools of evaluation such as DVHs, in order to compare and effectively evaluate different treatment plans.
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31.
  • Mavroidis, Panayiotis, et al. (författare)
  • Expected Clinical Impact of the Differences Between Planned and Delivered IMRT Dose Distributions
  • 2007
  • Ingår i: Proceedings in 49th AAPM Annual Meeting, Minneapolis, Minnesota, USA, July 22-26, 2007. - : Wiley.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • Purpose: Due to the highly conformal distributions that can be obtained with intensity modulated radiation therapy (IMRT), any discrepancy between the intended and delivered distributions would likely affect the clinical outcome. Consequently, there is a need for a measure that would quantify those differences in terms of a change in the expected clinical outcome.Material and Methods: To evaluate such a measure, the case of a cervix cancer was used where the bladder and rectum, are proximal and partially overlapping with the internal target volume. A solid phantom simulating the pelvic anatomy was fabricated and a treatment plan was developed to deliver the prescribed dose to the phantom. The phantom was then irradiated with films positioned in several transverse planes. The racetrack microtron at 50MV was used in the treatment planning and delivery processes. The dose distribution delivered was analyzed based on the film measurements and compared against the treatment plan. The differences in the measurements were evaluated using both physical and biological criteria.Results: For the computerized treatment plan, the maximum value of P+ was 84.1%, for a mean dose to the ITV of = 93.3Gy, associated relative standard deviation D/ = 16.8% and biologically effective uniform dose, ITV of 89.2 Gy. The delivered dose distribution from all the beams produced a P+ value of 77.0% for ITV = 93.2Gy, D/ = 19.0% and ITV of 83.5 Gy.Discussion and Conclusions: Whereas the physical comparison of dose distributions can assess the geometric accuracy of delivery, it does not reflect the clinical impact of any measured dose discrepancies. With highly conformal IMRT, the accuracy of the patient setup and treatment delivery, are critical for the success of the treatment. A method is proposed to evaluate the precision of the delivered plan based on changes in complication and control rates as they relate to uncertainties in dose delivery.
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32.
  • Mavroidis, Panayiotis, et al. (författare)
  • Interpretation of the dosimetric results of three uniformity regularization methods in terms of expected treatment outcome.
  • 2008
  • Ingår i: Medical physics (Lancaster). - : Wiley. - 0094-2405. ; 35:11, s. 5009-18
  • Tidskriftsartikel (refereegranskat)abstract
    • In IMRT treatment plan optimization there are various methods that try to regularize the variation of dose nonuniformity using purely dosimetric measures. However, although these methods can help in finding a good dose distribution, they do not provide any information regarding the expected treatment outcome. When a treatment plan optimization is performed using biological measures, the final goal should be some indication about the expected tumor control or normal tissue complications, which is the primary goal of treatment planning (the association of treatment configurations and dose prescription with the treatment outcome). In this study, this issue is analyzed distinguishing the dose-oriented treatment plan optimization from the response-oriented optimization. Three different dose distributions were obtained by using a dose-based optimization technique, an EUD-based optimization without applying any technique for regularizing the nonuniformity of the dose distribution, and an EUD-based optimization using a variational regularization technique, which controls dose nonuniformity. The clinical effectiveness of the three dose distributions was investigated by calculating the response probabilities of the tumors and organs-at-risk (OARs) involved in two head and neck and prostate cancer cases. The radiobiological models used are the linear-quadratic-Poisson and the Relative Seriality models. Furthermore, the complication-free tumor control probability and the biologically effective uniform dose (D) were used for treatment plan evaluation and comparison. The radiobiological comparison shows that the EUD-based optimization using L-curve regularization gives better results than the EUD-based optimization without regularization and dose-based optimization in both clinical cases. Concluding, it appears that the applied dose nonuniformity regularization technique is expected to improve the effectiveness of the optimized IMRT dose distributions. However, more patient cases are needed to validate the statistical significance of the results and conclusions presented in this paper.
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33.
  • Mavroidis, Panayiotis, et al. (författare)
  • Statistical methods for clinical verification of dose-response parameters related to esophageal stricture and AVM obliteration from radiotherapy
  • 2004
  • Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 49:16, s. 3797-3816
  • Tidskriftsartikel (refereegranskat)abstract
    • The purpose of this work is to provide some statistical methods for evaluating the predictive strength of radiobiological models and the validity of dose-response parameters for tumour control and normal tissue complications. This is accomplished by associating the expected complication rates, which are calculated using different models, with the clinical follow-up records. These methods are applied to 77 patients who received radiation treatment for head and neck cancer and 85 patients who were treated for arteriovenous malformation (AVM). The three-dimensional dose distribution delivered to esophagus and AVM nidus and the clinical follow-up results were available for each patient. Dose-response parameters derived by a maximum likelihood fitting were used as a reference to evaluate their compatibility with the examined treatment methodologies. The impact of the parameter uncertainties on the dose-response curves is demonstrated. The clinical utilization of the radiobiological parameters is illustrated. The radiobiological models (relative seriality and linear Poisson) and the reference parameters are validated to prove their suitability in reproducing the treatment outcome pattern of the patient material studied (through the probability of finding a worse fit, area under the ROC curve and chi2 test). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed, and the total volume of AVM. The estimated confidence intervals of the dose-response curves appear to have a significant supporting role on their clinical implementation and use.
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34.
  • Mavroidis, Panayiotis, et al. (författare)
  • Treatment plan comparison between helical tomotherapy and MLC-based IMRT using radiobiological measures.
  • 2007
  • Ingår i: Phys Med Biol. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 52:13, s. 3817-36
  • Tidskriftsartikel (refereegranskat)abstract
    • The rapid implementation of advanced treatment planning and delivery technologies for radiation therapy has brought new challenges in evaluating the most effective treatment modality. Intensity-modulated radiotherapy (IMRT) using multi-leaf collimators (MLC) and helical tomotherapy (HT) are becoming popular modes of treatment delivery and their application and effectiveness continues to be investigated. Presently, there are several treatment planning systems (TPS) that can generate and optimize IMRT plans based on user-defined objective functions for the internal target volume (ITV) and organs at risk (OAR). However, the radiobiological parameters of the different tumours and normal tissues are typically not taken into account during dose prescription and optimization of a treatment plan or during plan evaluation. The suitability of a treatment plan is typically decided based on dosimetric criteria such as dose-volume histograms (DVH), maximum, minimum, mean and standard deviation of the dose distribution. For a more comprehensive treatment plan evaluation, the biologically effective uniform dose (D) is applied together with the complication-free tumour control probability (P(+)). Its utilization is demonstrated using three clinical cases that were planned with two different forms of IMRT. In this study, three different cancer types at different anatomical sites were investigated: head and neck, lung and prostate cancers. For each cancer type, a linac MLC-based step-and-shoot IMRT plan and a HT plan were developed. The MLC-based IMRT treatment plans were developed on the Philips treatment-planning platform, using the Pinnacle 7.6 software release. For the tomotherapy HiArt plans, the dedicated tomotherapy treatment planning station was used, running version 2.1.2. By using D as the common prescription point of the treatment plans and plotting the tissue response probabilities versus D for a range of prescription doses, a number of plan trials can be compared based on radiobiological measures. The applied plan evaluation method shows that in the head and neck cancer case the HT treatment gives better results than MLC-based IMRT in terms of expected clinical outcome P(+) of 62.2% and 46.0%, D to the ITV of 72.3 Gy and 70.7 Gy, respectively). In the lung cancer and prostate cancer cases, the MLC-based IMRT plans are better over the clinically useful dose prescription range. For the lung cancer case, the HT and MLC-based IMRT plans give a P(+) of 66.9% and 72.9%, D to the ITV of 64.0 Gy and 66.9 Gy, respectively. Similarly, for the prostate cancer case, the two radiation modalities give a P(+) of 68.7% and 72.2%, D to the ITV of 86.0 Gy and 85.9 Gy, respectively. If a higher risk of complications (higher than 5%) could be allowed, the complication-free tumour control could increase by over 40%, 2% and 30% compared to the initial dose prescription for the three cancer cases, respectively. Both MLC-based IMRT and HT can encompass the often-large ITV required while they minimize the volume of the organs at risk receiving high doses. Radiobiological evaluation of treatment plans may provide an improved correlation of the delivered treatment with the clinical outcome by taking into account the dose-response characteristics of the irradiated targets and normal tissues. There may exist clinical cases, which may look dosimetrically similar but in radiobiological terms may be quite different. In such situations, traditional dose-based evaluation tools can be complemented by the use of P(+)--D diagrams to effectively evaluate and compare treatment plans.
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35.
  • Scott, Robert A., et al. (författare)
  • Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
  • 2012
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
  • Tidskriftsartikel (refereegranskat)abstract
    • Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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36.
  • Siaw, Joachim T., et al. (författare)
  • 11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma
  • 2020
  • Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:12
  • Tidskriftsartikel (refereegranskat)abstract
    • High-risk neuroblastomas typically display an undifferentiated or poorly differentiated morphology. It is therefore vital to understand molecular mechanisms that block the differentiation process. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in the maintenance of undifferentiated neural crest-derived progenitors through the repression of DLG2, a candidate tumor suppressor gene in neuroblastoma. DLG2 is expressed in the murine "bridge signature'' that represents the transcriptional transition state when neural crest cells or Schwann cell precursors differentiate to chromaffin cells of the adrenal gland. We show that the restoration of DLG2 expression spontaneously drives neuroblastoma cell differentiation, high-lighting the importance of DLG2 in this process. These findings are supported by genetic analyses of high-risk 11q deletion neuroblastomas, which identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other bridge genes may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastomas.
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37.
  • Sundström, Johan, Professor, 1971-, et al. (författare)
  • Risk factors for subarachnoid haemorrhage : a nationwide cohort of 950 000 adults
  • 2019
  • Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:6, s. 2018-2025
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
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38.
  • Tsougos, Ioannis, et al. (författare)
  • NTCP modelling and pulmonary function tests evaluation for the prediction of radiation induced pneumonitis in non-small-cell lung cancer radiotherapy.
  • 2007
  • Ingår i: Phys Med Biol. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 52:4, s. 1055-73
  • Tidskriftsartikel (refereegranskat)abstract
    • This work aims to evaluate the predictive strength of the relative seriality, parallel and Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis (RP), in a group of patients following lung cancer radiotherapy and also to examine their correlation with pulmonary function tests (PFTs). The study was based on 47 patients who received radiation therapy for stage III non-small-cell lung cancer. For each patient, lung dose volume histograms (DVHs) and the clinical treatment outcome were available. Clinical symptoms, radiological findings and pulmonary function tests incorporated in a post-treatment follow-up period of 18 months were used to assess the manifestation of radiation induced complications. Thirteen of the 47 patients were scored as having radiation induced pneumonitis, with RTOG criteria grade 3 and 28 of the 47 with RTOG criteria grade 2. Using this material, different methods of estimating the likelihood of radiation effects were evaluated, by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Lungs were evaluated as a paired organ as well as individual lungs. Of the NTCP models examined in the overall group considering the dose distribution in the ipsilateral lung, all models were able to predict radiation induced pneumonitis only in the case of grade 2 radiation pneumonitis score, with the LKB model giving the best results (chi2-test: probability of agreement between the observed and predicted results Pchi(chi2)=0.524 using the 0.05 significance level). The NTCP modelling considering lungs as a paired organ did not give statistically acceptable results. In the case of lung cancer radiotherapy, the application of different published radiobiological parameters alters the NTCP results, but not excessively as in the case of breast cancer radiotherapy. In this relatively small group of lung cancer patients, no positive statistical correlation could be established between the incidence of radiation pneumonitis as estimated by NTCP models and the pulmonary function test evaluation. However, the use of PFTs as markers or predictors for the incidence or severity of radiation induced pneumonitis must be investigated further.
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39.
  • Tzikas, Athanasios, et al. (författare)
  • Radiobiological Evaluation of Breast Cancer Radiotherapy Accounting for the Effects of Patient Positioning and Breathing in Dose Delivery. A Meta Analysis
  • 2013
  • Ingår i: Technology in Cancer Research & Treatment. - : SAGE Publications. - 1533-0346 .- 1533-0338. ; 12:1, s. 31-44
  • Tidskriftsartikel (refereegranskat)abstract
    • In breast cancer radiotherapy, significant discrepancies in dose delivery can contribute to underdosage of the tumor or overdosage of normal tissue, which is potentially related to a reduction of local tumor control and an increase of side effects. To study the impact of these factors in breast cancer radiotherapy, a meta analysis of the clinical data reported by Mavroidis et al. (2002) in Acta Oncol (41:471-85), showing the patient setup and breathing uncertainties characterizing three different irradiation techniques, were employed. The uncertainties in dose delivery are simulated based on fifteen breast cancer patients (5 mastectomized, 5 resected with negative node involvement (R) and 5 resected with positive node involvement (R+)), who were treated by three different irradiation techniques, respectively. The positioning and breathing effects were taken into consideration in the determination of the real dose distributions delivered to the CTV and lung in each patient. The combined frequency distributions of the positioning and breathing distributions were obtained by convolution. For each patient the effectiveness of the dose distribution applied is calculated by the Poisson and relative seriality models and a set of parameters that describe the dose-response relations of the target and lung. The three representative radiation techniques are compared based on radiobiological measures by using the complication-free tumor control probability, P+ and the biologically effective uniform dose, E, concepts. For the Mastectomy case, the average P+ values of the planned and delivered dose distributions are 93.8% for a (sic)(CTV) of 51.8 Gy and 85.0% for a (sic)(CTV) of 50.3 Gy, respectively. The respective total control probabilities, P-B values are 94.8% and 92.5%, whereas the corresponding total complication probabilities, P-I values are 0.9% and 7.4%. For the R- case, the average P+ values are 89.4% for a (sic)(CTV) of 48.9 Gy and 88.6% for a (sic)(CTV) of 49.0 Gy, respectively. The respective PB values are 89.8% and 89.9%, whereas the corresponding PI values are 0.4% and 1.2%. For the R+ case, the average P+ values are 86.1% for a (sic)(CTV) of 49.2 Gy and 85.5% for a (sic)(CTV) of 49.1 Gy, respectively. The respective PB values are 90.2% and 90.1%, whereas the corresponding P-I values are 4.1% and 4.6%. The combined effects of positioning uncertainties and breathing can introduce a significant deviation between the planned and delivered dose distributions in lung in breast cancer radiotherapy. The positioning and breathing uncertainties do not affect much the dose distribution to the CTV. The simulated delivered dose distributions show larger lung complication probabilities than the treatment plans. This means that in clinical practice the true expected complications are underestimated. Radiation pneumonitis of Grade 1-2 is more frequent and any radiotherapy optimization should use this as a more clinically relevant endpoint.
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40.
  • Wedenberg, Mina, et al. (författare)
  • Analytical description of the LET dependence of cell survival using the repairable-conditionally repairable damage model
  • 2010
  • Ingår i: Radiation Research. - 0033-7587 .- 1938-5404. ; 96, s. S534-S534
  • Tidskriftsartikel (refereegranskat)abstract
    • In light-ion radiation therapy, both the dose and the local energy spectrum, which is often characterized with the linear energy transfer (LET), must be considered. In treatment optimization, it is advantageous to use a radiobiological model that analytically accounts for both dose and LET for the ion type of interest. With such a model the biological effect can also be estimated for dose and LET combinations for which there are no observations in the underlying experimental data. In this study, the repairable-conditionally repairable (RCR) damage model was extended by expressing its parameters as functions of LET to provide a radiobiological model that accounts for both the dose and the LET for a given ion type and cell line. This LET-parameterized RCR model was fitted to published cell survival data for HSG and V79 cells irradiated with carbon ions and for T1 cells irradiated with helium ions. To test the robustness of the model, fittings to only a subset of the data were performed. Good agreement with the cell survival data was obtained, including survival data for LET values not used for model fitting, opening up the possibility of using the model in treatment planning for light ions.
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41.
  • Wiklund, Kristin, 1976-, et al. (författare)
  • A Monte Carlo program for the analysis of low-energy electron tracks in liquid water
  • 2011
  • Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 56:7, s. 1985-2003
  • Tidskriftsartikel (refereegranskat)abstract
    • A Monte Carlo code for the event-by-event simulation of electron transport in liquid water is presented. The code, written in C++, can accommodate different interaction models. Currently it implements cross sections for ionizing collisions calculated with the model developed by Dingfelder et al (1998 Radiat. Phys. Chem. 53 1–18, 2008 Radiat. Res. 169 584–94) and cross sections for elastic scattering computed within the static-exchange approximation (Salvat et al 2005 Comput. Phys. Commun. 165 157–90). The latter cross sections coincide with those recommended in ICRU Report 77 (2007). Other included interaction mechanisms are excitation by electron impact and dissociative attachment. The main characteristics of the code are summarized. Various track penetration parameters, including the detour factor, are defined as useful tools to quantify the geometrical extent of electron tracks in liquid water. Results obtained with the present microdosimetry code are given in the form of probability density functions for initial electron kinetic energies ranging from 0.1 to 10 keV. The sensitivity of the simulated distributions to the choice of alternative physics models has been briefly explored. The discrepancies with equivalent simulations reported by Wilson et al (2004 Radiat. Res. 161 591–6) stem from the adopted cross sections for elastic scattering, which determine largely the spatial evolution of low-energy electron tracks.
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42.
  • Wiklund, Kristin, 1976-, et al. (författare)
  • Impact of dose and sensitivity heterogeneity on TCP
  • 2014
  • Ingår i: Computational & Mathematical Methods in Medicine. - : Hindawi Limited. - 1748-670X .- 1748-6718.
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose.The combined influence of heterogeneity in dose and radiation sensitivity on the probability of tumor control has not yet been fully explored, neither by numerical simulations nor by analytical modeling. The present paper adds to the current experience and presents an analytical description and numerical simulations of the influence of macroscopic intercell dose variations and intercell sensitivity variations on the probability of controlling the tumor. Methods. Computer simulations of tumour control probability (TCP) accounting for heterogeneity in dose and radiation sensitivity were performed based on Bernoulli trials including cell repopulation during the course of treatment in an explicit manner, without performing approximations.The dose heterogeneity was simulated by random sampling from a normal distribution with a specified mean dose and standard deviation. Two scenarios were considered for the simulation of intercell heterogeneity of the sensitivity described by the parameters of the linear-quadratic model (LQ) for cell killing. An analytical expression for TCP accounting for heterogeneity in sensitivity was also proposed and validated against simulations. Results. The results show good agreement between numerical simulations and the calculated TCP using the proposed analytical expression for the case of a heterogeneous dose and sensitivity distributions.When the intercellular variations of dose and sensitivity are taken into account, the total dose required for achieving the same level of control as for the case of homogeneous distribution is only slightly higher, the influence of the variations in the two factors taken into account being additive. For the case of interpatient variations in dose and sensitivity, the combined effects result in a coefficient of synergy of less than one. Conclusions.The results of this study show that the interplay between cell or tumor variation in the sensitivity to radiation and the inherent heterogeneity in dose distribution is highly complex and therefore should be taken into account when predicting the outcome of a given treatment.
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43.
  • Wiklund, Kristin, 1976- (författare)
  • Modeling of dose and sensitivity heterogeneities in radiation therapy
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The increased interest in the use of light ion therapy is due to the high dose conformity to the target and the dense energy deposition along the tracks resulting in increased relative biological effectiveness compared to conventional radiation therapy. In spite of the good clinical experience, fundamental research on the characteristics of the ion beams is still needed in order to be able to fully explore their use. Therefore, a Monte Carlo track structure code, KITrack, simulating the transport of electrons in liquid water, has been developed and used for calculation of parameters of interest for beam characterization. The influence of the choice of the cross sections for the physical processes on the electron tracks has also been explored. As an alternative to Monte Carlo calculations a semi-analytical approach to calculate the radial dose distribution from ions, has been derived and validated.In advanced radiation therapy, accurate characterization of the beams has to be complemented by comprehensive radiobiological models, which relate the dose deposition into the cells to the outcome of the treatment. The second part of the study has therefore explored the influence of heterogeneity in the dose deposition into the cells as well as the heterogeneity in the cells sensitivity to radiation on the probability of controlling the tumor. Analytical expressions for tumor control probability including heterogeneous dose depositions or variation of radiation sensitivity of cells and tumors have been derived and validated with numerical simulations. The more realistic case of a combination of these effects has also been explored through numerical simulations.The MC code KITrack has evolved into an extremely useful tool for beam characterization. The tumor control probability, given by the analytical derived expression, can help improve radiation therapy. A novel anisotropy index has been proposed. It is a measure of the absence of isotropy and provides deeper understanding of the relationship between beam quality and biological effects.
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44.
  • Wiklund, Kristin, 1976-, et al. (författare)
  • Radial secondary electron dose profiles and biological effects in light-ion beams based on analytical and Monte Carlo calculations using distorted wave cross sections
  • 2008
  • Ingår i: Radiation Research. - 0033-7587 .- 1938-5404. ; 170:1, s. 83-92
  • Tidskriftsartikel (refereegranskat)abstract
    • To speed up dose calculation, an analytical pencil-beam method has been developed to calculate the mean radial dose distributions due to secondary electrons that are set in motion by light ions in water. For comparison, radial dose profiles calculated using a Monte Carlo technique have also been determined. An accurate comparison of the resulting radial dose profiles of the Bragg peak for (1)H(+), (4)He(2+) and (6)Li(3+) ions has been performed. The double differential cross sections for secondary electron production were calculated using the continuous distorted wave-eikonal initial state method (CDW-EIS). For the secondary electrons that are generated, the radial dose distribution for the analytical case is based on the generalized Gaussian pencil-beam method and the central axis depth-dose distributions are calculated using the Monte Carlo code PENELOPE. In the Monte Carlo case, the PENELOPE code was used to calculate the whole radial dose profile based on CDW data. The present pencil-beam and Monte Carlo calculations agree well at all radii. A radial dose profile that is shallower at small radii and steeper at large radii than the conventional 1/r(2) is clearly seen with both the Monte Carlo and pencil-beam methods. As expected, since the projectile velocities are the same, the dose profiles of Bragg-peak ions of 0.5 MeV (1)H(+), 2 MeV (4)He(2+) and 3 MeV (6)Li(3+) are almost the same, with about 30% more delta electrons in the sub keV range from (4)He(2+)and (6)Li(3+) compared to (1)H(+). A similar behavior is also seen for 1 MeV (1)H(+), 4 MeV (4)He(2+) and 6 MeV (6)Li(3+), all classically expected to have the same secondary electron cross sections. The results are promising and indicate a fast and accurate way of calculating the mean radial dose profile.
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45.
  •  
46.
  • Wiklund, Kristin, 1976-, et al. (författare)
  • The influence of dose heterogeneity on tumour control probability in fractionated radiation therapy
  • 2011
  • Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 56:23, s. 7585-7600
  • Tidskriftsartikel (refereegranskat)abstract
    • Theoretical modelling of tumour control probability (TCP) with respect to non-uniformity in the dose to the tumour, alternate fractionation schemes and tumour kinetics is a very useful tool for assessment of the influence of changes in dosimetric or radiobiological factors on the outcome of the treatment. Various attempts have been made to also include effects from non-uniform dose to the tumour volume, but the problem has not been fully solved and many factors were totally neglected or not accurately taken into account. This paper presents derivations of analytical expressions of TCP for macroscopic inter-cell dose variations and for random inter-fractional variations in average tumour dose, based on binomial statistics for the TCP and the well-known linear quadratic model for the cell survival. Numerical calculations have been performed to validate the analytical expressions. An analysis of the influence of the deterministic and stochastic heterogeneity in dose delivery on the TCP was performed. The precision requirements in dose delivery are discussed briefly with the support of the presented results. The main finding of this paper is that it is primarily the shape of the cell survival curve that governs how the response is affected by macroscopic dose variations. The analytical expressions for TCP accounting for heterogeneity in dose can quite well describe the TCP for varying dose from cell to cell and random dose in each fraction. An increased TCP is seen when a large number of fractions are used and the variations in dose to the cells are rather high for tissues with low alpha/beta.
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