Annette Kopp-Schneider
Research interests
-
InterestsStatistical Analysis, Data Analysis, R, SAS
Publications
-
1.12Impact points
An adaptive group sequential phase II design to compare treatments for survival endpoints in rare patient entities.
Journal of biopharmaceutical statistics. 01/2012; 22(2):294-311.
For rare diseases, standard treatments are often not available and essential study parameters are difficult or impossible to obtain. Therefore, designs of clinical trials for these diseases are often based on little information. Adaptive designs allow such trials to be started and to gain informatio... [more] For rare diseases, standard treatments are often not available and essential study parameters are difficult or impossible to obtain. Therefore, designs of clinical trials for these diseases are often based on little information. Adaptive designs allow such trials to be started and to gain information during the study. Motivated by a trial for a rare subtype of renal-cell carcinoma, we present a two-stage adaptive design for right-censored time-to-event data and a two-sided test. After the first stage, one can stop for futility or continue with reestimated sample size. The properties of such designs are analyzed by simulation studies.
-
4.41Impact points
Epstein-barr virus stimulates torque teno virus replication: a possible relationship to multiple sclerosis.
PloS one. 01/2012; 7(2):e32160.
Viral infections have been implicated in the pathogenesis of multiple sclerosis. Epstein-Barr virus (EBV) has frequently been investigated as a possible candidate and torque teno virus (TTV) has also been discussed in this context. Nevertheless, mechanistic aspects remain unresolved. We report viral... [more] Viral infections have been implicated in the pathogenesis of multiple sclerosis. Epstein-Barr virus (EBV) has frequently been investigated as a possible candidate and torque teno virus (TTV) has also been discussed in this context. Nevertheless, mechanistic aspects remain unresolved. We report viral replication, as measured by genome amplification, as well as quantitative PCR of two TTV-HD14 isolates isolated from multiple sclerosis brain in a series of EBV-positive and -negative lymphoblastoid and Burkitt's lymphoma cell lines. Our results demonstrate the replication of both transfected TTV genomes up to day 21 post transfection in all the evaluated cell lines. Quantitative amplification indicates statistically significant enhanced TTV replication in the EBV-positive cell lines, including the EBV-converted BJAB line, in comparison to the EBV-negative Burkitt's lymphoma cell line BJAB. This suggests a helper effect of EBV infections in the replication of TTV. The present study provides information on a possible interaction of EBV and TTV in the etiology and progression of multiple sclerosis.
-
4.59Impact points
Proposal for a New Prognostic Score for Linac-Based Radiosurgery in Cerebral Arteriovenous Malformations.
International journal of radiation oncology, biology, physics. 10/2011;
PURPOSE: We evaluate patient-, angioma-, and treatment-specific factors for successful obliteration of cerebral arteriovenous malformations (AVM) to develop a new appropriate score to predict patient outcome after linac-based radiosurgery (RS). METHODS AND MATERIALS: This analysis in based on 293 pa... [more] PURPOSE: We evaluate patient-, angioma-, and treatment-specific factors for successful obliteration of cerebral arteriovenous malformations (AVM) to develop a new appropriate score to predict patient outcome after linac-based radiosurgery (RS). METHODS AND MATERIALS: This analysis in based on 293 patients with cerebral AVM. Mean age at treatment was 38.8 years (4-73 years). AVM classification according Spetzler-Martin was 55 patients Grade I (20.5%), 114 Grade II (42.5%), 79 Grade III (29.5%), 19 Grade IV (7.1%), and 1 Grade V (0.4%). Median maximum AVM diameter was 3.0 cm (range, 0.3-10 cm). Median dose prescribed to the 80% isodose was 18 Gy (range, 12-22 Gy). Eighty-five patients (29.1%) had prior partial embolization; 141 patients (51.9%) experienced intracranial hemorrhage before RS. Median follow-up was 4.2 years. RESULTS: Age at treatment, maximum diameter, nidus volume, and applied dose were significant factors for successful obliteration. Under presumption of proportional hazard in the dose range between 12 and 22 Gy/80% isodose, an increase of obliteration rate of approximately 25% per Gy was seen. On the basis of multivariate analysis, a prediction score was calculated including AVM maximum diameter and age at treatment. The prediction error up to the time point 8 years was 0.173 for the Heidelberg score compared with the Kaplan-Meier value of 0.192. An increase of the score of 1 point results in a decrease of obliteration chance by a factor of 0.447. CONCLUSION: The proposed score is linac-based radiosurgery-specific and easy to handle to predict patient outcome. Further validation on an independent patient cohort is necessary.
-
2.65Impact points
High-resolution phase-contrast MRI of aortic and pulmonary blood flow during rest and physical exercise using a MRI compatible bicycle ergometer.
European journal of radiology. 10/2011; 80(1):103-8.
To establish high-resolution phase-contrast magnetic resonance imaging (PC-MRI) using a MRI compatible bicycle ergometer to quantify aortic and pulmonary blood flow during resting conditions and exercise. In 20 healthy volunteers (mean age, 26.8±5.0 years) high-resolution PC-MRI (mean temporal resol... [more] To establish high-resolution phase-contrast magnetic resonance imaging (PC-MRI) using a MRI compatible bicycle ergometer to quantify aortic and pulmonary blood flow during resting conditions and exercise. In 20 healthy volunteers (mean age, 26.8±5.0 years) high-resolution PC-MRI (mean temporal resolution, 7.4±3.2 ms) was performed in the ascending aorta (AA) and main pulmonary artery (PA) during physical rest and three exercise stages: stage 1, no-load operation; stage 2, heart rate increase 40% compared to rest; stage 3, heart rate increase 80% compared to rest. Flow quantification in AA and PA included flow volume (FV), average velocity (AV), peak velocity (PV) and time to PV (TP). In stage 1 only TP demonstrated a significant change. With progression to stage 2, all parameters altered significantly. Flow measurements during stage 3 evidenced further alterations only of AV and TP regarding both AA and PA. The deviation of the heart rate from the desired target value was significantly higher for stage 3 compared to stage 2, and 15% of the subjects did not reach the desired target heart rate of stage 3 at all. Flow quantification by high-resolution PC-MRI during exercise using a MRI compatible bicycle ergometer is feasible. Medium exercise stages are necessary and sufficient to demonstrate flow alterations in healthy volunteers. PC-MRI ergometry may give insights into aberrant hemodynamic conditions in patients with cardiovascular and pulmonary disease.
-
2.02Impact points
The feasibility of low mechanical index contrast enhanced ultrasound (CEUS) in distinguishing malignant from benign thoracic lesions.
Ultrasound in medicine & biology. 09/2011; 37(11):1747-54.
We proposed to assess the feasibility of low mechanical index (MI) contrast enhanced ultrasound (CEUS) in the characterisation of thoracic lesions. Fifty patients were prospectively examined by CEUS and images acquired on a low MI (0.17-0.24) setting following injection of SonoVue. From region-of-in... [more] We proposed to assess the feasibility of low mechanical index (MI) contrast enhanced ultrasound (CEUS) in the characterisation of thoracic lesions. Fifty patients were prospectively examined by CEUS and images acquired on a low MI (0.17-0.24) setting following injection of SonoVue. From region-of-interest (ROI) generated signal intensity (SI) time curves, the maximum SI, bolus arrival time (BAT), time to peak intensity (TTP), wash-in slope and mean transit time (MTT) were calculated. Using the Wilcoxon rank test; parameters and threshold values for positive differentiation were determined. In addition, for the parameters that allowed positive differentiation between malignant and benign lesions receiver operator curves (ROC) were obtained. The wash-in slope, TTP and MTT (p = 0.0003, <0.0001, 0.02) allowed positive differentiation. The sensitivity and specificity was 93% and 78%, with 6.87 s(-1) threshold value for the wash-in slope, 78% and 89% with 11.84 s threshold for the TTP and 48% and 89% with 78.6 s threshold for the MTT. CEUS is a useful tool for differentiating malignant and benign thoracic lesions.
-
1.42Impact points
Repeatability and reproducibility of quantitative whole-lung perfusion magnetic resonance imaging.
Journal of thoracic imaging. 08/2011; 26(3):230-9.
Magnetic resonance imaging (MRI) allows for quantitative evaluation of pulmonary perfusion and has shown high clinical usefulness for the evaluation and differentiation of different lung pathologies. The reproducibility of quantitative analysis of whole-lung perfusion has not been investigated previ... [more] Magnetic resonance imaging (MRI) allows for quantitative evaluation of pulmonary perfusion and has shown high clinical usefulness for the evaluation and differentiation of different lung pathologies. The reproducibility of quantitative analysis of whole-lung perfusion has not been investigated previously. Our aim was to assess the intraobserver and interobserver repeatability and reproducibility of perfusion MRI to prove the concept that perfusion is suitable for therapy monitoring. The study was approved by the International Review Board. Fourteen healthy volunteers were examined using a time-resolved FLASH 3-dimensional perfusion sequence (1.5-T MRI, TREAT, GRAPPA 2, coronal orientation, voxel size 3.9×3.9×6.3 mm(3)). Perfusion was assessed initially and after 24 hours during an inspiratory and an expiratory breath hold. For each examination, 0.05 mmol/kg BW of Gd-DTPA was injected. Perfusion parameters such as pulmonary blood flow (PBF), pulmonary blood volume, and mean transit time were calculated. The evaluation was performed independently by 2 blinded observers. Intraobserver and interobserver differences were determined. The intraobserver differences between the initial and follow-up examinations for pulmonary blood volume, mean transit time, and time to peak were not significantly different for observers 1 and 2. PBF showed a significant difference for both observers only on inspiration (P<0.006 for observer 1 and P<0.009 for observer 2). For interobserver evaluation, all parameters, except inspiratory PBF, were significantly different (P<0.0001). Intraobserver quantitative perfusion MRI showed reproducible results. However, the evaluation is highly dependent on the observer. Therefore, quantitative analysis of the serial examinations should be performed by the same observer.
-
8.98Impact points
E6 and E7 from beta HPV38 cooperate with ultraviolet light in the development of actinic keratosis-like lesions and squamous cell carcinoma in mice.
PLoS pathogens. 07/2011; 7(7):e1002125.
Cutaneous beta human papillomavirus (HPV) types appear to be involved in the development of non-melanoma skin cancer (NMSC); however, it is not entirely clear whether they play a direct role. We have previously shown that E6 and E7 oncoproteins from the beta HPV type 38 display transforming activiti... [more] Cutaneous beta human papillomavirus (HPV) types appear to be involved in the development of non-melanoma skin cancer (NMSC); however, it is not entirely clear whether they play a direct role. We have previously shown that E6 and E7 oncoproteins from the beta HPV type 38 display transforming activities in several experimental models. To evaluate the possible contribution of HPV38 in a proliferative tissue compartment during carcinogenesis, we generated a new transgenic mouse model (Tg) where HPV38 E6 and E7 are expressed in the undifferentiated basal layer of epithelia under the control of the Keratin 14 (K14) promoter. Viral oncogene expression led to increased cellular proliferation in the epidermis of the Tg animals in comparison to the wild-type littermates. Although no spontaneous formation of tumours was observed during the lifespan of the K14 HPV38 E6/E7-Tg mice, they were highly susceptible to 7,12-dimethylbenz(a)anthracene (DMBA)/12-0-tetradecanoylphorbol-13-acetate (TPA) two-stage chemical carcinogenesis. In addition, when animals were exposed to ultraviolet light (UV) irradiation, we observed that accumulation of p21(WAF1) and cell-cycle arrest were significantly alleviated in the skin of Tg mice as compared to wild-type controls. Most importantly, chronic UV irradiation of Tg mice induced the development of actinic keratosis-like lesions, which are considered in humans as precursors of squamous cell carcinomas (SCC), and subsequently of SCC in a significant proportion of the animals. In contrast, wild-type animals subjected to identical treatments did not develop any type of skin lesions. Thus, the oncoproteins E6 and E7 from beta HPV38 significantly contribute to SCC development in the skin rendering keratinocytes more susceptible to UV-induced carcinogenesis.
-
4.93Impact points
Robust biclustering by sparse singular value decomposition incorporating stability selection.
Bioinformatics (Oxford, England). 06/2011; 27(15):2089-97.
Over the past decade, several biclustering approaches have been published in the field of gene expression data analysis. Despite of huge diversity regarding the mathematical concepts of the different biclustering methods, many of them can be related to the singular value decomposition (SVD). Recentl... [more] Over the past decade, several biclustering approaches have been published in the field of gene expression data analysis. Despite of huge diversity regarding the mathematical concepts of the different biclustering methods, many of them can be related to the singular value decomposition (SVD). Recently, a sparse SVD approach (SSVD) has been proposed to reveal biclusters in gene expression data. In this article, we propose to incorporate stability selection to improve this method. Stability selection is a subsampling-based variable selection that allows to control Type I error rates. The here proposed S4VD algorithm incorporates this subsampling approach to find stable biclusters, and to estimate the selection probabilities of genes and samples to belong to the biclusters. So far, the S4VD method is the first biclustering approach that takes the cluster stability regarding perturbations of the data into account. Application of the S4VD algorithm to a lung cancer microarray dataset revealed biclusters that correspond to coregulated genes associated with cancer subtypes. Marker genes for different lung cancer subtypes showed high selection probabilities to belong to the corresponding biclusters. Moreover, the genes associated with the biclusters belong to significantly enriched cancer-related Gene Ontology categories. In a simulation study, the S4VD algorithm outperformed the SSVD algorithm and two other SVD-related biclustering methods in recovering artificial biclusters and in being robust to noisy data. R-Code of the S4VD algorithm as well as a documentation can be found at http://s4vd.r-forge.r-project.org/.
-
2.65Impact points
Morphologic and functional scoring of cystic fibrosis lung disease using MRI.
European journal of radiology. 03/2011;
Magnetic resonance imaging (MRI) gains increasing importance in the assessment of cystic fibrosis (CF) lung disease. The aim of this study was to develop a morpho-functional MR-scoring-system and to evaluate its intra- and inter-observer reproducibility and clinical practicability to monitor CF lung... [more] Magnetic resonance imaging (MRI) gains increasing importance in the assessment of cystic fibrosis (CF) lung disease. The aim of this study was to develop a morpho-functional MR-scoring-system and to evaluate its intra- and inter-observer reproducibility and clinical practicability to monitor CF lung disease over a broad severity range from infancy to adulthood. 35 CF patients with broad age range (mean 15.3years; range 0.5-42) were examined by morphological and functional MRI. Lobe based analysis was performed for parameters bronchiectasis/bronchial-wall-thickening, mucus plugging, abscesses/sacculations, consolidations, special findings and perfusion defects. The maximum global score was 72. Two experienced radiologists scored the images at two time points (interval 10weeks). Upper and lower limits of agreement, concordance correlation coefficients (CCC), total deviation index and coverage probability were calculated for global, morphology, function, component and lobar scores. Global scores ranged from 6 to 47. Intra- and inter-reader agreement for global scores were good (CCC: 0.98 (R1), 0.94 (R2), 0.97 (R1/R2)) and were comparable between high and low scores. Our results indicate that the proposed morpho-functional MR-scoring-system is reproducible and applicable for semi-quantitative evaluation of a large spectrum of CF lung disease severity. This scoring-system can be applied for the routine assessment of CF lung disease and maybe as endpoint for clinical trials.
-
5.65Impact points
Fine tuning of the threshold of T cell selection by the Nck adapters.
Journal of immunology (Baltimore, Md. : 1950). 11/2010; 185(12):7518-26.
Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. I... [more] Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. In this study we provide genetic evidence that the Nck adapter proteins are essential for thymic selection. In vivo Nck deletion resulted in a reduction of the thymic cellularity, defective positive selection of low-avidity T cells, and impaired deletion of thymocytes engaged by low-potency stimuli. Nck-deficient thymocytes were characterized by reduced ERK activation, particularly pronounced in mature single positive thymocytes. Taken together, our findings identify a crucial role for the Nck adapters in enhancing TCR signal strength, thereby fine-tuning the threshold of thymocyte selection and shaping the preimmune T cell repertoire.
-
9.43Impact points
Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire.
Proceedings of the National Academy of Sciences of the United States of America. 08/2010; 107(35):15529-34.
The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing pr... [more] The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing proteins Nck lower the threshold of T-cell responsiveness. The hallmarks of Nck deletion were T-cell lymphopenia and hyporeactivity to TCR-mediated stimulation. In the absence of the Nck adaptors, peripheral T cells expressing a TCR with low avidity for self-antigens were strongly reduced, whereas an overall impairment of T-cell activation by weak antigenic stimulation was observed. Mechanistically, Nck deletion resulted in a significant decrease in calcium mobilization and ERK phosphorylation upon TCR engagement. Taken together, our findings unveil a crucial role for the Nck adaptors in shaping the T-cell repertoire to ensure maximal antigenic coverage and optimal T cell excitability.
-
1.30Impact points
Application of a two-phenotype color-shift model with heterogeneous growth to a rat hepatocarcinogenesis experiment.
Mathematical biosciences. 04/2010; 224(2):95-100.
The color-shift model (CSM) was introduced by Kopp-Schneider et al. [1] to describe formation and progression of foci of altered hepatocytes (FAH). It incorporates the field-effect hypothesis which postulates that entire colonies of altered hepatocytes simultaneously alter their phenotype. In the or... [more] The color-shift model (CSM) was introduced by Kopp-Schneider et al. [1] to describe formation and progression of foci of altered hepatocytes (FAH). It incorporates the field-effect hypothesis which postulates that entire colonies of altered hepatocytes simultaneously alter their phenotype. In the original CSM, FAH grow with deterministic growth rate and change their phenotype after an exponentially distributed waiting time. A modification of the original color-shift model (CSM beta) is presented here in which the growth rate varies from focus to focus according to a beta distribution. The concept of an exponentially distributed waiting time to phenotype change is modified to the concept of a random radius at which phenotype changes and this radius is modelled as beta distributed. The original and the modified CSM are applied to data from an initiation-promotion rat hepatocarcinogenesis experiment with diethylnitrosomorpholine (DEN) and N-nitrosomorpholine (NNM), in which two phenotypes of FAH were observed in hematoxilin/eosin (H&E) stained liver sections. The Cramer-von-Mises Distance is used as a measure for the discrepancy between empirical and theoretical size distributions. Comparisons of model fit show that considerable improvement is obtained for CSM beta compared to the original CSM.
-
6.75Impact points
HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth.
Clinical cancer research : an official journal of the American Association for Cancer Research. 04/2010; 16(12):3240-52.
Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. Thi... [more] Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth. Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells. HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability. HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets.
-
3.71Impact points
Glossopharyngeal insufflation and pulmonary hemodynamics in elite breath hold divers.
Medicine and science in sports and exercise. 02/2010; 42(9):1688-95.
Acute voluntary lung hyperinflation provoked by glossopharyngeal insufflation (GI) elicits numerous, possibly deleterious, effects on the cardiopulmonary system by increasing intrathoracic pressures far above normal values. This study quantifies acute pulmonary hemodynamics during GI using phase-con... [more] Acute voluntary lung hyperinflation provoked by glossopharyngeal insufflation (GI) elicits numerous, possibly deleterious, effects on the cardiopulmonary system by increasing intrathoracic pressures far above normal values. This study quantifies acute pulmonary hemodynamics during GI using phase-contrast magnetic resonance imaging (MRI). Hemodynamic parameters were measured in nine elite male breath hold divers with a mean age of 30 yr (range = 20-43 yr) by velocity-encoding cine (VEC)-MRI of the main pulmonary artery (PA) before, during, and after GI. Simultaneously, GI-lung volume (GIVEC-MRI) was measured by MR-compatible spirometry. Hemodynamic parameters were associated with GIVEC-MRI. Highly significant changes during GI were shown for the mean flow in the PA, which decreased by 45% (P < 0.007), and right ventricular output and cardiac index, which decreased by 41% and 40%, respectively (P < 0.007). Acceleration time also decreased highly significant by 36% during GI (P < 0.007). All hemodynamic parameters except acceleration time returned to baseline after GI. Acute voluntary lung hyperinflation mimics changes seen in pulmonary arterial hypertension, but unlike the latter, these changes are fully reversible shortly after cessation of voluntary lung hyperinflation. Persistent changes due to repetitive GI could not be detected.
-
4.12Impact points
Modelling the genesis and treatment of cancer: The potential role of physiologically based pharmacodynamics.
European journal of cancer (Oxford, England : 1990). 11/2009;
Physiologically based modelling of pharmacodynamics/toxicodynamics requires an a priori knowledge on the underlying mechanisms causing toxicity or causing the disease. In the context of cancer, the objective of the expert meeting was to discuss the molecular understanding of the disease, modelling a... [more] Physiologically based modelling of pharmacodynamics/toxicodynamics requires an a priori knowledge on the underlying mechanisms causing toxicity or causing the disease. In the context of cancer, the objective of the expert meeting was to discuss the molecular understanding of the disease, modelling approaches used so far to describe the process, preclinical models of cancer treatment and to evaluate modelling approaches developed based on improved knowledge. Molecular events in cancerogenesis can be detected using 'omics' technology, a tool applied in experimental carcinogenesis, but also for diagnostics and prognosis. The molecular understanding forms the basis for new drugs, for example targeting protein kinases specifically expressed in cancer. At present, empirical preclinical models of tumour growth are in great use as the development of physiological models is cost and resource intensive. Although a major challenge in PKPD modelling in oncology patients is the complexity of the system, based in part on preclinical models, successful models have been constructed describing the mechanism of action and providing a tool to establish levels of biomarker associated with efficacy and assisting in defining biologically effective dose range selection for first dose in man. To follow the concentration in the tumour compartment enables to link kinetics and dynamics. In order to obtain a reliable model of tumour growth dynamics and drug effects, specific aspects of the modelling of the concentration-effect relationship in cancer treatment that need to be accounted for include: the physiological/circadian rhythms of the cell cycle; the treatment with combinations and the need to optimally choose appropriate combinations of the multiple agents to study; and the schedule dependence of the response in the clinical situation.
-
4.59Impact points
Time- and Dose-Dependency of Radiographic Normal Tissue Changes of the Lung After Stereotactic Radiotherapy.
International journal of radiation oncology, biology, physics. 11/2009;
PURPOSE: Normal tissue changes (NTC) of the normal lung parenchyma are commonly seen after stereotactic single-dose radiotherapy (radiosurgery) of lung tumors. The aim of this study was to investigate the extent and dynamics of NTCs after radiosurgery. METHODS AND MATERIALS: Fifty lung tumors in 49 ... [more] PURPOSE: Normal tissue changes (NTC) of the normal lung parenchyma are commonly seen after stereotactic single-dose radiotherapy (radiosurgery) of lung tumors. The aim of this study was to investigate the extent and dynamics of NTCs after radiosurgery. METHODS AND MATERIALS: Fifty lung tumors in 49 patients were treated with radiosurgery. Follow-up CTs were anatomically matched to the treatment planning CTs, incorporating the treatment plan and enabling spatial correlation of initial radiation dose distribution and subsequent NTCs of the lung. Lung parenchyma was divided into nine areas of different radiation dose exposures (range, 6-35 Gy). Areas were investigated and compared at different time points according to the development of NTCs. RESULTS: Twenty-six patients developed NTCs during follow-up. The evaluation of the dependency of the extent of NTCs on the amount of radiation dose lead to a linear model for the fixed effects: Fraction of reacting volume =Intercept(T) +0.0208 * Dose ("Dose" should be given in Gy). Dose had a slope of 0.0208 (fraction of normal tissue reaction/Gy) (SE 0.000804, p < 0.0001), implying a significant correlation between dose level and the extent of NTC. CONCLUSION: For radiosurgery of lung tumors, a significant correlation of radiation dose and the extent of NTCs could be demonstrated. Using the introduced formula, a preview on the extent of NTCs to develop in normal lung parenchyma according to the dose level can be performed.
-
3.59Impact points
Simulation-based comparison of two approaches frequently used for dynamic contrast-enhanced MRI.
European radiology. 10/2009;
PURPOSE: The purpose was to compare two approaches for the acquisition and analysis of dynamic-contrast-enhanced MRI data with respect to differences in the modelling of the arterial input-function (AIF), the dependency of the model parameters on physiological parameters and their numerical stabilit... [more] PURPOSE: The purpose was to compare two approaches for the acquisition and analysis of dynamic-contrast-enhanced MRI data with respect to differences in the modelling of the arterial input-function (AIF), the dependency of the model parameters on physiological parameters and their numerical stability. Eight hundred tissue concentration curves were simulated for different combinations of perfusion, permeability, interstitial volume and plasma volume based on two measured AIFs and analysed according to the two commonly used approaches. The transfer constants (Approach 1) K (trans) and (Approach 2) k (ep) were correlated with all tissue parameters. K (trans) showed a stronger dependency on perfusion, and k (ep) on permeability. The volume parameters (Approach 1) v (e) and (Approach 2) A were mainly influenced by the interstitial and plasma volume. Both approaches allow only rough characterisation of tissue microcirculation and microvasculature. Approach 2 seems to be somewhat more robust than 1, mainly due to the different methods of CA administration.
-
4.34Impact points
4D-CT-based target volume definition in stereotactic radiotherapy of lung tumours: Comparison with a conventional technique using individual margins.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 09/2009;
PURPOSE: To investigate the dosimetric benefit of integration of 4D-CT in the planning target volume (PTV) definition process compared to conventional PTV definition using individual margins in stereotactic body radiotherapy (SBRT) of lung tumours. MATERIAL AND METHODS: Two different PTVs were defin... [more] PURPOSE: To investigate the dosimetric benefit of integration of 4D-CT in the planning target volume (PTV) definition process compared to conventional PTV definition using individual margins in stereotactic body radiotherapy (SBRT) of lung tumours. MATERIAL AND METHODS: Two different PTVs were defined: PTV(conv) consisting of the helical-CT-based clinical target volume (CTV) enlarged isotropically for each spatial direction by the individually measured amount of motion in the 4D-CT, and PTV(4D) encompassing the CTVs defined in the 4D-CT phases displaying the extremes of the tumour position. Tumour motion as well as volumetric and dosimetric differences and relations of both PTVs were evaluated. RESULTS: Volumetric examinations revealed a significant reduction of the mean PTV by 4D-CT from 57.7 to 40.7cm(3) (31%) (p<0.001). A significant inverse correlation was found for the motion vector and the amount of inclusion of PTV(4D) in PTV(conv) (r=-0.69, 90% confidence limits: -0.87 and -0.34, p=0.007). Mean lung dose (MLD) was decreased significantly by 17% (p<0.001). CONCLUSIONS: In SBRT of lung tumours the mere use of individual margins for target volume definition cannot compensate for the additional effects that the implementation of 4D-CT phases can offer.
-
1.95Impact points
Respiratory Displacement of the Thoracic Aorta: Physiological Phenomenon With Potential Implications for Thoracic Endovascular Repair.
Cardiovascular and interventional radiology. 06/2009;
The purpose of this study was to assess the magnitude and direction of respiratory displacement of the ascending and descending thoracic aorta during breathing maneuvers. In 11 healthy nonsmokers, dynamic magnetic resonance imaging was performed in transverse orientation at the tracheal bifurcation ... [more] The purpose of this study was to assess the magnitude and direction of respiratory displacement of the ascending and descending thoracic aorta during breathing maneuvers. In 11 healthy nonsmokers, dynamic magnetic resonance imaging was performed in transverse orientation at the tracheal bifurcation during maximum expiration and inspiration as well as tidal breathing. The magnitude and direction of aortic displacement was determined relatively to resting respiratory position for the ascending (AA) and descending (DA) aorta. To estimate a respiratory threshold for occurrence of distinct respiratory aortic motion, the latter was related to the underlying change in anterior-posterior thorax diameter. Compound displacement between maximum expiration and inspiration was 24.3 +/- 6.0 mm for the AA in the left anterior direction and 18.2 +/- 5.5 mm for the DA in the right anterior direction. The mean respiratory thorax excursion during tidal breathing was 8.9 +/- 2.8 mm. The respiratory threshold, i.e., the increase in thorax diameter necessary to result in respiratory aortic displacement, was estimated to be 15.7 mm. The data suggest that after a threshold of respiratory thorax excursion is exceeded, respiration is accompanied by significant displacement of the thoracic aorta. Although this threshold may not be reached during tidal breathing in the majority of individuals, segmental differences during forced respiration impact on aortic geometry, may result in additional extrinsic forces on the aortic wall, and may be of significance for aortic prostheses designed for thoracic endovascular aortic repair.
-
6.75Impact points
Histone deacetylase 8 in neuroblastoma tumorigenesis.
Clinical cancer research : an official journal of the American Association for Cancer Research. 02/2009; 15(1):91-9.
PURPOSE: The effects of pan-histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental tumor biological processes such as cell cycle control, differentiation, and apoptosis. However, because of the unselective nature of these compounds, little is known ab... [more] PURPOSE: The effects of pan-histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental tumor biological processes such as cell cycle control, differentiation, and apoptosis. However, because of the unselective nature of these compounds, little is known about the contribution of individual HDAC family members to tumorigenesis and progression. The purpose of this study was to evaluate the role of individual HDACs in neuroblastoma tumorigenesis. EXPERIMENTAL DESIGN: We have investigated the mRNA expression of all HDAC1-11 family members in a large cohort of primary neuroblastoma samples covering the full spectrum of the disease. HDACs associated with disease stage and survival were subsequently functionally evaluated in cell culture models. RESULTS: Only HDAC8 expression was significantly correlated with advanced disease and metastasis and down-regulated in stage 4S neuroblastoma associated with spontaneous regression. High HDAC8 expression was associated with poor prognostic markers and poor overall and event-free survival. The knockdown of HDAC8 resulted in the inhibition of proliferation, reduced clonogenic growth, cell cycle arrest, and differentiation in cultured neuroblastoma cells. The treatment of neuroblastoma cell lines as well as short-term-culture neuroblastoma cells with an HDAC8-selective small-molecule inhibitor inhibited cell proliferation and clone formation, induced differentiation, and thus reproduced the HDAC8 knockdown phenotype. Global histone 4 acetylation was not affected by HDAC8 knockdown or by selective inhibitor treatment. CONCLUSIONS: Our data point toward an important role of HDAC8 in neuroblastoma pathogenesis and identify this HDAC family member as a specific drug target for the differentiation therapy of neuroblastoma.
Following (11)
-
Harald Enzmann
BfArM -
Daniele Viarisio
Deutsches Krebsforschungszentrum -
Larissa Savelyeva
Deutsches Krebsforschungszentrum -
Martin Sill
Deutsches Krebsforschungszentrum -
Jean-Louis Steimer
Novartis
Topics (3)
