Dianna D. Cody

CT dose index and patient dose: They are not the same thing

Estimates of individual patient risk, and epidemiologic studies assessing potential late effects, must use patient size–specific dose estimates—they cannot use only scanner output (volume CT dose index or dose-length product).

Correlations between vertebral regional bone mineral density (Rbmd) and whole bone fracture load

To assess the significance of regional quantitative computed tomography measurements of bone density with respect to mechanical strength in the human lumbar spine, 58 vertebrae (from 12 males, 10 females) were scanned in vitro with multiple-thin-slice quantitative com-puted tomography and then compressed to fracture. With computer graphics, 18 specific regions of physical density and 10 combination averages of density were identified within each vertebral body. To ensure the statistical independence of data, the individual vertebral specimens were assigned to one of three groups (T11-L1, L2-L3, or L4-L5). Use of best-subsets procedures resulted in regression models to predict fracture strength. These models used specific regional density values and often the age and sex of the donors. The correlation coefficients that resulted from the multipte regression models ranged from r = 0.88 to r = 0.95. When the density values were multiplied by the minimum cross-sectional area of the vertebral body, similar regional density averages were selected, and the predictive values were slightly improved (r = 0.94–0.97). The heterogeneity of the density samples (measured as standard deviation) hi multiple regression fashion also produced strong correlation coefficients (r = 0.88–0.94). The bone density in an anterior cylinder of the midplane region, the location measured most often In quantitative computed tomography densl-tometry, was strongly correlated (r = 0.85) to fracture load for the T12-L1 group (N = 20), but was not slgnrfl-cart for the other two gnnips of vertebrae. Trie cancettous bone density from the female date was not found to be significantly different from the male date set These data suggest that when the density of specific regions in the vertebral mam body are measured, most of the variance in the whole-bone strength could be predicted, and these optimal regions (a relative measure of cancellous heterogeneity) appeared to vary with spine level. Using the bone densfef from.regions of the cancellous Interior may uttlmately yield clinically useful information rolovant to patient treatment dedsfons.

High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor

Recent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic KRAS, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands.

Inhibition of Mammalian Target of Rapamycin Reverses Alveolar Epithelial Neoplasia Induced by Oncogenic K-ras

The serine/threonine kinase AKT and its downstream mediator mammalian target of rapamycin (mTOR) are activated in lung adenocarcinoma, and clinical trials are under way to test whether inhibition of mTOR is useful in treating lung cancer. Here, we report that mTOR inhibition blocked malignant progression in K-ras(LA1) mice, which undergo somatic activation of the K-ras oncogene and display morphologic changes in alveolar epithelial cells that recapitulate those of precursors of human lung adenocarcinoma. Levels of phospho-S6(Ser236/235), a downstream mediator of mTOR, increased with malignant progression (normal alveolar epithelial cells to adenocarcinoma) in K-ras(LA1) mice and in patients with lung adenocarcinoma. Atypical alveolar hyperplasia, an early neoplastic change, was prominently associated with macrophages and expressed high levels of phospho-S6(Ser236/235). mTOR inhibition in K-ras(LA1) mice by treatment with the rapamycin analogue CCI-779 reduced the size and number of early epithelial neoplastic lesions (atypical alveolar hyperplasia and adenomas) and induced apoptosis of intraepithelial macrophages. LKR-13, a lung adenocarcinoma cell line derived from K-ras(LA1) mice, was resistant to treatment with CCI-779 in vitro. However, LKR-13 cells grown as syngeneic tumors recruited macrophages, and those tumors regressed in response to treatment with CCI-779. Lastly, conditioned medium from primary cultures of alveolar macrophages stimulated the proliferation of LKR-13 cells. These findings provide evidence that the expansion of lung adenocarcinoma precursors induced by oncogenic K-ras requires mTOR-dependent signaling and that host factors derived from macrophages play a critical role in adenocarcinoma progression.

In Vivo Respiratory-Gated Micro-CT Imaging in Small-Animal Oncology Models

Micro-computed tomography(micro-CT) is becoming an accepted research tool for the noninvasive examination of laboratory animals such as mice and rats, but to date, in vivo scanning has largely been limited to the evaluation of skeletal tissues. We use a commercially available micro-CT device to perform respiratory gated in vivo acquisitions suitable for thoracic imaging. The instrument is described, along with the scan protocol and animal preparation techniques. Preliminary results confirm that lung tumors as small as 1 mm in diameter are visible in vivo with these methods. Radiation dose was evaluated using several approaches, and was found to be approximately 0.15 Gy for this respiratory-gated micro-CT imaging protocol. The combination of high-resolution CT imaging and respiratory-gated acquisitions appears well-suited to serial in vivo scanning.

A Monte Carlo based method to estimate radiation dose from multidetector CT (MDCT): cylindrical and anthropomorphic phantoms

The purpose of this work was to extend the verification of Monte Carlo based methods for estimating radiation dose in computed tomography (CT) exams beyond a single CT scanner to a multidetector CT (MDCT) scanner, and from cylindrical CTDI phantom measurements to both cylindrical and physical anthropomorphic phantoms. Both cylindrical and physical anthropomorphic phantoms were scanned on an MDCT under the specified conditions. A pencil ionization chamber was used to record exposure for the cylindrical phantom, while MOSFET (metal oxide semiconductor field effect transistor) detectors were used to record exposure at the surface of the anthropomorphic phantom. Reference measurements were made in air at isocentre using the pencil ionization chamber under the specified conditions. Detailed Monte Carlo models were developed for the MDCT scanner to describe the x-ray source (spectra, bowtie filter, etc) and geometry factors (distance from focal spot to isocentre, source movement due to axial or helical scanning, etc). Models for the cylindrical (CTDI) phantoms were available from the previous work. For the anthropomorphic phantom, CT image data were used to create a detailed voxelized model of the phantoms geometry. Anthropomorphic phantom material compositions were provided by the manufacturer. A simulation of the physical scan was performed using the mathematical models of the scanner, phantom and specified scan parameters. Tallies were recorded at specific voxel locations corresponding to the MOSFET physical measurements. Simulations of air scans were performed to obtain normalization factors to convert results to absolute dose values. For the CTDI body (32 cm) phantom, measurements and simulation results agreed to within 3.5% across all conditions. For the anthropomorphic phantom, measured surface dose values from a contiguous axial scan showed significant variation and ranged from 8 mGy/100 mAs to 16 mGy/100 mAs. Results from helical scans of overlapping pitch (0.9375) and extended pitch (1.375) were also obtained. Comparisons between the MOSFET measurements and the absolute dose value derived from the Monte Carlo simulations demonstrate agreement in terms of absolute dose values as well as the spatially varying characteristics. This work demonstrates the ability to extend models from a single detector scanner using cylindrical phantoms to an MDCT scanner using both cylindrical and anthropomorphic phantoms. Future work will be extended to voxelized patient models of different sizes and to other MDCT scanners.

High Expression of Ligands for Chemokine Receptor CXCR2 in Alveolar Epithelial Neoplasia Induced by Oncogenic Kras

CXCL8, a ligand for the chemokine receptor CXCR2, was recently reported to be a transcriptional target of Ras signaling, but its role in Ras-induced tumorigenesis has not been fully defined. Here, we investigated the role of KC and MIP-2, the murine homologues of CXCL8, in Kras(LA1) mice, which develop lung adenocarcinoma owing to somatic activation of the KRAS oncogene. We first investigated biological evidence of CXCR2 ligands in Kras(LA1) mice. Malignant progression of normal alveolar epithelial cells to adenocarcinoma in Kras(LA1) mice was associated with enhanced intralesional vascularity and neutrophilic inflammation, which are hallmarks of chemoattraction by CXCR2 ligands. In in vitro migration assays, supernatants of bronchoalveolar lavage samples from Kras(LA1) mice chemoattracted murine endothelial cells, alveolar inflammatory cells, and the LKR-13 lung adenocarcinoma cell line derived from Kras(LA1) mice, an effect that was abrogated by pretreatment of the cells with a CXCR2-neutralizing antibody. CXCR2 and its ligands were highly expressed in LKR-13 cells and premalignant alveolar lesions in Kras(LA1) mice. Treatment of Kras(LA1) mice with a CXCR2-neutralizing antibody inhibited the progression of premalignant alveolar lesions and induced apoptosis of vascular endothelial cells within alveolar lesions. Whereas the proliferation of LKR-13 cells in vitro was resistant to treatment with the antibody, LKR-13 cells established as syngeneic tumors were sensitive, supporting a role for the tumor microenvironment in the activity of CXCR2. Thus, high expression of CXCR2 ligands may contribute to the expansion of early alveolar neoplastic lesions induced by oncogenic KRAS.

Radiation dose to the fetus for pregnant patients undergoing multidetector CT imaging: Monte carlo simulations estimating fetal dose for a range of gestational age and patient size1

PURPOSE To use Monte Carlo simulations of a current-technology multidetector computed tomographic (CT) scanner to investigate fetal radiation dose resulting from an abdominal and pelvic examination for a range of actual patient anatomies that include variation in gestational age and maternal size. MATERIALS AND METHODS Institutional review board approval was obtained for this HIPAA-compliant retrospective study. Twenty-four models of maternal and fetal anatomy were created from image data from pregnant patients who had previously undergone clinically indicated CT examination. Gestational age ranged from less than 5 weeks to 36 weeks. Simulated helical scans of the abdominal and pelvic region were performed, and a normalized dose (in milligrays per 100 mAs) was calculated for each fetus. Stepwise multiple linear regression was performed to analyze the correlation of dose with gestational age and anatomic measurements of maternal size and fetal location. Results were compared with several existing fetal dose estimation methods. RESULTS Normalized fetal dose estimates from the Monte Carlo simulations ranged from 7.3 to 14.3 mGy/100 mAs, with an average of 10.8 mGy/100 mAs. Previous methods yielded values of 10-14 mGy/100 mAs. The correlation between gestational age and fetal dose was not significant (P = .543). Normalized fetal dose decreased linearly with increasing patient perimeter (R(2) = 0.681, P < .001), and a two-factor model with patient perimeter and fetal depth demonstrated a strong correlation with fetal dose (R(2) = 0.799, P < .002). CONCLUSION A method for the estimation of fetal dose from models of actual patient anatomy that represented a range of gestational age and patient size was developed. Fetal dose correlated with maternal perimeter and varied more than previously recognized. This correlation improves when maternal size and fetal depth are combined.

An Official American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guideline: Evaluation of Suspected Pulmonary Embolism In Pregnancy

BACKGROUND Pulmonary embolism (PE) is a leading cause of maternal mortality in the developed world. Along with appropriate prophylaxis and therapy, prevention of death from PE in pregnancy requires a high index of clinical suspicion followed by a timely and accurate diagnostic approach. METHODS To provide guidance on this important health issue, a multidisciplinary panel of major medical stakeholders was convened to develop evidence-based guidelines for evaluation of suspected pulmonary embolism in pregnancy using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. In formulation of the recommended diagnostic algorithm, the important outcomes were defined to be diagnostic accuracy and diagnostic yield; the panel placed a high value on minimizing cumulative radiation dose when determining the recommended sequence of tests. RESULTS Overall, the quality of the underlying evidence for all recommendations was rated as very low or low, with some of the evidence considered for recommendations extrapolated from studies of the general population. Despite the low-quality evidence, strong recommendations were made for three specific scenarios: performance of chest radiography (CXR) as the first radiation-associated procedure; use of lung scintigraphy as the preferred test in the setting of a normal CXR; and performance of computed-tomographic pulmonary angiography (CTPA) rather than digital subtraction angiography (DSA) in a pregnant woman with a nondiagnostic ventilation-perfusion (V/Q) result. DISCUSSION The recommendations presented in this guideline are based upon the currently available evidence; availability of new clinical research data and development and dissemination of new technologies will necessitate a revision and update.

The feasibility of a scanner-independent technique to estimate organ dose from MDCT scans: Using CTDIvol to account for differences between scanners

PURPOSE Monte Carlo radiation transport techniques have made it possible to accurately estimate the radiation dose to radiosensitive organs in patient models from scans performed with modern multidetector row computed tomography (MDCT) scanners. However, there is considerable variation in organ doses across scanners, even when similar acquisition conditions are used. The purpose of this study was to investigate the feasibility of a technique to estimate organ doses that would be scanner independent. This was accomplished by assessing the ability of CTDIvol measurements to account for differences in MDCT scanners that lead to organ dose differences. METHODS Monte Carlo simulations of 64-slice MDCT scanners from each of the four major manufacturers were performed. An adult female patient model from the GSF family of voxelized phantoms was used in which all ICRP Publication 103 radiosensitive organs were identified. A 120 kVp, full-body helical scan with a pitch of 1 was simulated for each scanner using similar scan protocols across scanners. From each simulated scan, the radiation dose to each organ was obtained on a per mA s basis (mGy/mA s). In addition, CTDIvol values were obtained from each scanner for the selected scan parameters. Then, to demonstrate the feasibility of generating organ dose estimates from scanner-independent coefficients, the simulated organ dose values resulting from each scanner were normalized by the CTDIvol value for those acquisition conditions. RESULTS CTDIvol values across scanners showed considerable variation as the coefficient of variation (CoV) across scanners was 34.1%. The simulated patient scans also demonstrated considerable differences in organ dose values, which varied by up to a factor of approximately 2 between some of the scanners. The CoV across scanners for the simulated organ doses ranged from 26.7% (for the adrenals) to 37.7% (for the thyroid), with a mean CoV of 31.5% across all organs. However, when organ doses are normalized by CTDIvoI values, the differences across scanners become very small. For the CTDIvol, normalized dose values the CoVs across scanners for different organs ranged from a minimum of 2.4% (for skin tissue) to a maximum of 8.5% (for the adrenals) with a mean of 5.2%. CONCLUSIONS This work has revealed that there is considerable variation among modern MDCT scanners in both CTDIvol and organ dose values. Because these variations are similar, CTDIvol can be used as a normalization factor with excellent results. This demonstrates the feasibility of establishing scanner-independent organ dose estimates by using CTDIvol to account for the differences between scanners.