Kyriaki Theodorou

Dose-Response Relations for Anal Sphincter Regarding Fecal Leakage and Blood or Phlegm in Stools after Radiotherapy for Prostate Cancer

Background:The estimation of the parameters that describe the dose-response relations of anal sphincter regarding the clinical endpoints of fecal leakage and blood or phlegm in stools is important in the optimization of prostate cancer radiotherapy. Also, the validity of the relative seriality model for this clinical case needs to be examined by associating the clinical follow-up results with the predicted complication rates.Patients and Methods:In this study, 65 patients who received radiation therapy for clinically localized prostate adenocarcinoma are analyzed. The clinical treatment outcome and the three-dimensional dose distribution delivered to anal sphincter were available for each patient. A questionnaire was used for assessing the clinical bowel and urinary symptoms. A maximum likelihood fitting was performed to calculate the best estimates of the parameters used by the relative seriality model. The clinical utilization of the calculated parameters in predicting anal sphincter complication probabilities was illustrated by applying the best estimate of the parameters to a subset of the patient population.Results:The estimated values of the parameters for the two clinical endpoints are D50 = 70.2 Gy, γ = 1.22, s = 0.35 for fecal leakage and D50 = 74.0 Gy, γ = 0.75, s ≈ 0 for blood or phlegm in stools. The standard deviations of the parameters were also calculated together with the confidence intervals of the dose-response curves. The analysis proved that the treatment outcome pattern of the patient material can suitably be reproduced by the relative seriality model (probability of finding a worse fit = 60.2%, the area under the receiver operating characteristic curve = 0.72 and 0.69 and χ2-test = 0.97 and 0.86, respectively).Conclusion:Fecal leakage is characterized by a medium relative seriality whereas blood or phlegm in stools was found to have strong volume dependence (low relative seriality). Diminishing the biologically effective uniform dose to anal sphincter < 40–45 Gy may significantly reduce the risk of fecal leakage or blood or phlegm in stools for patients irradiated for prostate cancer.Hintergrund:Um die Strahlenbehandlung des Prostatakarzinoms optimieren zu können, ist ein Modell der Dosis-Wirkungs-Beziehung für die Analsphinkterfunktion notwendig, dessen Parameter verlässlich geschätzt werden können. Es sollte die klinischen Endpunkte Stuhlinkontinenz und Blut oder Schleim im Stuhl beschreiben. Zusätzlich sollte die Gültigkeit des Relative-Seriality-Modells überprüft werden, indem die Befunde des klinischen Follow-up mit den prognostizierten Komplikationsraten verglichen werden.Patienten und Methodik:Diese Studie umfasst 65 Patienten, die wegen eines klinisch manifesten lokalisierten Adenokarzinoms der Prostata eine Strahlenbehandlung erhalten hatten. Das klinische Ergebnis und die Dosisverteilung im Analsphinkter waren für jeden Patienten verfügbar. Klinische Symptome des Darms und der Harnwege wurden mittels eines Fragebogens erfasst. Die Parameter des Relative-Seriality-Modells wurden mit Hilfe der Maximum-Likelihood-Methode bestimmt. Bei einer Untergruppe der Patienten wurden die besten Schätzwerte der Parameter angewendet. Der klinische Nutzen für die Prognose von Komplikationen des Analsphinkters konnte dargestellt werden.Ergebnisse:Die Schätzwerte der Parameter der zwei klinischen Endpunkte sind D50 = 70,2 Gy, γ = 1,22, s = 0,35 für Stuhlinkontinenz und D50 = 74,0 Gy, γ = 0,75, s ≈ 0 für Blut oder Schleim im Stuhl. Die Standardabweichungen der Parameter wurden ebenso berechnet wie die Konfidenzintervalle. Die Analyse (untersucht wurden: Probability of Finding worse Fit = 60,2%, die Fläche unter ROC-Kurven 0,72 bzw. 0,69 und χ2 = 0,97 und 0,86) beweist, dass das Behandlungsergebnis bei den untersuchten Patienten mit Hilfe des Relative-Seriality-Modells gut wiedergegeben wird.Schlussfolgerungen:Die Stuhlinkontinenz zeigt eine mittlere Relative Seriality, während für Blut oder Schleim im Stuhl eine starke Volumenabhängigkeit gefunden wurde (geringe Relative Seriality). Eine Reduktion der biologisch effektiven, uniformen Dosis des Analsphinkters unter 40-45 Gy könnte die Risiken der Stuhlinkontinenz und von Blut oder Schleim im Stuhl für Prostatakarzinom-Patienten signifikant senken.

Dose-Response Relations for Anal Sphincter Regarding Fecal Leakage and Blood or Phlegm in Stools after Radiotherapy for Prostate Cancer Radiobiological Study of 65 Consecutive Patients

Background:The estimation of the parameters that describe the dose-response relations of anal sphincter regarding the clinical endpoints of fecal leakage and blood or phlegm in stools is important in the optimization of prostate cancer radiotherapy. Also, the validity of the relative seriality model for this clinical case needs to be examined by associating the clinical follow-up results with the predicted complication rates.Patients and Methods:In this study, 65 patients who received radiation therapy for clinically localized prostate adenocarcinoma are analyzed. The clinical treatment outcome and the three-dimensional dose distribution delivered to anal sphincter were available for each patient. A questionnaire was used for assessing the clinical bowel and urinary symptoms. A maximum likelihood fitting was performed to calculate the best estimates of the parameters used by the relative seriality model. The clinical utilization of the calculated parameters in predicting anal sphincter complication probabilities was illustrated by applying the best estimate of the parameters to a subset of the patient population.Results:The estimated values of the parameters for the two clinical endpoints are D50 = 70.2 Gy, γ = 1.22, s = 0.35 for fecal leakage and D50 = 74.0 Gy, γ = 0.75, s ≈ 0 for blood or phlegm in stools. The standard deviations of the parameters were also calculated together with the confidence intervals of the dose-response curves. The analysis proved that the treatment outcome pattern of the patient material can suitably be reproduced by the relative seriality model (probability of finding a worse fit = 60.2%, the area under the receiver operating characteristic curve = 0.72 and 0.69 and χ2-test = 0.97 and 0.86, respectively).Conclusion:Fecal leakage is characterized by a medium relative seriality whereas blood or phlegm in stools was found to have strong volume dependence (low relative seriality). Diminishing the biologically effective uniform dose to anal sphincter < 40–45 Gy may significantly reduce the risk of fecal leakage or blood or phlegm in stools for patients irradiated for prostate cancer.Hintergrund:Um die Strahlenbehandlung des Prostatakarzinoms optimieren zu können, ist ein Modell der Dosis-Wirkungs-Beziehung für die Analsphinkterfunktion notwendig, dessen Parameter verlässlich geschätzt werden können. Es sollte die klinischen Endpunkte Stuhlinkontinenz und Blut oder Schleim im Stuhl beschreiben. Zusätzlich sollte die Gültigkeit des Relative-Seriality-Modells überprüft werden, indem die Befunde des klinischen Follow-up mit den prognostizierten Komplikationsraten verglichen werden.Patienten und Methodik:Diese Studie umfasst 65 Patienten, die wegen eines klinisch manifesten lokalisierten Adenokarzinoms der Prostata eine Strahlenbehandlung erhalten hatten. Das klinische Ergebnis und die Dosisverteilung im Analsphinkter waren für jeden Patienten verfügbar. Klinische Symptome des Darms und der Harnwege wurden mittels eines Fragebogens erfasst. Die Parameter des Relative-Seriality-Modells wurden mit Hilfe der Maximum-Likelihood-Methode bestimmt. Bei einer Untergruppe der Patienten wurden die besten Schätzwerte der Parameter angewendet. Der klinische Nutzen für die Prognose von Komplikationen des Analsphinkters konnte dargestellt werden.Ergebnisse:Die Schätzwerte der Parameter der zwei klinischen Endpunkte sind D50 = 70,2 Gy, γ = 1,22, s = 0,35 für Stuhlinkontinenz und D50 = 74,0 Gy, γ = 0,75, s ≈ 0 für Blut oder Schleim im Stuhl. Die Standardabweichungen der Parameter wurden ebenso berechnet wie die Konfidenzintervalle. Die Analyse (untersucht wurden: Probability of Finding worse Fit = 60,2%, die Fläche unter ROC-Kurven 0,72 bzw. 0,69 und χ2 = 0,97 und 0,86) beweist, dass das Behandlungsergebnis bei den untersuchten Patienten mit Hilfe des Relative-Seriality-Modells gut wiedergegeben wird.Schlussfolgerungen:Die Stuhlinkontinenz zeigt eine mittlere Relative Seriality, während für Blut oder Schleim im Stuhl eine starke Volumenabhängigkeit gefunden wurde (geringe Relative Seriality). Eine Reduktion der biologisch effektiven, uniformen Dosis des Analsphinkters unter 40-45 Gy könnte die Risiken der Stuhlinkontinenz und von Blut oder Schleim im Stuhl für Prostatakarzinom-Patienten signifikant senken.

Differentiation of glioblastoma multiforme from metastatic brain tumor using proton magnetic resonance spectroscopy, diffusion and perfusion metrics at 3 T

Abstract Purpose: To assess the contribution of 1H-magnetic resonance spectroscopy (1H-MRS), diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI) and dynamic susceptibility contrast-enhanced (DSCE) imaging metrics in the differentiation of glioblastomas from solitary metastasis, and particularly to clarify the controversial reports regarding the hypothesis that there should be a significant differentiation between the intratumoral and peritumoral areas. Methods: Conventional MR imaging, 1H-MRS, DWI, DTI and DSCE MRI was performed on 49 patients (35 glioblastomas multiforme, 14 metastases) using a 3.0-T MR unit. Metabolite ratios, apparent diffusion coefficient (ADC), fractional anisotropy (FA) and relative cerebral blood volume (rCBV) were measured in the intratumoral and peritumoral regions of the lesions. Receiver-operating characteristic analysis was used to obtain the cut-off values for the parameters presenting a statistical difference between the two tumor groups. Furthermore, we investigated the potential effect of the region of interest (ROI) size on the quantification of diffusion properties in the intratumoral region of the lesions, by applying two different ROI methods. Results: Peritumoral N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, Cho/NAA and rCBV significantly differentiated glioblastomas from intracranial metastases. ADC and FA presented no significant difference between the two tumor groups. Conclusions: 1H-MRS and dynamic susceptibility measurements in the peritumoral regions may definitely aid in the differentiation of glioblastomas and solitary metastases. The quantification of the diffusion properties in the intratumoral region is independent of the ROI size placed.

Investigating brain tumor differentiation with diffusion and perfusion metrics at 3T MRI using pattern recognition techniques.

The aim of this study was to evaluate the contribution of diffusion and perfusion MR metrics in the discrimination of intracranial brain lesions at 3T MRI, and to investigate the potential diagnostic and predictive value that pattern recognition techniques may provide in tumor characterization using these metrics as classification features. Conventional MRI, diffusion weighted imaging (DWI), diffusion tensor imaging (DTI) and dynamic-susceptibility contrast imaging (DSCI) were performed on 115 patients with newly diagnosed intracranial tumors (low-and- high grade gliomas, meningiomas, solitary metastases). The Mann-Whitney U test was employed in order to identify statistical differences of the diffusion and perfusion parameters for different tumor comparisons in the intra-and peritumoral region. To assess the diagnostic contribution of these parameters, two different methods were used; the commonly used receiver operating characteristic (ROC) analysis and the more sophisticated SVM classification, and accuracy, sensitivity and specificity levels were obtained for both cases. The combination of all metrics provided the optimum diagnostic outcome. The highest predictive outcome was obtained using the SVM classification, although ROC analysis yielded high accuracies as well. It is evident that DWI/DTI and DSCI are useful techniques for tumor grading. Nevertheless, cellularity and vascularity are factors closely correlated in a non-linear way and thus difficult to evaluate and interpret through conventional methods of analysis. Hence, the combination of diffusion and perfusion metrics into a sophisticated classification scheme may provide the optimum diagnostic outcome. In conclusion, machine learning techniques may be used as an adjunctive diagnostic tool, which can be implemented into the clinical routine to optimize decision making.

The role of diffusion and perfusion weighted imaging in the differential diagnosis of cerebral tumors: a review and future perspectives

The role of conventional Magnetic Resonance Imaging (MRI) in the detection of cerebral tumors has been well established. However its excellent soft tissue visualization and variety of imaging sequences are in many cases non-specific for the assessment of brain tumor grading. Hence, advanced MRI techniques, like Diffusion-Weighted Imaging (DWI), Diffusion Tensor Imaging (DTI) and Dynamic-Susceptibility Contrast Imaging (DSCI), which are based on different contrast principles, have been used in the clinical routine to improve diagnostic accuracy. The variety of quantitative information derived from these techniques provides significant structural and functional information in a cellular level, highlighting aspects of the underlying brain pathophysiology. The present work, reviews physical principles and recent results obtained using DWI/DTI and DSCI, in tumor characterization and grading of the most common cerebral neoplasms, and discusses how the available MR quantitative data can be utilized through advanced methods of analysis, in order to optimize clinical decision making.

Prediction of AVM obliteration after stereotactic radiotherapy using radiobiological modelling

This study was carried out in order to derive the radiobiological parameters of the dose-response relation for the obliteration of arteriovenous malformation (AVM) following single fraction stereotactic radiotherapy. Furthermore, the accuracy by which the linear Poisson model predicts the probability of obliteration and how the haemorrhage history, location and volume of the AVM influence its radiosensitivity are investigated. The study patient material consists of 85 patients who received radiation for AVM therapy. Radiation-induced AVM obliterations were assessed on the basis of post-irradiation angiographies and other radiological findings. For each patient the dose delivered to the clinical target volume and the clinical treatment outcome were available. These data were used in a maximum likelihood analysis to calculate the best estimates of the parameters of the linear Poisson model. The uncertainties of these parameters were also calculated and their individual influence on the dose-response curve was studied. AVM radiosensitivity was assumed to be the same for all the patients. The radiobiological model used was proved suitable for predicting the treatment outcome pattern of the studied patient material. The radiobiological parameters of the model were calculated for different AVM locations, bleeding histories and AVM sizes. The range of parameter variability had considerable effect on the dose-response curve of AVM. The correlation between the dosimetric data and their corresponding clinical effect could be accurately modelled using the linear Poisson model. The derived response parameters can be introduced into the clinical routine with the calculated accuracy assuming the same methodology in target definition and delineation. The known volume dependence of AVM radiosensitivity was confirmed. Moreover, a trend relating AVM location with its radiosensitivity was observed.

Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy.

The purpose of this work is to evaluate the predictive strength of the relative seriality, parallel and LKB normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis, in a large group of patients following breast cancer radiotherapy, and furthermore, to illustrate statistical methods for examining whether certain published radiobiological parameters are compatible with a clinical treatment methodology and patient group characteristics. The study is based on 150 consecutive patients who received radiation therapy for breast cancer. For each patient, the 3D dose distribution delivered to lung and the clinical treatment outcome were available. Clinical symptoms and radiological findings, along with a patient questionnaire, were used to assess the manifestation of radiation-induced complications. Using this material, different methods of estimating the likelihood of radiation effects were evaluated. This was attempted by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Additionally, the need for an update of the criteria that are being used in the current clinical practice was also examined. The patient material was selected without any conscious bias regarding the radiotherapy treatment technique used. The treatment data of each patient were applied to the relative seriality, LKB and parallel NTCP models, using published parameter sets. Of the 150 patients, 15 experienced radiation-induced pneumonitis (grade 2) according to the radiation pneumonitis scoring criteria used. Of the NTCP models examined, the relative seriality model was able to predict the incidence of radiation pneumonitis with acceptable accuracy, although radiation pneumonitis was developed by only a few patients. In the case of modern breast radiotherapy, radiobiological modelling appears to be very sensitive to model and parameter selection giving clinically acceptable results in certain cases selectively (relative seriality model with Seppenwoolde et al and Gagliardi et al parameter sets). The use of published parameters should be considered as safe only after their examination using local clinical data. The variation of inter-patient radiosensitivity seems to play a significant role in the prediction of such low incidence rate complications. Scoring grades were combined to give stronger evidence of radiation pneumonitis since their differences could not be strictly associated with dose. This obviously reveals a weakness of the scoring related to this endpoint, and implies that the probability of radiation pneumonitis induction may be too low to be statistically analysed with high accuracy, at least with the latest advances of dose delivery in breast radiotherapy.

Statistical methods for clinical verification of dose-response parameters related to esophageal stricture and AVM obliteration from radiotherapy

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.

Psychosocial Correlates of Insomnia in an Adolescent Population.

This study examines the nature of the relationship between psychosocial factors and insomnia complaints in an adolescent non-clinical population. It is a cross-sectional study of a stratified sample of 2,195 Greek adolescent high-school students. Subjects were given the Athens insomnia scale, the Symptom Checklist scale (SCL-90-R) and a questionnaire concerning demographic characteristics. None of the subjects had received help for insomnia complaints or other overt psychopathology. Adolescents classified as suffering from insomnia presented higher levels of general psychopathology. Age, tobacco and alcohol use, self-reported patterns of communication in the family, perceived economic status and school performance were identified as correlates of the insomnia complaints. A significant number of adolescents fail to receive appropriate treatment for insomnia. Psychosocial correlates are important factors to consider when faced with insomnia complaints in this age group. More research is needed in important timelines in the developmental history of a young adult.

Correlation between radiation-induced telomerase activity and human telomerase reverse transcriptase mRNA expression in HeLa cells

Purpose: To quantify and correlate human telomerase reverse transcriptase (hTERT) mRNA expression with telomerase activity (TA) after ionizing irradiation of HeLa cells. Materials and methods: TA and hTERT mRNA expression were evaluated, at 24-h intervals, in HeLa cells cultured for up to 144 h, before and after treatment with increasing doses of 6 MV photon ionizing radiation (5 – 20 Gy), using the telomeric repeat amplification protocol (TRAP) assay and real-time reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Cell viability was determined using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. A prototype phantom was constructed for accurate irradiation of HeLa cells. Results: Treated cells showed a decrease in viability with increasing radiation dose, and a correlation was observed with post-treatment period. TA and hTERT mRNA expression of HeLa cells increased for the first 24 h after irradiation. The maximal increases were approximately two times the un-irradiated cell levels at 24 h post-irradiation, followed by a decrease and a return to the control levels 72 h post-irradiation. The time-course of telomerase activation after 24 h, differed among radiation doses. A dose-dependent G2/M arrest was observed 24 h post-irradiation, along with an increase in polyploidy 48 h post-irradiation and afterwards. Conclusion: A correlation between TA and hTERT mRNA expression and a radiation induced cell cycle dependent modification of hTERT mRNA expression was established for the first 24 h post-irradiation.