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Recent documents in eScholarship@UMMS
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Stereoscopic digital mammography: improved specificity and reduced rate of recall in a prospective clinical trial

Tue, 01/27/2015 - 1:41pm

PURPOSE: To compare stereoscopic digital mammography (DM) with standard DM for the rate of patient recall and the detection of cancer in a screening population at elevated risk for breast cancer.

MATERIALS AND METHODS: Starting in September 2004 and ending in December 2007, this prospective HIPAA-compliant, institutional review board-approved screening trial, with written informed consent, recruited female patients at elevated risk for breast cancer (eg, personal history of breast cancer or breast cancer in a close relative). A total of 1298 examinations from 779 patients (mean age, 58.6 years; range, 32-91 years) comprised the analyzable data set. A paired study design was used, with each enrolled patient serving as her own control. Patients underwent both DM and stereoscopic DM examinations in a single visit, findings of which were interpreted independently by two experienced radiologists, each using a Breast Imaging Reporting and Data System (BI-RADS) assessment (BI-RADS category 0, 1, or 2). All patients determined to have one or more findings with either or both modalities were recalled for standard diagnostic evaluation. The results of 1-year follow-up or biopsy were used to determine case truth.

RESULTS: Compared with DM, stereoscopic DM showed significantly higher specificity (91.2% [1167 of 1279] vs 87.8% [1123 of 1279]; P = .0024) and accuracy (90.9% [1180 of 1298] vs 87.4% [1135 of 1298]; P = .0023) for detection of cancer. Sensitivity for detection of cancer was not significantly different for stereoscopic DM (68.4% [13 of 19]) compared with DM (63.2% [12 of 19], P .99). The recall rate for stereoscopic DM was 9.6% (125 of 1298) and that for DM was 12.9% (168 of 1298) (P = .0018).

CONCLUSION: Compared with DM, stereoscopic DM significantly improved specificity for detection of cancer, while maintaining comparable sensitivity. The recall rate was significantly reduced with stereoscopic DM compared with DM.


Dedicated breast CT: fibroglandular volume measurements in a diagnostic population

Tue, 01/27/2015 - 1:41pm

PURPOSE: To determine the mean and range of volumetric glandular fraction (VGF) of the breast in a diagnostic population using a high-resolution flat-panel cone-beam dedicated breast CT system. This information is important for Monte Carlo-based estimation of normalized glandular dose coefficients and for investigating the dependence of VGF on breast dimensions, race, and pathology.

METHODS: Image data from a clinical trial investigating the role of dedicated breast CT that enrolled 150 women were retrospectively analyzed to determine the VGF. The study was conducted in adherence to a protocol approved by the institutional human subjects review boards and written informed consent was obtained from all study participants. All participants in the study were assigned BI-RADS((R)) 4 or 5 as per the American College of Radiology assessment categories after standard diagnostic work-up and underwent dedicated breast CT exam prior to biopsy. A Gaussian-kernel based fuzzy c-means algorithm was used to partition the breast CT images into adipose and fibroglandular tissue after segmenting the skin. Upon determination of the accuracy of the algorithm with a phantom, it was applied to 137 breast CT volumes from 136 women. VGF was determined for each breast and the mean and range were determined. Pathology results with classification as benign, malignant, and hyperplasia were available for 132 women, and were used to investigate if the distributions of VGF varied with pathology.

RESULTS: The algorithm was accurate to within +/-1.9% in determining the volume of an irregular shaped phantom. The study mean (+/- inter-breast SD) for the VGF was 0.172 +/- 0.142 (range: 0.012-0.719). VGF was found to be negatively correlated with age, breast dimensions (chest-wall to nipple length, pectoralis to nipple length, and effective diameter at chest-wall), and total breast volume, and positively correlated with fibroglandular volume. Based on pathology, pairwise statistical analysis (Mann-Whitney test) indicated that at the 0.05 significance level, there was no significant difference in distributions of VGF without adjustment for age between malignant and nonmalignant breasts (p = 0.41). Pairwise comparisons of the distributions of VGF in increasing order of mammographic breast density indicated all comparisons were statistically significant (p < 0.002).

CONCLUSIONS: This study used a different clinical prototype breast CT system than that in previous studies to image subjects from a different geographical region, and used a different algorithm for analysis of image data. The mean VGF estimated from this study is within the range reported in previous studies, indicating that the choice of 50% glandular weight fraction to represent an average breast for Monte Carlo-based estimation of normalized glandular dose coefficients in mammography needs revising. In the study, the distributions of VGF did not differ significantly with pathology.

Experimental demonstration of benchtop x-ray fluorescence computed tomography (XFCT) of gold nanoparticle-loaded objects using lead- and tin-filtered polychromatic cone-beams

Tue, 01/27/2015 - 1:41pm

This report presents the first experimental demonstration, to our knowledge, of benchtop polychromatic cone-beam x-ray fluorescence computed tomography (XFCT) for a simultaneous determination of the spatial distribution and amount of gold nanoparticles (GNPs) within small-animal-sized objects. The current benchtop experimental setup successfully produced XFCT images accurately showing the regions containing small amount of GNPs (on the order of 0.1 mg) within a 3 cm diameter plastic phantom. In particular, the performance of the current XFCT setup was improved remarkably (e.g., at least a factor of 3 reduction in XFCT scan time) using a tin-filtered polychromatic beam in comparison with a lead-filtered beam. The results of this study strongly suggest that the current benchtop XFCT configuration can be made practical with a few modifications such as the deployment of array detectors, while meeting realistic constraints on x-ray dose, scan time and image resolution for routine pre-clinical in vivo imaging with GNPs.

Dedicated breast CT: radiation dose for circle-plus-line trajectory

Tue, 01/27/2015 - 1:41pm

PURPOSE: Dedicated breast CT prototypes used in clinical investigations utilize single circular source trajectory and cone-beam geometry with flat-panel detectors that do not satisfy data-sufficiency conditions and could lead to cone beam artifacts. Hence, this work investigated the glandular dose characteristics of a circle-plus-line trajectory that fulfills data-sufficiency conditions for image reconstruction in dedicated breast CT.

METHODS: Monte Carlo-based computer simulations were performed using the GEANT4 toolkit and was validated with previously reported normalized glandular dose coefficients for one prototype breast CT system. Upon validation, Monte Carlo simulations were performed to determine the normalized glandular dose coefficients as a function of x-ray source position along the line scan. The source-to-axis of rotation distance and the source-to-detector distance were maintained constant at 65 and 100 cm, respectively, in all simulations. The ratio of the normalized glandular dose coefficient at each source position along the line scan to that for the circular scan, defined as relative normalized glandular dose coefficient (RD(g)N), was studied by varying the diameter of the breast at the chest wall, chest-wall to nipple distance, skin thickness, x-ray beam energy, and glandular fraction of the breast.

RESULTS: The RD(g)N metric when stated as a function of source position along the line scan, relative to the maximum length of line scan needed for data sufficiency, was found to be minimally dependent on breast diameter, chest-wall to nipple distance, skin thickness, glandular fraction, and x-ray photon energy. This observation facilitates easy estimation of the average glandular dose of the line scan. Polynomial fit equations for computing the RD(g)N and hence the average glandular dose are provided.

CONCLUSIONS: For a breast CT system that acquires 300-500 projections over 2pi for the circular scan, the addition of a line trajectory with equal source spacing and constant x-ray beam quality (kVp and HVL) and mAs matched to the circular scan, will result in less than 0.18% increase in average glandular dose to the breast per projection along the line scan.

Semi-automated segmentation and classification of digital breast tomosynthesis reconstructed images

Tue, 01/27/2015 - 1:41pm

Digital breast tomosynthesis (DBT) is a limited-angle tomographic x-ray imaging technique that reduces the effect of tissue superposition observed in planar mammography. An integrated imaging platform that combines DBT with near infrared spectroscopy (NIRS) to provide co-registered anatomical and functional imaging is under development. Incorporation of anatomic priors can benefit NIRS reconstruction. In this work, we provide a segmentation and classification method to extract potential lesions, as well as adipose, fibroglandular, muscle and skin tissue in reconstructed DBT images that serve as anatomic priors during NIRS reconstruction. The method may also be adaptable for estimating tumor volume, breast glandular content, and for extracting lesion features for potential application to computer aided detection and diagnosis.

Evaluation of an improved algorithm for producing realistic 3D breast software phantoms: application for mammography

Tue, 01/27/2015 - 1:41pm

PURPOSE: This work presents an improved algorithm for the generation of 3D breast software phantoms and its evaluation for mammography.

METHODS: The improved methodology has evolved from a previously presented 3D noncompressed breast modeling method used for the creation of breast models of different size, shape, and composition. The breast phantom is composed of breast surface, duct system and terminal ductal lobular units, Cooper's ligaments, lymphatic and blood vessel systems, pectoral muscle, skin, 3D mammographic background texture, and breast abnormalities. The key improvement is the development of a new algorithm for 3D mammographic texture generation. Simulated images of the enhanced 3D breast model without lesions were produced by simulating mammographic image acquisition and were evaluated subjectively and quantitatively. For evaluation purposes, a database with regions of interest taken from simulated and real mammograms was created. Four experienced radiologists participated in a visual subjective evaluation trial, as they judged the quality of the simulated mammograms, using the new algorithm compared to mammograms, obtained with the old modeling approach. In addition, extensive quantitative evaluation included power spectral analysis and calculation of fractal dimension, skewness, and kurtosis of simulated and real mammograms from the database.

RESULTS: The results from the subjective evaluation strongly suggest that the new methodology for mammographic breast texture creates improved breast models compared to the old approach. Calculated parameters on simulated images such as beta exponent deducted from the power law spectral analysis and fractal dimension are similar to those calculated on real mammograms. The results for the kurtosis and skewness are also in good coincidence with those calculated from clinical images. Comparison with similar calculations published in the literature showed good agreement in the majority of cases.

CONCLUSIONS: The improved methodology generated breast models with increased realism compared to the older model as shown in evaluations of simulated images by experienced radiologists. It is anticipated that the realism will be further improved using an advanced image simulator so that simulated images may be used in feasibility studies in mammography.

Modeling the performance characteristics of computed radiography (CR) systems

Tue, 01/27/2015 - 1:41pm

Computed radiography (CR) using storage phosphors is widely used in digital radiography and mammography. A cascaded linear systems approach wherein several parameter values were estimated using Monte Carlo methods was used to model the image formation process of a single-side read flying spot CR system using a granular phosphor. Objective image quality metrics such as modulation transfer function and detective quantum efficiency were determined using this model and show good agreement with published empirical data. A model such as that addressed in this work could allow for improved understanding of the effect of storage phosphor physical properties and CR reader parameters on objective image quality metrics for existing and evolving CR systems.

Imaging nanoprobe for prediction of outcome of nanoparticle chemotherapy by using mammography

Tue, 01/27/2015 - 1:41pm

PURPOSE: To prospectively predict the effectiveness of a clinically used nanochemotherapeutic agent by detecting and measuring the intratumoral uptake of an x-ray contrast agent nanoprobe by using digital mammography.

MATERIALS AND METHODS: All animal procedures were approved by the institutional animal care and use committee. A long-circulating 100-nm-scale injectable liposomal probe encapsulating 155 mg/mL iodine was developed. Preliminary studies were performed to identify the agent dose that would result in adequate tumor enhancement without enhancement of the normal vasculature in rats. This dose was used to image a rat breast tumor (n = 14) intermittently for 3 days by using a digital mammography system; subsequently, the animals were treated with liposomal doxorubicin. The predictive capability of the probe was characterized by creating good- and bad-prognosis subgroups, on the basis of tumor enhancement found during imaging, and analyzing the tumor growth after treatment of the animals in these two subgroups.

RESULTS: A dose of 455 mg of iodine per kilogram of body weight was found to produce an undetectable signal from the blood while achieving enough intratumoral accumulation of the probe to produce adequate signal for detection. The good- and bad-prognosis subgroups demonstrated differential tumor growth rates (P < .003). An inverse linear relationship between the contrast enhancement rate constant during imaging and the tumor growth rate constant during treatment was found (slope = -0.576, R(2) = 0.838).

CONCLUSION: In this animal model, quantitative measurement of vascular permeability enabled prediction of therapeutic responsiveness of tumors to liposomal doxorubicin.

Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals

Fri, 01/23/2015 - 11:30am

Long intergenic noncoding RNAs (lincRNAs) play diverse regulatory roles in human development and disease, but little is known about their evolutionary history and constraint. Here, we characterize human lincRNA expression patterns in nine tissues across six mammalian species and multiple individuals. Of the 1898 human lincRNAs expressed in these tissues, we find orthologous transcripts for 80% in chimpanzee, 63% in rhesus, 39% in cow, 38% in mouse, and 35% in rat. Mammalian-expressed lincRNAs show remarkably strong conservation of tissue specificity, suggesting that it is selectively maintained. In contrast, abundant splice-site turnover suggests that exact splice sites are not critical. Relative to evolutionarily young lincRNAs, mammalian-expressed lincRNAs show higher primary sequence conservation in their promoters and exons, increased proximity to protein-coding genes enriched for tissue-specific functions, fewer repeat elements, and more frequent single-exon transcripts. Remarkably, we find that approximately 20% of human lincRNAs are not expressed beyond chimpanzee and are undetectable even in rhesus. These hominid-specific lincRNAs are more tissue specific, enriched for testis, and faster evolving within the human lineage.

Effect of preinjury warfarin use on outcomes after head trauma in Medicare beneficiaries

Fri, 01/23/2015 - 11:30am

BACKGROUND: Elderly Americans are at increased risk of head trauma, particularly fall related. The effect of warfarin on head trauma outcomes remains controversial.

METHODS: Medicare beneficiaries with head injuries from 2009 to 2011 were identified by International Classification of Diseases (ICD)-9 code. Preinjury warfarin use was determined using Part D claims. Multiple logistic regression models determined the association of preinjury warfarin on need for hospitalization, intensive care unit care, and occurrence of intracranial hemorrhage. Association between warfarin and in-hospital mortality was assessed using a Cox proportional hazard model.

RESULTS: Of 11,078 head injured patients, 5.2% were injured while on warfarin. Preinjury warfarin increased the odds of intracranial hemorrhage by 40% and doubled the risk of 30-day in-hospital mortality after adjusting for demographic and clinical factors.

CONCLUSIONS: Warfarin at the time of head injury increases the risk of adverse outcomes in Medicare beneficiaries with head injuries. Caution should be used when initiating anticoagulation in elderly Americans at risk for trauma.

HIV Stigma, Testing Attitudes and Health Care Access Among African-Born Men Living in the United States

Fri, 01/23/2015 - 11:30am

The purpose of this study was to describe HIV-testing attitudes, HIV related stigma and health care access in African-born men taking part in the African Health Cup (AHC), a soccer tournament held annually to improve HIV awareness and testing. Venue sampling was used to collect survey and qualitative interview data related to HIV-testing attitudes, stigma and experiences associated with the AHC. The sample included 135 survey respondents and 27 interview participants. AHC participants were successfully accessing health care services. Although the AHC was viewed positively, HIV testing rates remain low due to stigma and privacy concerns. This population continues to have misconceptions about HIV transmission and to use condoms inconsistently. The AHC is a successful intervention to engage African-born men in HIV awareness and education. More work is needed to enhance these AHC aspects and address stigma and privacy concerns related to using onsite health screenings. Continuing to develop novel strategies to educate African-born immigrants about HIV is urgently needed.

Pregnant women's interest in a website or mobile application for healthy gestational weight gain

Fri, 01/23/2015 - 11:30am

We examined pregnant women's interest in using a website or mobile application to help them gain a healthy amount of weight during pregnancy. Pregnant women (N = 64) completed a short questionnaire during routine prenatal care at hospital-based obstetric clinics in central Massachusetts during April-August 2012. Eighty-six percent reported interest in using a website or mobile application to help them gain a healthy amount of weight; interest ranged from 67% to 100% across demographics, clinical characteristics, and technology use. The Internet is a promising modality for delivering interventions to prevent excessive gestational weight gain and associated maternal and child health consequences.

Use and Perceived Effectiveness of Coping Skills among Police Officer Spouses

Thu, 01/22/2015 - 3:00pm

Discusses her research on the types of psychological stressors faced by the spouses of police officers and their methods of coping.

Assessment of Competence Restoration: Determining the Threshold

Thu, 01/22/2015 - 3:00pm

Discusses the legal precedent and research basis of evaluating a defendant's mental competency to stand trial, the variables that contribute to non-restorable incompetence to stand trial, and the differences between patients who are restorable to competency versus those who are not restorable to competency.

Prototypical Recombinant Multi-Protease Inhibitor Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type-1

Wed, 01/21/2015 - 4:22pm

The many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI-resistance and the assessment of new PIs. To address these challenges, we created a panel of recombinant multi-PI resistant infectious molecular clones designed to represent the spectrum of clinically relevant multi-PI resistant viruses. To assess the representativeness of this panel, we examined the sequences of the panel's viruses in the context of a correlation network of PI-resistance amino acid substitutions in sequences from more than 10,000 patients. The panel of recombinant infectious molecular clones comprised 29 of 41 study-defined PI-resistance amino acid substitutions and 23 of the 27 tightest amino acid substitution clusters. Based on their phenotypic properties, the clones were classified into four groups with increasing cross-resistance to the PIs most commonly used for salvage therapy: lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). The panel of recombinant infectious molecular clones has been made available without restriction through the NIH AIDS Research and Reference Reagent Program. The public availability of the panel makes it possible to compare the inhibitory activity of different PIs with one another. The diversity of the panel and the high-level PI resistance of its clones suggest that investigational PIs active against the clones in this panel will retain antiviral activity against most, if not all clinically relevant PI-resistant viruses.

Interview with Celia Schiffer

Wed, 01/21/2015 - 4:22pm

Celia Schiffer, a Professor in Biochemistry and Molecular Pharmacology; a former Director of UMass Center for AIDS Research; and a Founder and Co-Director for the Institute for Drug Resistance (University of Massachusetts Medical School, MA, USA). Schiffer has an undergraduate degree in physics from the University of Chicago, with a PhD in biophysics from University of California, San Francisco (CA, USA). She was a postdoctoral associate first at the ETH in Zurich and then at Genentech in San Francisco. Schiffer has published more than 100 peer reviewed journal articles. Her laboratory primarily uses structural biology, biophysical and chemistry techniques to study the molecular basis for drug resistance in anti-virals including: HIV, Hepatitis C, Influenza and Dengue. Her laboratory designs, synthesizes and tests new antiviral inhibitors that should be more robust to resistance. She has overseen more than US$30 million in research funding. She is also an outstanding mentor and educator, receiving a faculty mentoring award, a highly sought after PhD advisor.

Interview conducted by Hannah Coaker, Assistant Commissioning Editor.

A sensitive assay using a native protein substrate for screening HIV-1 maturation inhibitors targeting the protease cleavage site between the matrix and capsid

Wed, 01/21/2015 - 4:22pm

The matrix/capsid processing site in the HIV-1 Gag precursor is likely the most sensitive target to inhibit HIV-1 replication. We have previously shown that modest incomplete processing at the site leads to a complete loss of virion infectivity. In the study presented here, a sensitive assay based on fluorescence polarization that can monitor cleavage at the MA/CA site in the context of the folded protein substrate is described. The substrate, an MA/CA fusion protein, was labeled with the fluorescein-based FlAsH (fluorescein arsenical hairpin) reagent that binds to a tetracysteine motif (CCGPCC) that was introduced within the N-terminal domain of CA. By limiting the size of CA and increasing the size of MA (with an N-terminal GST fusion), we were able to measure significant differences in polarization values as a function of HIV-1 protease cleavage. The sensitivity of the assay was tested in the presence of increasing amounts of an HIV-1 protease inhibitor, which resulted in a gradual decrease in the fluorescence polarization values demonstrating that the assay is sensitive in discerning changes in protease processing. The high-throughput screening assay validation in 384-well plates showed that the assay is reproducible and robust with an average Z' value of 0.79 and average coefficient of variation values of <3%. The robustness and reproducibility of the assay were further validated using the LOPAC(1280) compound library, demonstrating that the assay provides a sensitive high-throughput screening platform that can be used with large compound libraries for identifying novel maturation inhibitors targeting the MA/CA site of the HIV-1 Gag polyprotein.

Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance

Wed, 01/21/2015 - 4:22pm

The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (PIs) using the substrate envelope model, which confines inhibitors within the consensus volume of natural substrates, providing inhibitors less susceptible to resistance because a mutation affecting such inhibitors will simultaneously affect viral substrate processing. The designed PIs share a common chemical scaffold but utilize various moieties that optimally fill the substrate envelope, as confirmed by crystal structures. The designed PIs retain robust binding to MDR protease variants and display exceptional antiviral potencies against different clades of HIV as well as a panel of 12 drug-resistant viral strains. The substrate envelope model proves to be a powerful strategy to develop potent and robust inhibitors that avoid drug resistance.

Efficient Computation of Small-Molecule Configurational Binding Entropy and Free Energy Changes by Ensemble Enumeration

Wed, 01/21/2015 - 4:22pm

Here we present a novel, end-point method using the dead-end-elimination and A* algorithms to efficiently and accurately calculate the change in free energy, enthalpy, and configurational entropy of binding for ligand-receptor association reactions. We apply the new approach to the binding of a series of human immunodeficiency virus (HIV-1) protease inhibitors to examine the effect ensemble reranking has on relative accuracy as well as to evaluate the role of the absolute and relative ligand configurational entropy losses upon binding in affinity differences for structurally related inhibitors. Our results suggest that most thermodynamic parameters can be estimated using only a small fraction of the full configurational space, and we see significant improvement in relative accuracy when using an ensemble versus single-conformer approach to ligand ranking. We also find that using approximate metrics based on the single-conformation enthalpy differences between the global minimum energy configuration in the bound as well as unbound states also correlates well with experiment. Using a novel, additive entropy expansion based on conditional mutual information, we also analyze the source of ligand configurational entropy loss upon binding in terms of both uncoupled per degree of freedom losses as well as changes in coupling between inhibitor degrees of freedom. We estimate entropic free energy losses of approximately +24 kcal/mol, 12 kcal/mol of which stems from loss of translational and rotational entropy. Coupling effects contribute only a small fraction to the overall entropy change (1-2 kcal/mol) but suggest differences in how inhibitor dihedral angles couple to each other in the bound versus unbound states. The importance of accounting for flexibility in drug optimization and design is also discussed.