Combined identification and prediction algorithms

Рассматривается задача построения математической модели зависимости выходных переменных от входных переменных стохастического объекта с учетом априорных знаний о зависимости. Для решения этой проблемы используются как параметрические, так и непараметрические подходы. В работе предлагаются комбинированные алгоритмы идентификации и прогнозирования стохастических объектов с использованием линейной комбинации непараметрических и параметрических оценок регрессии

Integrated-boost IMRT or 3-D-CRT using FET-PET based auto-contoured target volume delineation for glioblastoma multiforme - a dosimetric comparison

<p>Abstract</p> <p>Background</p> <p>Biological brain tumor imaging using O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET)-PET combined with inverse treatment planning for locally restricted dose escalation in patients with glioblastoma multiforme seems to be a promising approach.</p> <p>The aim of this study was to compare inverse with forward treatment planning for an integrated boost dose application in patients suffering from a glioblastoma multiforme, while biological target volumes are based on FET-PET and MRI data sets.</p> <p>Methods</p> <p>In 16 glioblastoma patients an intensity-modulated radiotherapy technique comprising an integrated boost (IB-IMRT) and a 3-dimensional conventional radiotherapy (3D-CRT) technique were generated for dosimetric comparison. FET-PET, MRI and treatment planning CT (P-CT) were co-registrated. The integrated boost volume (PTV1) was auto-contoured using a cut-off tumor-to-brain ratio (TBR) of ≥ 1.6 from FET-PET. PTV2 delineation was MRI-based. The total dose was prescribed to 72 and 60 Gy for PTV1 and PTV2, using daily fractions of 2.4 and 2 Gy.</p> <p>Results</p> <p>After auto-contouring of PTV1 a marked target shape complexity had an impact on the dosimetric outcome. Patients with 3-4 PTV1 subvolumes vs. a single volume revealed a significant decrease in mean dose (67.7 vs. 70.6 Gy). From convex to complex shaped PTV1 mean doses decreased from 71.3 Gy to 67.7 Gy. The homogeneity and conformity for PTV1 and PTV2 was significantly improved with IB-IMRT. With the use of IB-IMRT the minimum dose within PTV1 (61.1 vs. 57.4 Gy) and PTV2 (51.4 vs. 40.9 Gy) increased significantly, and the mean EUD for PTV2 was improved (59.9 vs. 55.3 Gy, p < 0.01). The EUD for PTV1 was only slightly improved (68.3 vs. 67.3 Gy). The EUD for the brain was equal with both planning techniques.</p> <p>Conclusion</p> <p>In the presented planning study the integrated boost concept based on inversely planned IB-IMRT is feasible. The FET-PET-based automatically contoured PTV1 can lead to very complex geometric configurations, limiting the achievable mean dose in the boost volume. With IB-IMRT a better homogeneity and conformity, compared to 3D-CRT, could be achieved.</p

PLoS One

Age-related macular degeneration (AMD) is a common, progressive multifactorial vision-threatening disease and many genetic and environmental risk factors have been identified. The risk of AMD is influenced by lifestyle and diet, which may be reflected by an altered metabolic profile. Therefore, measurements of metabolites could identify biomarkers for AMD, and could aid in identifying high-risk individuals. Hypothesis-free technologies such as metabolomics have a great potential to uncover biomarkers or pathways that contribute to disease pathophysiology. To date, only a limited number of metabolomic studies have been performed in AMD. Here, we aim to contribute to the discovery of novel biomarkers and metabolic pathways for AMD using a targeted metabolomics approach of 188 metabolites. This study focuses on non-advanced AMD, since there is a need for biomarkers for the early stages of disease before severe visual loss has occurred. Targeted metabolomics was performed in 72 patients with early or intermediate AMD and 72 control individuals, and metabolites predictive for AMD were identified by a sparse partial least squares discriminant analysis. In our cohort, we identified four metabolite variables that were most predictive for early and intermediate stages of AMD. Increased glutamine and phosphatidylcholine diacyl C28:1 levels were detected in non-advanced AMD cases compared to controls, while the rate of glutaminolysis and the glutamine to glutamate ratio were reduced in non-advanced AMD. The association of glutamine with non-advanced AMD corroborates a recent report demonstrating an elevated glutamine level in early AMD using a different metabolomics technique. In conclusion, this study indicates that metabolomics is a suitable method for the discovery of biomarker candidates for AMD. In the future, larger metabolomics studies could add to the discovery of novel biomarkers in yet unknown AMD pathways and expand our insights in AMD pathophysiology

Ophthalmology

OBJECTIVE: In the current study we aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date. In addition, we aimed to determine the effect of AMD-associated genetic variants on metabolite levels, and aimed to investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. DESIGN: Case-control assocation analysis of metabolomics data. SUBJECTS: 2,267 AMD cases and 4,266 controls from five European cohorts. METHODS: Metabolomics was performed using a high-throughput H-NMR metabolomics platform, which allows the quantification of 146 metabolite measurements and 79 derivative values. Metabolome-AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d/C3 ratio) were investigated using linear regression. MAIN OUTCOME MEASURES: Metabolites associated with AMD RESULTS: We identified 60 metabolites that were significantly associated with AMD, including increased levels of large and extra-large HDL subclasses and decreased levels of VLDL, amino acids and citrate. Out of 52 AMD-associated genetic variants, seven variants were significantly associated with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, LIPC) with metabolites belonging to the large and extra-large HDL subclasses. In addition, 57 out of 60 metabolites were significantly associated with complement activation levels, and these associations were independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. CONCLUSIONS: Lipoprotein levels were associated with AMD-associated genetic variants, while decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways, and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%

Imaging of sodium in the brain: a brief review

Sodium-based MRI plays a vital role in the study of metabolism and can unveil valuable information about emerging and existing pathology – in particular in the human brain. Sodium is the second most abundant MR active nucleus in living tissue and, due to its quadrupolar nature, has magnetic properties not common to conventional proton MRI, which can reveal further insights, such as information on the compartmental distribution of intra- and extracellular sodium. Nevertheless, the use of sodium nuclei for imaging comes at the expense of a lower sensitivity and significantly reduced relaxation times, making in vivo sodium studies feasible only at high magnetic field strength and by the use of dedicated pulse sequences.Hybrid imaging combining sodium MRI and positron emission tomography (PET) simultaneously is a novel and promising approach to access information on dynamic metabolism with much increased, PET-derived specificity. Application of this new methodology is demonstrated herein using examples from tumour imaging

Relapse patterns after radiochemotherapy of glioblastoma with FET PET-guided boost irradiation and simulation to optimize radiation target volume

BackgroundO-(2-18 F-fluoroethyl)-L-tyrosine-(FET)-PET may be helpful to improve the definition of radiation target volumes in glioblastomas compared with MRI. We analyzed the relapse patterns in FET-PET after a FET- and MRI-based integrated-boost intensity-modulated radiotherapy (IMRT) of glioblastomas to perform an optimized target volume definition.MethodsA relapse pattern analysis was performed in 13 glioblastoma patients treated with radiochemotherapy within a prospective phase-II-study between 2008 and 2009. Radiotherapy was performed as an integrated-boost intensity-modulated radiotherapy (IB-IMRT). The prescribed dose was 72 Gy for the boost target volume, based on baseline FET-PET (FET-1) and 60 Gy for the MRI-based (MRI-1) standard target volume. The single doses were 2.4 and 2.0 Gy, respectively. Location and volume of recurrent tumors in FET-2 and MRI-2 were analyzed related to initial tumor, detected in baseline FET-1. Variable target volumes were created theoretically based on FET-1 to optimally cover recurrent tumor.ResultsThe tumor volume overlap in FET and MRI was poor both at baseline (median 12 %; range 0–32) and at time of recurrence (13 %; 0–100). Recurrent tumor volume in FET-2 was localized to 39 % (12–91) in the initial tumor volume (FET-1). Over the time a shrinking (mean 12 (5–26) ml) and shifting (mean 6 (1–10 mm) of the resection cavity was seen. A simulated target volume based on active tumor in FET-1 with an additional safety margin of 7 mm around the FET-1 volume covered recurrent FET tumor volume (FET-2) significantly better than a corresponding target volume based on contrast enhancement in MRI-1 with a same safety margin of 7 mm (100 % (54–100) versus 85 % (0–100); p < 0.01). A simulated planning target volume (PTV), based on FET-1 and additional 7 mm margin plus 5 mm margin for setup-uncertainties was significantly smaller than the conventional, MR-based PTV applied in this study (median 160 (112–297) ml versus 231 (117–386) ml, p < 0.001).ConclusionsIn this small study recurrent tumor volume in FET-PET (FET-2) overlapped only to one third with the boost target volume, based on FET-1. The shrinking and shifting of the resection cavity may have an influence considering the limited overlap of initial and relapse tumor volume. A simulated target volume, based on FET-1 with 7 mm margin covered 100 % of relapse volume in median and led to a significantly reduced PTV, compared to MRI-based PTVs. This approach may achieve similar therapeutic efficacy but lower side effects offering a broader window to intensify concomitant systemic treatment focusing distant failures

Effects of dietary tryptophan and phenylalanine-tyrosine depletion on phasic alertness in healthy adults - A pilot study

Background: The synthesis of the neurotransmitters serotonin (5-HT) and dopamine (DA) in the brain can be directly altered by dietary manipulation of their relevant precursor amino acids (AA). There is evidence that altered serotonergic and dopaminergic neurotransmission are both associated with impaired attentional control. Specifically, phasic alertness is one specific aspect of attention that has been linked to changes in 5-HT and DA availability in different neurocircuitries related to attentional processes. The present study investigated the impact of short-term reductions in central nervous system 5-HT and DA synthesis, which was achieved by dietary depletion of the relevant precursor AA, on phasic alertness in healthy adult volunteers; body weight–adapted dietary tryptophan and phenylalanine–tyrosine depletion (PTD) techniques were used.Methods: The study employed a double-blind between-subject design. Fifty healthy male and female subjects were allocated to three groups in a randomized and counterbalanced manner and received three different dietary challenge conditions: acute tryptophan depletion (ATD, for the depletion of 5-HT; N=16), PTD (for the depletion of DA; N=17), and a balanced AA load (BAL; N=17), which served as a control condition. Three hours after challenge intake (ATD/PTD/BAL), phasic alertness was assessed using a standardized test battery for attentional performance (TAP). Blood samples for AA level analyses were obtained at baseline and 360 min after the challenge intake.Results: Overall, there were no significant differences in phasic alertness for the different challenge conditions. Regarding PTD administration, a positive correlation between the reaction times and the DA-related depletion magnitude was detected via the lower plasma tyrosine levels and the slow reaction times of the first run of the task. In contrast, higher tryptophan concentrations were associated with slower reaction times in the fourth run of the task in the same challenge group.Conclusion: The present study is the first to demonstrate preliminary data that support an association between decreased central nervous system DA synthesis, which was achieved by dietary depletion strategies, and slower reaction times in specific runs of a task designed to assess phasic alertness in healthy adult volunteers; these findings are consistent with previous evidence that links phasic alertness with dopaminergic neurotransmission. A lack of significant differences between the three groups could be due to compensatory mechanisms and the limited sample size, as well as the dietary challenge procedures administered to healthy participants and the strict exclusion criteria used. The potential underlying neurochemical processes related to phasic alertness should be the subject of further investigations

Interfraktionäre Lagevariation der Rektumvorderwand unter primärer bzw. postoperativer perkutaner Strahlentherapie des Prostatakarzinoms

Hintergrund: Im Rahmen multidisziplinärer Therapiestrategien werden Patienten mit Prostatakarzinom zunehmend mit operativen Verfahren und perkutaner Strahlentherapie (RT) innerhalb ihrer Krankheitsverläufe individuell behandelt. Ob die Resektion der Prostata die interfraktionäre Lagevariation (LV) der Rektumvorderwand (RVW) beeinflusst, soll diese prospektive Untersuchung zeigen. Material und Methode: Von insgesamt 23 Patienten (Pat.) waren 20 für die Studie auswertbar. Alle Pat. wurden aufgrund eines histologisch nachgewiesenen Prostatakarzinoms im Bereich der Prostataloge bestrahlt. 60% der Pat. erhielten die RT nach vorangegangener radikaler Prostatovesikulektomie (Gruppe A) aufgrund R1-Resektion oder eines PSA-Rezidivs, 40% der Pat. als definitive RT (Gruppe B). Im Behandlungsverlauf wurden jeweils 6 wöchentliche CT-Datensätze angefertigt und mit dem Referenz-CT im Bestrahlunsplanungssystem Oncentra® MasterPlan, Nucletron BV, Veenendahl/NL, Version 1.4.3.1-3.0) registriert. In allen 138 CT-Datensätzen wurde das Rektumvolumen konturiert und die LV anhand einer virtuellen Messebene (caudal des Acetabulum) als Entfernung von der RVW in jeweils 5 Messpunkten (A-E, coronare Ebene, Abstand jeweils 10mm) berechnet. Als LV wurde die jeweilige Abweichung vom Referenz-CT definiert. Die statistische Auswertung erfolgte mit PASW-Statistics 18.0 (SPSS Inc.). Ergebnisse: Bei 80% aller Pat. lag die erfasste LVRVW nach ventral > 5mm (A: 91,7%; B: 75%), bei 50% aller Pat. > 10mm (A: 58%; B: 7,5%) bei 40% aller Pat. >15mm (A: 50%; B: 25%) und bei 20% aller Pat. >20mm (A: 25%; B: 12,5%). Die LVRVW nach dorsal war bei 90% aller Pat. > 5mm (A: 100%; B: 75%), bei 70% aller Pat. > 10mm (A: 75%; B: 62,5%), bei 50% aller Pat. >15mm (A: 41,7%; B: 25%) und bei 30% aller Pat. > 20mm (A: 33,3%; B: 25%). Die postoperativ behandelten Pat. (A) wiesen im Vergleich mit den primär Behandelten (B) in allen Bereichen, sowohl nach ventral als auch nach dorsal, eine jeweils höhere LVRVW auf. Schlussfolgerung: Die zielvolumenrelevante LVRVW betrifft Pat. nach Prostatektomie in größerem Ausmass als Patienten mit primärer RT. Diese Beobachtung zeigt auf, wie wenig starre kompensatorische Sicherheitssäume bei der Zielvolumendefinition insbesondere bei der postoperativen RT der Prostataloge geeignet sind. Dies ist insbesondere für den Einsatz hochkonformaler Techniken (z.B. IMRT,IMAT, VMAT) mit geringen Sicherheitssäumen von Bedeutung, wenn diese ohne tägliche Online-Verifikation (CT) eingesetzt werden. Inwiefern sich die erhöhte LVRVW der postoperativen Pat. auch in mehr anorektale Spättoxizitäten wiederspiegelt, wird die Auswertung der klinischen Daten zeigen