Optimization of the primary collimator settings for fractionated IMRT stereotactic radiotherapy.

Advances in field-shaping techniques for stereotactic radiosurgery/radiotherapy have allowed dynamic adjustment of field shape with gantry rotation (dynamic conformal arc) in an effort to minimize dose to critical structures. Recent work evaluated the potential for increased sparing of dose to normal tissues when the primary collimator setting is optimized to only the size necessary to cover the largest shape of the dynamic micro multi leaf field. Intensity-modulated radiotherapy (IMRT) is now a treatment option for patients receiving stereotactic radiotherapy treatments. This multisegmentation of the dose delivered through multiple fixed treatment fields provides for delivery of uniform dose to the tumor volume while allowing sparing of critical structures, particularly for patients whose tumor volumes are less suited for rotational treatment. For these segmented fields, the total number of monitor units (MUs) delivered may be much greater than the number of MUs required if dose delivery occurred through an unmodulated treatment field. As a result, undesired dose delivered, as leakage through the leaves to tissues outside the area of interest, will be proportionally increased. This work will evaluate the role of optimization of the primary collimator setting for these IMRT treatment fields, and compare these results to treatment fields where the primary collimator settings have not been optimized.     

Metabolism of MK-0524, a prostaglandin D2 receptor 1 antagonist, in microsomes and hepatocytes from preclinical species and humans.

(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The major in vitro and in vivo metabolite of MK-0524 is the acyl glucuronic acid conjugate of the parent compound, M2. To compare metabolism of MK-0524 across preclinical species and humans, studies were undertaken to determine the in vitro kinetic parameters (K(m) and V(max)) for the glucuronidation of MK-0524 in Sprague-Dawley rat, beagle dog, cynomolgus monkey, and human liver microsomes, human intestinal microsomes, and in recombinant human UDP glucuronosyltransferases (UGT). A comparison of K(m) values indicated that UGT1A9 has the potential to catalyze the glucuronidation of MK-0524 in the liver, whereas UGT1A3 and UGT2B7 have the potential to catalyze the glucuronidation in the intestine. MK-0524 also was subject to phase I oxidative metabolism; however, the rate was significantly lower than that of glucuronidation. The rate of phase I metabolism was ranked as follows: rat approximately monkey > human intestine > dog > human liver with qualitatively similar metabolite profiles across species. In all the cases, the major metabolites were the monohydroxylated epimers (M1 and M4) and the keto-metabolite, M3. Use of inhibitory monoclonal antibodies and recombinant human cytochromes P450 suggested that CYP3A4 was the major isozyme involved in the oxidative metabolism of MK-0524, with a minor contribution from CYP2C9. The major metabolite in hepatocyte preparations was the acyl glucuronide, M2, with minor amounts of M1, M3, M4, and their corresponding glucuronides. Overall, the in vivo metabolism of MK-0524 is expected to proceed via glucuronidation, with minor contributions from oxidative pathways.     

Synthesis of [14C] ‐ and [13C6]‐labeled tipranavir and its potential hydroxyl metabolite and the glucuronide conjugate

Tipranavir or Aptivus^® is a non‐peptidic protease inhibitor approved for the combination treatment with ritonavir of HIV infection. Tipranavir labeled with radioactive and stable isotopes of carbon was required for drug metabolism (excretion, distribution, and absorption) studies and to develop bioanalytical methods needed for the support of clinical studies. [7‐¹⁴C]‐Benzoic acid and uniformly labeled benzoic acid (ring‐¹³C₆ 99 at% ¹³C) were used to prepare [¹⁴C]‐ and [¹³C₆]‐labeled tipranavir, respectively. Radioactively labeled tipranavir was prepared with a specific activity of 54 mCi/mmol (2GBq/mmol); it was necessary to dilute its specific activity with unlabeled tipranavir to 28 mCi/mmol (46.45 µCi/mg) because of its instability. The N‐hydroxyl metabolite (12) and the glucuronide conjugate (13), the most abundant metabolites of tipranavir (when administered in conjunction with ritonavir) were also synthesized. Copyright © 2008 John Wiley & Sons, Ltd.     

Attenuation smear: A ‘paradoxical’ increase in counts due to attenuation artifact

Background: Attenuation is a well recognized cause of reconstruction artifacts in SPECT imaging. Occasionally, we have noted an increase in activity extending from the apical septal portion of the ventricle in women with significant breast attenuation. Although the idea that attenuation can produce an increase in activity on the reconstructed images seems paradoxical at first, it is consistent with the process of filtered back projection. Methods: We filled a cardiac phantom with 1 mCi of Technetium-99m, placed it in a water filled anthropomorphic torso phantom and imaged it over a 180° orbit. Next, a breast phantom designed to simulate a significant degree of breast attenuation was placed on the torso phantom and imaging was repeated. The images were reconstructed first using conventional filtered back projection then with maximum likelihood. Results: When the phantoms with and without breast attenuation were reconstructed using filtered back projection and compared, the phantom with breast attenuation had a large smear of activity extending anteriorly from the apical septal wall which was very similar to the abnormalities previously noted in clinical images; the phantom without breast attenuation had no such defect. This artifact was significantly less prominent when the images were reconstructed using the maximum likelihood technique. Conclusions: Attenuation artifact can also produce a seemingly paradoxical increase in counts on the reconstructed image but this phenomenon is consistent with the workings of filtered back projection.     

Follow-up study of anxiety disorder and alcohol dependence in comorbid alcoholism treatment patients

BACKGROUND: Anxiety disorders are present in a high percentage of alcoholism treatment patients. We tested the prediction that having a comorbid anxiety disorder increases the prospective risk for relapse to drinking after alcoholism treatment. We also explored the prospective associations of specific anxiety syndromes (and depression) with drinking and anxiety outcomes. METHODS: We assessed the diagnostic status and daily drinking patterns of 82 individuals approximately one week after they entered alcoholism treatment (baseline) and again approximately 120 days later (follow-up) (n=53). RESULTS: Consistent with study predictions, those with a baseline anxiety disorder (approximately 55%) were significantly more likely than others to meet various definitions of drinking relapse over the course of the follow-up. Regression models showed that baseline social phobia was the single best predictor of a return to any drinking after treatment, whereas panic disorder was the single best predictor of a relapse to alcohol dependence after treatment. Having multiple anxiety disorders (versus any specific anxiety disorder) at the baseline was the strongest predictor of having at least one active ("persistent") anxiety disorder at the follow-up. Cross-sectional analysis at the follow-up showed that anxiety disorder persisted in the absence of a relapse to alcohol dependence far more often than relapse to alcohol dependence occurred in the absence of a persistent anxiety disorder. CONCLUSIONS: Screening for comorbid anxiety disorder in alcoholism treatment patients is warranted and, where found, should be considered a marker of high relapse risk relative to that of noncomorbid patients. The capacity of specific anxiety treatment to mitigate relapse risk among comorbid patients remains an open question.     

Evolutionary robotics: a new scientific tool for studying cognition

We survey developments in artificial neural networks, in behavior-based robotics, and in evolutionary algorithms that set the stage for evolutionary robotics (ER) in the 1990s. We examine the motivations for using ER as a scientific tool for studying minimal models of cognition, with the advantage of being capable of generating integrated sensorimotor systems with minimal (or controllable) prejudices. These systems must act as a whole in close coupling with their environments, which is an essential aspect of real cognition that is often either bypassed or modeled poorly in other disciplines. We demonstrate with three example studies: homeostasis under visual inversion, the origins of learning, and the ontogenetic acquisition of entrainment.     

Predictors of lung cancer among asbestos-exposed men in the {beta}-carotene and retinol efficacy trial

Despite numerous published studies, debate continues regarding the risk of developing lung cancer among men exposed occupationally to asbestos, particularly those without radiographic or functional evidence of asbestosis. The beta-Carotene and Retinol Efficacy Trial (CARET), a study of vitamin supplementation for chemoprevention of lung cancer, has followed 4,060 heavily exposed US men for 9-17 years. Lung cancer incidence for 1989-2002 was analyzed using a stratified proportional hazards model. The study confirmed excessive rates of lung cancer among men with radiographic asbestosis. Comparison of study arms revealed a strong, unanticipated synergy between radiographic profusion category and the active intervention. In the large subgroup of men with normal lung parenchyma on chest radiograph at baseline, there was evidence of exposure-related lung cancer risk: Men with more than 40 years' exposure in high-risk trades had a risk approximately fivefold higher than men with 5-10 years, after adjustment for covariates. The effect in these men was independent of study intervention arm, but pleural plaques on the baseline radiograph and abnormal baseline flow rate were strong independent predictors of subsequent lung cancer. Residual confounding by subclinical asbestosis, exposure to unmeasured lung carcinogens, or differences in smoking are unlikely to explain these observations better than a carcinogenic effect of asbestos per se.     

Video-assisted surgery represents more than a loss of three-dimensional vision

BACKGROUND: Loss of depth cues is a major challenge facing surgeons performing video-assisted surgery (VAS). Whether the degradation of image quality from a video-displayed image plays a direct role in performance of VAS has not been studied. METHODS: Twenty-four volunteer novice subjects were randomized to binocular direct-vision (BDV), monocular direct-vision (MDV), or video-imaging (VI) conditions. Each subject completed ten trials of a simple cutting task in a box trainer using standard laparoscopic instruments. RESULTS: VI subjects made significantly fewer correct incisions than both of the other groups for all trials. Differences between the BDV and MDV groups did not reach statistical significance. Improvement in performance was more rapid in the BDV group than in either the MDV or VI groups. CONCLUSIONS: The degradation of image quality with VI has a detrimental influence on VAS performance above and beyond the loss of binocular vision.