Assessment of different patient-to-phantom matching criteria applied in Monte Carlo-based computed tomography dosimetry.

PURPOSE: To quantify differences in computationally estimated computed tomography (CT) organ doses for patient-specific voxel phantoms to estimated organ doses in matched computational phantoms using different matching criteria. MATERIALS AND METHODS: Fifty-two patient-specific computational voxel phantoms were created through CT image segmentation. In addition, each patient-specific phantom was matched to six computational phantoms of the same gender based, respectively, on age and gender (reference phantoms), height and weight, effective diameter (both central slice and exam range average), and water equivalent diameter (both central slice and exam range average). Each patient-specific phantom and matched computational phantom were then used to simulate six different torso examinations using a previously validated Monte Carlo CT dosimetry methodology that accounts for tube current modulation. Organ doses for each patient-specific phantom were then compared with the organ dose estimates of each of the matched phantoms. RESULTS: Relative to the corresponding patient-specific phantoms, the root mean square of the difference in organ dose was 39.1%, 20.3%, 22.7%, 21.6%, 20.5%, and 17.6%, for reference, height and weight, effective diameter (central slice and scan average), and water equivalent diameter (central slice and scan average), respectively. The average magnitude of difference in organ dose was 24%, 14%, 16.9%, 16.2%, 14%, and 11.9%, respectively. CONCLUSION: Overall, these data suggest that matching a patient to a computational phantom in a library is superior to matching to a reference phantom. Water equivalent diameter is the superior matching metric, but it is less feasible to implement in a clinical and retrospective setting. For these reasons, height-and-weight matching is an acceptable and reliable method for matching a patient to a member of a computational phantom library with regard to CT dosimetry.

Physical validation of a Monte Carlo-based, phantom-derived approach to computed tomography organ dosimetry under tube current modulation.

PURPOSE: To physically validate the accuracy of a Monte Carlo-based, phantom-derived methodology for computed tomography (CT) dosimetry that utilizes organ doses from precomputed axial scans and that accounts for tube current modulation (TCM). METHODS: The output of a Toshiba Aquilion ONE CT scanner was modeled, based on physical measurement, in the Monte Carlo radiation transport code MCNPX (v2.70). CT examinations were taken of two anthropomorphic phantoms representing pediatric and adult patients (15-yr-old female and adult male) at various energies, in which physical organ dose measurements were made using optically stimulated luminescence dosimeters (OSLDs). These exams (chest-abdomen-pelvis) were modeled using organ dose data obtained from the computationally equivalent phantom of each anthropomorphic phantom. TCM was accounted for by weighting all organ dose contributions by both the relative attenuation of the phantom and the image-derived mA value (from the DICOM header) at the same z-extent (cranial-caudal direction) of the axial dose data. RESULTS: The root mean squares of percent difference in organ dose when comparing the physical organ dose measurements to the computational estimates were 21.2, 12.1, and 15.1% for the uniform (no attenuation weighting), weighted (computationally derived), and image-based methodologies, respectively. CONCLUSIONS: Overall, these data suggest that the Monte Carlo-based dosimetry presented in this work is viable for CT dosimetry. Additionally, for CT exams with TCM, local attenuation weighting of organ dose contributions from precomputed axial dosimetry libraries increases organ dose accuracy.

VirtualDose: a software for reporting organ doses from CT for adult and pediatric patients.

This paper describes the development and testing of VirtualDose--a software for reporting organ doses for adult and pediatric patients who undergo x-ray computed tomography (CT) examinations. The software is based on a comprehensive database of organ doses derived from Monte Carlo (MC) simulations involving a library of 25 anatomically realistic phantoms that represent patients of different ages, body sizes, body masses, and pregnant stages. Models of GE Lightspeed Pro 16 and Siemens SOMATOM Sensation 16 scanners were carefully validated for use in MC dose calculations. The software framework is designed with the 'software as a service (SaaS)' delivery concept under which multiple clients can access the web-based interface simultaneously from any computer without having to install software locally. The RESTful web service API also allows a third-party picture archiving and communication system software package to seamlessly integrate with VirtualDose's functions. Software testing showed that VirtualDose was compatible with numerous operating systems including Windows, Linux, Apple OS X, and mobile and portable devices. The organ doses from VirtualDose were compared against those reported by CT-Expo and ImPACT-two dosimetry tools that were based on the stylized pediatric and adult patient models that were known to be anatomically simple. The organ doses reported by VirtualDose differed from those reported by CT-Expo and ImPACT by as much as 300% in some of the patient models. These results confirm the conclusion from past studies that differences in anatomical realism offered by stylized and voxel phantoms have caused significant discrepancies in CT dose estimations.

The UF/NCI family of hybrid computational phantoms representing the current US population of male and female children, adolescents, and adults--application to CT dosimetry.

Substantial increases in pediatric and adult obesity in the US have prompted a major revision to the current UF/NCI (University of Florida/National Cancer Institute) family of hybrid computational phantoms to more accurately reflect current trends in larger body morphometry. A decision was made to construct the new library in a gridded fashion by height/weight without further reference to age-dependent weight/height percentiles as these become quickly outdated. At each height/weight combination, circumferential parameters were defined and used for phantom construction. All morphometric data for the new library were taken from the CDC NHANES survey data over the time period 1999-2006, the most recent reported survey period. A subset of the phantom library was then used in a CT organ dose sensitivity study to examine the degree to which body morphometry influences the magnitude of organ doses for patients that are underweight to morbidly obese in body size. Using primary and secondary morphometric parameters, grids containing 100 adult male height/weight bins, 93 adult female height/weight bins, 85 pediatric male height/weight bins and 73 pediatric female height/weight bins were constructed. These grids served as the blueprints for construction of a comprehensive library of patient-dependent phantoms containing 351 computational phantoms. At a given phantom standing height, normalized CT organ doses were shown to linearly decrease with increasing phantom BMI for pediatric males, while curvilinear decreases in organ dose were shown with increasing phantom BMI for adult females. These results suggest that one very useful application of the phantom library would be the construction of a pre-computed dose library for CT imaging as needed for patient dose-tracking.

Diagnostic and prognostic significance of CD200 expression and its stability in plasma cell myeloma.

AIM: Previous studies showed that CD200 expression is a prognostic factor for plasma cell myeloma (PCM), but the prognostic effect is conflicting between studies. We studied CD200 protein expression and the stability of expression in PCM to clarify its potential utility in diagnosis, prognosis and monitoring of disease. METHOD: CD200 expression was studied in 77 cases of PCM by immunohistochemistry on paraffin sections from decalcified bone marrow biopsies. RESULT: There were 16 newly diagnosed cases and 61 post-treatment cases from 54 patients: 37 men and 17 women, with a median age of 62 years (range, 41­88 years). CD200 demonstrated moderate to strong membrane expression in positive cases. Fifty-six of 77 cases (73%) showed CD200 expression. Twenty of the 22 (91%) patients with serial specimens demonstrated stable CD200 expression (n=15) or lack of CD200 expression (n=5). One patient lost CD200 expression, while another one gained CD200 expression during treatment. The clinical, pathologic and cytogenetic features between the CD200+ group and the CD200− group were similar in most instances. However, CD200 expression was associated with lower serum ß2-microglobulin (p=0.03). There was no significant difference in overall survival and progression-free survival between the CD200+ and CD200− patients (p>0.05). CONCLUSIONS: CD200 is expressed in a majority of PCM cases, and the expression is stable during the treatment process. Therefore, immunohistochemical expression of CD200 is a useful marker for the diagnosis and follow-up of PCM.

Monte Carlo simulations of adult and pediatric computed tomography exams: validation studies of organ doses with physical phantoms.

PURPOSE: To validate the accuracy of a Monte Carlo source model of the Siemens SOMATOM Sensation 16 CT scanner using organ doses measured in physical anthropomorphic phantoms. METHODS: The x-ray output of the Siemens SOMATOM Sensation 16 multidetector CT scanner was simulated within the Monte Carlo radiation transport code, MCNPX version 2.6. The resulting source model was able to perform various simulated axial and helical computed tomographic (CT) scans of varying scan parameters, including beam energy, filtration, pitch, and beam collimation. Two custom-built anthropomorphic phantoms were used to take dose measurements on the CT scanner: an adult male and a 9-month-old. The adult male is a physical replica of the University of Florida reference adult male hybrid computational phantom, while the 9-month-old is a replica of the University of Florida Series B 9-month-old voxel computational phantom. Each phantom underwent a series of axial and helical CT scans, during which organ doses were measured using fiber-optic coupled plastic scintillator dosimeters developed at the University of Florida. The physical setup was reproduced and simulated in MCNPX using the CT source model and the computational phantoms upon which the anthropomorphic phantoms were constructed. Average organ doses were then calculated based upon these MCNPX results. RESULTS: For all CT scans, good agreement was seen between measured and simulated organ doses. For the adult male, the percent differences were within 16% for axial scans, and within 18% for helical scans. For the 9-month-old, the percent differences were all within 15% for both the axial and helical scans. These results are comparable to previously published validation studies using GE scanners and commercially available anthropomorphic phantoms. CONCLUSIONS: Overall results of this study show that the Monte Carlo source model can be used to accurately and reliably calculate organ doses for patients undergoing a variety of axial or helical CT examinations on the Siemens SOMATOM Sensation 16 scanner.

Organ doses for reference pediatric and adolescent patients undergoing computed tomography estimated by Monte Carlo simulation.

PURPOSE: To establish an organ dose database for pediatric and adolescent reference individuals undergoing computed tomography (CT) examinations by using Monte Carlo simulation. The data will permit rapid estimates of organ and effective doses for patients of different age, gender, examination type, and CT scanner model. METHODS: The Monte Carlo simulation model of a Siemens Sensation 16 CT scanner previously published was employed as a base CT scanner model. A set of absorbed doses for 33 organs∕tissues normalized to the product of 100 mAs and CTDI(vol) (mGy∕100 mAs mGy) was established by coupling the CT scanner model with age-dependent reference pediatric hybrid phantoms. A series of single axial scans from the top of head to the feet of the phantoms was performed at a slice thickness of 10 mm, and at tube potentials of 80, 100, and 120 kVp. Using the established CTDI(vol)- and 100 mAs-normalized dose matrix, organ doses for different pediatric phantoms undergoing head, chest, abdomen-pelvis, and chest-abdomen-pelvis (CAP) scans with the Siemens Sensation 16 scanner were estimated and analyzed. The results were then compared with the values obtained from three independent published methods: CT-Expo software, organ dose for abdominal CT scan derived empirically from patient abdominal circumference, and effective dose per dose-length product (DLP). RESULTS: Organ and effective doses were calculated and normalized to 100 mAs and CTDI(vol) for different CT examinations. At the same technical setting, dose to the organs, which were entirely included in the CT beam coverage, were higher by from 40 to 80% for newborn phantoms compared to those of 15-year phantoms. An increase of tube potential from 80 to 120 kVp resulted in 2.5-2.9-fold greater brain dose for head scans. The results from this study were compared with three different published studies and∕or techniques. First, organ doses were compared to those given by CT-Expo which revealed dose differences up to several-fold when organs were partially included in the scan coverage. Second, selected organ doses from our calculations agreed to within 20% of values derived from empirical formulae based upon measured patient abdominal circumference. Third, the existing DLP-to-effective dose conversion coefficients tended to be smaller than values given in the present study for all examinations except head scans. CONCLUSIONS: A comprehensive organ∕effective dose database was established to readily calculate doses for given patients undergoing different CT examinations. The comparisons of our results with the existing studies highlight that use of hybrid phantoms with realistic anatomy is important to improve the accuracy of CT organ dosimetry. The comprehensive pediatric dose data developed here are the first organ-specific pediatric CT scan database based on the realistic pediatric hybrid phantoms which are compliant with the reference data from the International Commission on Radiological Protection (ICRP). The organ dose database is being coupled with an adult organ dose database recently published as part of the development of a user-friendly computer program enabling rapid estimates of organ and effective dose doses for patients of any age, gender, examination types, and CT scanner model.

Pharmacologic antagonism of the oral aversive taste-directed response to capsaicin in a mouse brief access taste aversion assay.

Chemosensory signaling by the tongue is a primary determinant of ingestive behavior and is mediated by specific interactions between tastant molecules and G protein-coupled and ion channel receptors. The functional relationship between tastant and receptor should be amenable to pharmacologic methods and manipulation. We have performed a pharmacologic characterization of the taste-directed licking of mice presented with solutions of capsaicin and other transient receptor potential vanilloid-1 (TRPV1) agonists using a brief access taste aversion assay. Dose-response functions for lick-rate suppression were established for capsaicin (EC(50) = 0.5 microM), piperine (EC(50) = 2 muM), and resiniferatoxin (EC(50) = 0.02 microM). Little or no effect on lick rate was observed in response to the full TRPV1 agonist olvanil. Capsaicin lick rates of wild-type and transient receptor potential melastatin-5 (TRPM5) knockout mice were equivalent, indicating that TRPM5, a critical component of aversive signaling for many bitter tastants, did not contribute to the capsaicin taste response. The selective TRPV1 antagonists N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (10 microM) and (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (AMG9810) (10 microM) effectively blocked capsaicin- and piperine-mediated lick suppression. However, (E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)-N-phenylprop-2-enamide (SB 366791) and capsazepine, also TRPV1 antagonists, were without effect at test concentrations of up to 30 and 100 microM, respectively. Our results demonstrate that TRPV1-mediated oral aversiveness presents a pharmacologic profile differing from what has been reported previously for TRPV1 pain signaling and, furthermore, that aversive tastes can be evaluated and controlled pharmacologically.

TRPV1: contribution to retinal ganglion cell apoptosis and increased intracellular Ca2+ with exposure to hydrostatic pressure.

PURPOSE: Elevated hydrostatic pressure induces retinal ganglion cell (RGC) apoptosis in culture. The authors investigated whether the transient receptor potential vanilloid 1 (TRPV1) channel, which contributes to pressure sensing and Ca(2+)-dependent cell death in other systems, also contributes to pressure-induced RGC death and whether this contribution involves Ca(2+). METHODS: trpv1 mRNA expression in RGCs was probed with the use of PCR and TRPV1 protein localization through immunocytochemistry. Subunit-specific antagonism (iodo-resiniferatoxin) and agonism (capsaicin) were used to probe how TRPV1 activation affects the survival of isolated RGCs at ambient and elevated hydrostatic pressure (+70 mm Hg). Finally, for RGCs under pressure, the authors tested whether EGTA chelation of Ca(2+) improves survival and whether, with the Ca(2+) dye Fluo-4 AM, TRPV1 contributes to increased intracellular Ca(2+). RESULTS: RGCs express trpv1 mRNA, with robust TRPV1 protein localization to the cell body and axon. For isolated RGCs under pressure, TRPV1 antagonism increased cell density and reduced apoptosis to ambient levels (P

Quantitative assessment of TRPM5-dependent oral aversiveness of pharmaceuticals using a mouse brief-access taste aversion assay.

Many orally administered pharmaceuticals are regarded by humans as aversive, most often described as 'bitter'. Taste aversiveness often leads to patient noncompliance and reduced treatment effectiveness. 'Bitter' taste is mediated by T2R G-protein coupled receptors through a peripheral signaling pathway critically dependent upon function of the TRPM5 ion channel. The brief-access taste aversion (BATA) assay operationally defines aversive taste as suppression of the rate at which a rodent licks from sipper tubes that deliver tastant solutions or suspensions. We have used a mouse BATA assay for rapid quantification of oral aversiveness from a set of 20 active pharmaceutical ingredients (APIs). Robust lick-rate dose-response functions were obtained from both C57BL/6J wild type (WT) and C57BL/6J/TRPM5-/- (TRPM5 knockout) mouse strains, generating reliable determinations of potency and relative maximal oral aversiveness for each API. A subset of APIs was also evaluated in a human bitterness assessment test; effective concentrations for half-maximum responses (EC50s) from both the human test and WT mouse BATA were equivalent. Relative to WT potencies, EC50s from TRPM5 knockout mice were right-shifted more than 10-fold for most APIs. However, APIs were identified for which EC50s were essentially identical in both mouse strains, indicating a TRPM5-independent alternative aversive pathway. Our results suggest the BATA assay will facilitate formulation strategies and taste assessment of late development-phase APIs.