A BAYESIAN APPROACH TO DOSE-RESPONSE ASSESSMENT AND DRUG-DRUG INTERACTION ANALYSIS: APPLICATION TO IN VITRO STUDIES

The considerable search for synergistic agents in cancer research is motivated by the therapeutic benefits achieved by combining anti-cancer agents. Synergistic agents make it possible to reduce dosage while maintaining or enhancing a desired effect. Other favorable outcomes of synergistic agents include reduction in toxicity and minimizing or delaying drug resistance. Dose-response assessment and drug-drug interaction analysis play an important part in the drug discovery process, however analysis are often poorly done. This dissertation is an effort to notably improve dose-response assessment and drug-drug interaction analysis. The most commonly used method in published analysis is the Median-Effect Principle/Combination Index method (Chou and Talalay, 1984). The Median-Effect Principle/Combination Index method leads to inefficiency by ignoring important sources of variation inherent in dose-response data and discarding data points that do not fit the Median-Effect Principle. Previous work has shown that the conventional method yields a high rate of false positives (Boik, Boik, Newman, 2008; Hennessey, Rosner, Bast, Chen, 2010) and, in some cases, low power to detect synergy. There is a great need for improving the current methodology. We developed a Bayesian framework for dose-response modeling and drug-drug interaction analysis. First, we developed a hierarchical meta-regression dose-response model that accounts for various sources of variation and uncertainty and allows one to incorporate knowledge from prior studies into the current analysis, thus offering a more efficient and reliable inference. Second, in the case that parametric dose-response models do not fit the data, we developed a practical and flexible nonparametric regression method for meta-analysis of independently repeated dose-response experiments. Third, and lastly, we developed a method, based on Loewe additivity that allows one to quantitatively assess interaction between two agents combined at a fixed dose ratio. The proposed method makes a comprehensive and honest account of uncertainty within drug interaction assessment. Extensive simulation studies show that the novel methodology improves the screening process of effective/synergistic agents and reduces the incidence of type I error. We consider an ovarian cancer cell line study that investigates the combined effect of DNA methylation inhibitors and histone deacetylation inhibitors in human ovarian cancer cell lines. The hypothesis is that the combination of DNA methylation inhibitors and histone deacetylation inhibitors will enhance antiproliferative activity in human ovarian cancer cell lines compared to treatment with each inhibitor alone. By applying the proposed Bayesian methodology, in vitro synergy was declared for DNA methylation inhibitor, 5-AZA-2'-deoxycytidine combined with one histone deacetylation inhibitor, suberoylanilide hydroxamic acid or trichostatin A in the cell lines HEY and SKOV3. This suggests potential new epigenetic therapies in cell growth inhibition of ovarian cancer cells.

Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats.

BACKGROUND: Methylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). METHODS: The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. RESULTS: Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% +/- 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% +/- 5.9% after 2.5 mg/kg MPD, and 56.5% +/- 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among these brain areas. CONCLUSION: These results suggest that an acute treatment of MPD produces electrophysiologically detectable alterations at the neuronal level, as well as observable, behavioral responses. The present study is the first to investigate the acute dose-response effects of MPD on behavior in terms of locomotor activity and in the brain involving the sensory inputs of VTA, NAc, and PFC neurons in intact, non-anesthetized, freely behaving rats previously implanted with permanent electrodes.

Acute and chronic methylphenidate dose-response assessment on three adolescent male rat strains.

Methylphenidate (MPD), commonly known as Ritalin, is the most frequently prescribed drug to treat children and adults with attention deficit hyperactivity disorder (ADHD). Adolescence is a period of development involving numerous neuroplasticities throughout the central nervous system (CNS). Exposure to a psychostimulant such as MPD during this crucial period of neurodevelopment may cause transient or permanent changes in the CNS. Genetic variability may also influence these differences. Thus, the objective of the present study was to determine whether acute and chronic administration of MPD (0.6, 2.5, or 10.0mg/kg, i.p.) elicit effects among adolescent WKY, SHR, and SD rats and to compare whether there were strain differences. An automated, computerized, open-field activity monitoring system was used to study the dose-response characteristics of acute and repeated MPD administration throughout the 11-day experimental protocol. Results showed that all three adolescent rat groups exhibited dose-response characteristics following acute and chronic MPD administration, as well as strain differences. These strain differences depended on the MPD dose and locomotor index. Chronic treatment of MPD in these animals did not elicit behavioral sensitization, a phenomenon described in adult rats that is characterized by the progressive augmentation of the locomotor response to repeated administration of the drug. These results suggest that the animal's age at time of drug treatment and strain/genetic variability play a crucial role in the acute and chronic effect of MPD and in the development of behavioral sensitization.

Improving the accuracy of radiation pneumonitis dose response models

The prognosis for lung cancer patients remains poor. Five year survival rates have been reported to be 15%. Studies have shown that dose escalation to the tumor can lead to better local control and subsequently better overall survival. However, dose to lung tumor is limited by normal tissue toxicity. The most prevalent thoracic toxicity is radiation pneumonitis. In order to determine a safe dose that can be delivered to the healthy lung, researchers have turned to mathematical models predicting the rate of radiation pneumonitis. However, these models rely on simple metrics based on the dose-volume histogram and are not yet accurate enough to be used for dose escalation trials. The purpose of this work was to improve the fit of predictive risk models for radiation pneumonitis and to show the dosimetric benefit of using the models to guide patient treatment planning. The study was divided into 3 specific aims. The first two specifics aims were focused on improving the fit of the predictive model. In Specific Aim 1 we incorporated information about the spatial location of the lung dose distribution into a predictive model. In Specific Aim 2 we incorporated ventilation-based functional information into a predictive pneumonitis model. In the third specific aim a proof of principle virtual simulation was performed where a model-determined limit was used to scale the prescription dose. The data showed that for our patient cohort, the fit of the model to the data was not improved by incorporating spatial information. Although we were not able to achieve a significant improvement in model fit using pre-treatment ventilation, we show some promising results indicating that ventilation imaging can provide useful information about lung function in lung cancer patients. The virtual simulation trial demonstrated that using a personalized lung dose limit derived from a predictive model will result in a different prescription than what was achieved with the clinically used plan; thus demonstrating the utility of a normal tissue toxicity model in personalizing the prescription dose.

A dose-response analysis of a school-based nutrition intervention in middle school children

Childhood obesity in the US has reached epidemic proportions. Minority children are affected the most by this epidemic. Although there is no clear relationship between obesity and fruits and vegetables consumption, studies suggest that eating fruits and vegetables could be helpful in preventing childhood obesity. A few school-based interventions targeting youth have been effective at increasing fruits and vegetables intake.^ In Austin, Texas, the Sustainable Food Center delivered the Sprouting Healthy Kids (SHK) program that targeted low socio-economic status children in four intervention middle schools. The SHK program delivered six intervention components. This school-based intervention included: a cafeteria component, in-class lessons, an after-school garden program, a field trip to a local farm, food tasting, and farmers' visits to schools. This study aimed to determine the effects of the SHK intervention in middle school students' preferences, motivation, knowledge, and self-efficacy towards fruits and vegetables intake, as well as the actual fruits and vegetables intake. The study also aimed to determine the effects of exposure to different doses of the SHK intervention on participants' fruits and vegetable intake.^ The SHK was delivered during Spring 2009. A total of 214 students completed the pre-and-posttest surveys measuring self-report fruits and vegetables intake as well as intrapersonal factors. The results showed that the school cafeteria, the food tasting, the after school program, and the farmers' visits had a positive effect on the participants' motivation, knowledge, and self-efficacy towards fruits and vegetables intake. The farmers' visits and the food tasting components increased participants' fruits and vegetables intake. Exposure to two or more intervention components increased participants' fruits and vegetables intake. The statistically significant dose-response effect size was .352, which suggests that each intervention component increased participants' fruits and vegetables consumption this amount. Certain intervention components were more effective than others. Food tasting and farmers visits increased participants fruits and vegetables intake, therefore these components should be offered in an ongoing basis. This study suggests that exposure to multiple intervention components increased behaviors and attitudes towards fruits and vegetables consumption. Findings are consistent that SHK can influence behaviors of middle school students.^

Monitoring of industrial exposure for chloracne

This study (1) established comedogenicity dose response curves for the pure compounds of 3,3$\sp\prime$,4,4$\sp\prime$-tetrachloroazobenzene (TCAB) and 3,3$\sp\prime$,4,4$\sp\prime$-tetrachloroazoxybenzene (TCAOB) individually and as a couple-compound using a rabbit ear model; (2) used a rabbit ear model to establish comedogenicity potential for TCAB and TCAOB as they existed in a given industrial herbicide manufacture process; (3) evaluated actual environmental contamination in a herbicide industrial setting by air monitoring and wipe sampling; (4) biologically monitored potentially exposed workers for alterations in follicular orifice size as an index of actual exposure to chloracnegenic compounds; and (5) biologically monitored potentially exposed workers for changes in weight, cholesterol, triglycerides and blood sugar.^ A silastic monomer mold (an objective measure) was used to measure change in follicular orifice size over time. This required taking impressions of (1) skin of the forehead and right and left malar crescents of workers and (2) the skin of the external ear of the rabbit. Molds were stained using a solution of hematoxylin and digitized using a Nikon UFX microscope (magnification 300 X), a drawing tube and a digitizing tablet attached to an IBM Personal Computer. Comedogenicity assays were used to establish dose-response curves for TCAB, TCAOB and the couple-compound TCAB + TCAOB.^ No evidence of chloracne or toxicity was observed in any of the workers. Nor, was there a statistically significant increase in size of follicular orifice means measured over time. This was attributed to extensive personal and environmental hygiene programs along with teaching the workers about chloracne, its cause and its prevention. These programs may have been the greatest factor in preventing the development of chloracne in this group of workers. Monitoring of the plant environment showed relatively high concentrations of the couple-compound (TCAB + TCAOB). Comedogenicity assays showed a linear dose-response relationship over time for TCAB, TCAOB and the couple-compound. An antagonistic action was found for the TCAB/TCAOB of the couple-compound; such action may provide some protection to workers in this type of setting. It is speculated that the observed antagonistic action may be due to the difference in binding affinities of TCAB/TCAOB for receptor sites. ^

Evidence for the role of agonist binding frequency in receptor -mediated activation of adenylate cyclase

$\beta$-adrenergic receptor-mediated activation of adenylate cyclase exhibits an agonist-specific separation between the dose/response curve (characterized by the EC$\sb{50}$) and the dose/binding curve (characterized by the K$\sb{\rm d}$). Cyclase activity can be near-maximal when receptor occupancy is quite low (EC$\sb{50}$ $\ll$ K$\sb{\rm d}$). This separation between the binding and response curves can be explained by the assumption that the rate of cyclase activation is proportional to the concentration of agonist-bound receptors, since the receptor is mobile and can activate more than one cyclase (the Collision Coupling Model of Tolkovsky and Levitzki). Here it is established that agonist binding frequency plays an additional role in adenylate cyclase activation in S49 murine lymphoma cells. Using epinephrine (EC$\sb{50}$ = 10 nM, K$\sb{\rm d}$ = 2 $\mu$M), the rate of cyclase activation decreased by 80% when a small (1.5%) receptor occupancy was restricted (by addition of the antagonist propranolol) to a small number (1.5%) of receptors rather than being proportionally distributed among the cell's entire population of receptors. Thus adenylate cyclase activity is not proportional to receptor occupancy in all circumstances. Collisions between receptor and cyclase pairs apparently occur a number of times in rapid sequence (an encounter); the high binding frequency of epinephrine ensures that discontiguous regions of the cell surface experience some period of agonist-bound receptor activity per small unit time minimizing "wasted" collisions between activated cyclase and bound receptor within an encounter. A contribution of agonist binding frequency to activation is thus possible when: (1) the mean lifetime of the agonist-receptor complex is shorter than the mean encounter time, and (2) the absolute efficiency (intrinsic ability to promote cyclase activation per collision) of the agonist-receptor complex is high. These conclusions are supported by experiments using agonists of different efficiencies and binding frequencies. These results are formalized in the Encounter Coupling Model of adenylate cyclase activation, which takes into explicit account the agonist binding frequency, agonist affinity for the $\beta$-adrenergic receptor, agonist efficiency, encounter frequency and the encounter time between receptor and cyclase. ^

The assumptions and effects of conservative procedures in low -dose risk assessment for setting safety standards

Conservative procedures in low-dose risk assessment are used to set safety standards for known or suspected carcinogens. However, the assumptions upon which the methods are based and the effects of these methods are not well understood.^ To minimize the number of false-negatives and to reduce the cost of bioassays, animals are given very high doses of potential carcinogens. Results must then be extrapolated to much smaller doses to set safety standards for risks such as one per million. There are a number of competing methods that add a conservative safety factor into these calculations.^ A method of quantifying the conservatism of these methods was described and tested on eight procedures used in setting low-dose safety standards. The results using these procedures were compared by computer simulation and by the use of data from a large scale animal study.^ The method consisted of determining a "true safe dose" (tsd) according to an assumed underlying model. If one assumed that Y = the probability of cancer = P(d), a known mathematical function of the dose, then by setting Y to some predetermined acceptable risk, one can solve for d, the model's "true safe dose".^ Simulations were generated, assuming a binomial distribution, for an artificial bioassay. The eight procedures were then used to determine a "virtual safe dose" (vsd) that estimates the tsd, assuming a risk of one per million. A ratio R = ((tsd-vsd)/vsd) was calculated for each "experiment" (simulation). The mean R of 500 simulations and the probability R $<$ 0 was used to measure the over and under conservatism of each procedure.^ The eight procedures included Weil's method, Hoel's method, the Mantel-Byran method, the improved Mantel-Byran, Gross's method, fitting a one-hit model, Crump's procedure, and applying Rai and Van Ryzin's method to a Weibull model.^ None of the procedures performed uniformly well for all types of dose-response curves. When the data were linear, the one-hit model, Hoel's method, or the Gross-Mantel method worked reasonably well. However, when the data were non-linear, these same methods were overly conservative. Crump's procedure and the Weibull model performed better in these situations. ^

Whence a healthy mind: Correlation of physical fitness and academic performance among schoolchildren

Background. Public schools are a key forum in the fight for child health because of the opportunities they present for physical activity and fitness surveillance. However, because schools are evaluated and funded on the basis of standardized academic performance rather than physical activity, empirical research evaluating the connections between fitness and academic performance is needed to justify curriculum allocations to physical activity. ^ Methods. Analyses were based on a convenience sample of 315,092 individually-matched standardized academic (TAKS™) and fitness (FITNESSGRAM®) test records collected by 13 Texas school districts under state mandates. We categorized each fitness result in quintiles by age and gender and used a mixed effects regression model to compare the academic performance of the top and bottom fitness groups for each fitness test and grade level combination. ^ Results. All fitness variables except BMI showed significant, positive associations with academic performance after sociodemographic covariate adjustments, with effect sizes ranging from 0.07 (95% CI: 0.05,0.08) in girls trunklift-TAKS reading to 0.34 (0.32,0.35) in boys cardiovascular-TAKS math. Cardiovascular fitness showed the largest inter-quintile difference in TAKS score (32-75 points), followed by curl-ups. After an additional adjustment for BMI and curl-ups, cardiovascular associations peaked in 8th-9 th grades (maximum inter-quintile difference 142 TAKS points; effect size 0.75 (0.69,0.82) for 8th grade girls math) and showed dose-response characteristics across quintiles (p<0.001 for both genders and outcomes). BMI analysis demonstrated limited, non-linear association with academic performance after adjustment for sociodemographic, cardiovascular fitness and curl-up variables. Low-BMI Hispanic high school boys showed significantly lower TAKS scores than the moderate (but not high) BMI group. High-BMI non-Hispanic white high school girls showed significantly lower scores than the moderate (but not low) BMI group. ^ Conclusions. In this study, fitness was strongly and significantly related to academic performance. Cardiovascular fitness showed a distinct dose-response association with academic performance independent of other sociodemographic and fitness variables. The association peaked in late middle to early high school. The independent association of BMI to academic performance was only found in two sub-groups and was non-linear, with both low and high BMI posing risk relative to moderate BMI but not to each other. In light of our findings, we recommend that policymakers consider PE mandates in middle-high school and require linkage of academic and fitness records to facilitate longitudinal surveillance. School administrators should consider increasing PE time in pursuit of higher academic test scores, and PE practitioners should emphasize cardiovascular fitness over BMI reduction.^

The role of serotonin in depression and clotting in the coronary artery disease population

Background: The mechanisms underlying the relationship between depression and acute coronary syndrome (ACS) remain unclear. Platelet serotonin has been associated with both depression and coronary artery disease in stable outpatients. Understanding the association between depression and platelet serotonin, during ACS, may explain some of the acute cardiovascular events seen in some individuals with depression. ^ Objectives: This study was designed to evaluate whether levels of platelet serotonin, during ACS, differ between individuals who screen positive for depression and individuals who screen negative for depression and to determine if a dose-response relationship exists between depressive symptoms and platelet serotonin levels. ^ Methods: In this cross-sectional study, data was collected on 51 patients hospitalized for ACS. Multiple linear regression models were used to determine if a relationship exists between depression and platelet serotonin levels. ^ Results: Of the 51 ACS patients, 24 screened positive for depression and 27 screened negative for depression. Platelet serotonin levels were not significantly different between the depressed group (942.10 ± 461.3) and the non-depressed group (1192.41 ± 764.3) (p= .293 and β= -4.093) and a dose-response relationship between depressive symptoms and platelet serotonin levels was not found (p= .250 and β= -.254). ^ Discussion: In this study, a relationship between depression and platelet serotonin levels was not found. Future research should focus on gaining a better understanding of the variables that may influence platelet serotonin levels in the ACS population. ^

Evaluation of Polymer Gel Dosimeters for Measurements of Dose and LET in Proton Beams

This project assessed the effectiveness of polymer gel dosimeters as tools for measuring the dose deposited by and LET of a proton beam. A total of three BANG® dosimeter formulations were evaluated: BANG®-3-Pro-2 BANGkits™ for dose measurement and two BANG®-3 variants, the LET-Baseline and LET-Meter dosimeters, for LET measurement. All dosimeters were read out using an OCT scanner. The basic characteristics of the BANGkits™ were assessed in a series of photon and electron irradiations. The dose-response relationship was found to be sigmoidal with a threshold for response of approximately 15 cGy. The active region of the dosimeter, the volume in which dosimeter response is not inhibited by oxygen, was found to make up roughly one fourth of the total dosimeter volume. Delivering a dose across multiple fractions was found to yield a greater response than delivering the same dose in a single irradiation. The dosimeter was found to accurately measure a dose distribution produced by overlapping photon fields, yielding gamma pass rates of 95.4% and 93.1% from two planar gamma analyses. Proton irradiations were performed for measurements of proton dose and LET. Initial irradiations performed through the side of a dosimeter led to OCT artifacts. Gamma pass rates of 85.7% and 89.9% were observed in two planar gamma analyses. In irradiations performed through the base of a dosimeter, gel response was found to increase with height in the dosimeter, even in areas of constant dose. After a correction was applied, gamma pass rates of 94.6% and 99.3% were observed in two planar gamma analyses. Absolute dose measurements were substantially higher (33%-100%) than the delivered doses for proton irradiations. Issues encountered while calibrating the LET-Meter gel restricted analysis of the LET measurement data to the SOBP of a proton beam. LET-Meter overresponse was found to increase linearly with track-average LET across the LET range that could be investigated (1.5 keV/micron – 3.5 keV/micron).

Evaluation of PRESAGE® dosimeters for brachytherapy sources and the 3D dosimetry and characterization of the new AgX100 125I seed model

With continuous new improvements in brachytherapy source designs and techniques, method of 3D dosimetry for treatment dose verifications would better ensure accurate patient radiotherapy treatment. This study was aimed to first evaluate the 3D dose distributions of the low-dose rate (LDR) Amersham 6711 OncoseedTM using PRESAGE® dosimeters to establish PRESAGE® as a suitable brachytherapy dosimeter. The new AgX100 125I seed model (Theragenics Corporation) was then characterized using PRESAGE® following the TG-43 protocol. PRESAGE® dosimeters are solid, polyurethane-based, 3D dosimeters doped with radiochromic leuco dyes that produce a linear optical density response to radiation dose. For this project, the radiochromic response in PRESAGE® was captured using optical-CT scanning (632 nm) and the final 3D dose matrix was reconstructed using the MATLAB software. An Amersham 6711 seed with an air-kerma strength of approximately 9 U was used to irradiate two dosimeters to 2 Gy and 11 Gy at 1 cm to evaluate dose rates in the r=1 cm to r=5 cm region. The dosimetry parameters were compared to the values published in the updated AAPM Report No. 51 (TG-43U1). An AgX100 seed with an air-kerma strength of about 6 U was used to irradiate two dosimeters to 3.6 Gy and 12.5 Gy at 1 cm. The dosimetry parameters for the AgX100 were compared to the values measured from previous Monte-Carlo and experimental studies. In general, the measured dose rate constant, anisotropy function, and radial dose function for the Amersham 6711 showed agreements better than 5% compared to consensus values in the r=1 to r=3 cm region. The dose rates and radial dose functions measured for the AgX100 agreed with the MCNPX and TLD-measured values within 3% in the r=1 to r=3 cm region. The measured anisotropy function in PRESAGE® showed relative differences of up to 9% with the MCNPX calculated values. It was determined that post-irradiation optical density change over several days was non-linear in different dose regions, and therefore the dose values in the r=4 to r=5 cm regions had higher uncertainty due to this effect. This study demonstrated that within the radial distance of 3 cm, brachytherapy dosimetry in PRESAGE® can be accurate within 5% as long as irradiation times are within 48 hours.

Simulation of Drosophila circadian oscillations, mutations, and light responses by a model with VRI, PDP-1, and CLK.

A model of Drosophila circadian rhythm generation was developed to represent feedback loops based on transcriptional regulation of per, Clk (dclock), Pdp-1, and vri (vrille). The model postulates that histone acetylation kinetics make transcriptional activation a nonlinear function of [CLK]. Such a nonlinearity is essential to simulate robust circadian oscillations of transcription in our model and in previous models. Simulations suggest that two positive feedback loops involving Clk are not essential for oscillations, because oscillations of [PER] were preserved when Clk, vri, or Pdp-1 expression was fixed. However, eliminating positive feedback by fixing vri expression altered the oscillation period. Eliminating the negative feedback loop in which PER represses per expression abolished oscillations. Simulations of per or Clk null mutations, of per overexpression, and of vri, Clk, or Pdp-1 heterozygous null mutations altered model behavior in ways similar to experimental data. The model simulated a photic phase-response curve resembling experimental curves, and oscillations entrained to simulated light-dark cycles. Temperature compensation of oscillation period could be simulated if temperature elevation slowed PER nuclear entry or PER phosphorylation. The model makes experimental predictions, some of which could be tested in transgenic Drosophila.

IMPROVING QUANTITATIVE TREATMENT RESPONSE MONITORING WITH DEFORMABLE IMAGE REGISTRATION

Quantitative imaging with 18F-FDG PET/CT has the potential to provide an in vivo assessment of response to radiotherapy (RT). However, comparing tissue tracer uptake in longitudinal studies is often confounded by variations in patient setup and potential treatment induced gross anatomic changes. These variations make true response monitoring for the same anatomic volume a challenge, not only for tumors, but also for normal organs-at-risk (OAR). The central hypothesis of this study is that more accurate image registration will lead to improved quantitation of tissue response to RT with 18F-FDG PET/CT. Employing an in-house developed “demons” based deformable image registration algorithm, pre-RT tumor and parotid gland volumes can be more accurately mapped to serial functional images. To test the hypothesis, specific aim 1 was designed to analyze whether deformably mapping tumor volumes rather than aligning to bony structures leads to superior tumor response assessment. We found that deformable mapping of the most metabolically avid regions improved response prediction (P<0.05). The positive predictive power for residual disease was 63% compared to 50% for contrast enhanced post-RT CT. Specific aim 2 was designed to use parotid gland standardized uptake value (SUV) as an objective imaging biomarker for salivary toxicity. We found that relative change in parotid gland SUV correlated strongly with salivary toxicity as defined by the RTOG/EORTC late effects analytic scale (Spearman’s ρ = -0.96, P<0.01). Finally, the goal of specific aim 3 was to create a phenomenological dose-SUV response model for the human parotid glands. Utilizing only baseline metabolic function and the planned dose distribution, predicting parotid SUV change or salivary toxicity, based upon specific aim 2, became possible. We found that the predicted and observed parotid SUV relative changes were significantly correlated (Spearman’s ρ = 0.94, P<0.01). The application of deformable image registration to quantitative treatment response monitoring with 18F-FDG PET/CT could have a profound impact on patient management. Accurate and early identification of residual disease may allow for more timely intervention, while the ability to quantify and predict toxicity of normal OAR might permit individualized refinement of radiation treatment plan designs.

THE CALIBRATION AND IMPLEMENTATION OF CR-39 NUCLEAR TRACK DETECTOR MATERIAL AS A FAST NEUTRON MICRODOSIMETER

A detailed microdosimetric characterization of the M. D. Anderson 42 MeV (p,Be) fast neutron beam was performed using the techniques of microdosimetry and a 1/2 inch diameter Rossi proportional counter. These measurements were performed at 5, 15, and 30 cm depths on the central axis, 3 cm inside, and 3 cm outside the field edge for 10 $\times$ 10 and 20 $\times$ 20 cm field sizes. Spectra were also measured at 5 and 15 cm depth on central axis for a 6 $\times$ 6 cm field size. Continuous slowing down approximation calculations were performed to model the nuclear processes that occur in the fast neutron beam. Irradiation of the CR-39 was performed using a tandem electrostatic accelerator for protons of 10, 6, and 3 MeV and alpha particles of 15, 10, and 7 MeV incident energy on target at angles of incidence from 0 to 85 degrees. The critical angle as well as track etch rate and normal incidence diameter versus linear energy transfer (LET) were obtained from these measurements. The bulk etch rate was also calculated from these measurements. Dose response of the material was studied, and the angular distribution of charged particles created by the fast neutron beam was measured with CR-39. The efficiency of CR-39 was calculated versus that of the Rossi chamber, and an algorithm was devised for derivation of LET spectra from the major and minor axis dimensions of the observed tracks. The CR-39 was irradiated in the same positions as the Rossi chamber, and the derived spectra were compared directly. ^