Drug hypersensitivity reactions: review of the state of the science for prediction and diagnosis.

Drug hypersensitivity reactions (DHRs) are a type of adverse drug reaction that can occur with different classes of drugs and affect multiple organ systems and patient populations. DHRs can be classified as allergic or non-allergic based on the cellular mechanisms involved. Whereas non-allergic reactions rely mainly on the innate immune system, allergic reactions involve the generation of an adaptive immune response. Consequently, drug allergies are DHRs for which an immunological mechanism, with antibody and/or T cell, is demonstrated. Despite decades of research, methods to predict the potential for a new chemical entity to cause DHRs or to correctly attribute DHRs to a specific mechanism and a specific molecule are not well-established. This review will focus on allergic reactions induced by systemically administered low molecular weight (LMW) drugs with an emphasis on drug- and patient-specific factors that could influence the development of DHRs. Strategies for predicting and diagnosing DHRs, including potential tools based on the current state of the science, will also be discussed.

Outcomes of kidney transplantation in patients with myeloma and amyloidosis in the USA.

BACKGROUND: Recent improvement in treatment and patient survival has opened the eligibility of kidney transplantation to patients who developed end-stage kidney disease (ESKD) from plasma cell dyscrasias (PCDs). Data on clinical outcomes in this population are lacking. METHODS: We conducted a retrospective study of United Network for Organ Sharing/Organ Procurement and Transplantation Network dataset (2006-2018) to compare patient and graft outcomes of kidney transplant recipients with ESKD due to PCD versus other causes. RESULTS: Among 168 369 adult first kidney transplant recipients, 0.22-0.43% per year had PCD as the cause of ESKD. The PCD group had worse survival than the non-PCD group for both living and deceased donor types {adjusted hazard ratio [aHR] 2.24 [95% confidence interval (CI) 1.67-2.99] and aHR 1.40 [95% CI 1.08-1.83], respectively}. The PCD group had worse survival than the diabetes group, but only among living donors [aHR 1.87 (95% CI 1.37-2.53) versus aHR 1.16 (95% CI 0.89-1.2)]. Graft survival in patients with PCD were worse than non-PCD in both living and deceased donors [aHR 1.72 (95% CI 1.91-2.56) and aHR 1.30 (95% CI 1.03-1.66)]. Patient and graft survival were worse in amyloidosis but not statistically different in multiple myeloma compared with the non-PCD group. CONCLUSION: The study data are crucial when determining kidney transplant eligibility and when discussing transplant risks in patients with PCD.

Characterization of an Anti-CD70 Half-Life Extended Bispecific T-Cell Engager (HLE-BiTE) and Associated On-Target Toxicity in Cynomolgus Monkeys.

Bispecific T-cell engager (BiTE) molecules have great potential to treat cancer. Nevertheless, dependent on the targeted tumor antigen, the mechanism of action that drives efficacy may also contribute to on-target/off-tumor toxicities. In this study, we characterize an anti-CD70 half-life extended BiTE molecule (termed N6P) which targets CD70, a TNF family protein detected in several cancers. First, the therapeutic potential of N6P was demonstrated using in vitro cytotoxicity assays and an orthotopic xenograft mouse study resulting in potent killing of CD70+ cancer cells. Next, in vitro characterization demonstrated specificity for CD70 and equipotent activity against human and cynomolgus monkey CD70+ cells. To understand the potential for on-target toxicity, a tissue expression analysis was performed and indicated CD70 is primarily restricted to lymphocytes in normal healthy tissues and cells. Therefore, no on-target toxicity was expected to be associated with N6P. However, in a repeat-dose toxicology study using cynomolgus monkeys, adverse N6P-mediated inflammation was identified in multiple tissues frequently involving the mesothelium and epithelium. Follow-up immunohistochemistry analysis revealed CD70 expression in mesothelial and epithelial cells in some tissues with N6P-mediated injury, but not in control tissues or those without injury. Collectively, the data indicate that for some target antigens such as CD70, BiTE molecules may exhibit activity in tissues with very low antigen expression or the antigen may be upregulated under stress enabling molecule activity. This work illustrates how a thorough understanding of expression and upregulation is needed to fully address putative liabilities associated with on-target/off-tumor activity of CD3 bispecific molecules.

A retrospective analysis of tumor lysis syndrome management in a quaternary care hospital.

PURPOSE: Due to an increased use of rasburicase, the study's purpose was to evaluate both the management of tumor lysis syndrome and the utilization of rasburicase in the hospital system. Additionally, the efficacy of flat dose rasburicase in lowering uric acid levels was evaluated. Based on the study's findings, the investigators will evaluate the usefulness of implementing a tumor lysis syndrome order set. METHODS: This study evaluated patients from January 2013 through December 2016 for the rasburicase dose and the tumor lysis syndrome therapy administered. RESULTS: Overall, 251 patients were included: prophylactic rasburicase group (n = 125) vs. treatment rasburicase group (n = 126) and of rasburicase 3 mg (R3) group (n = 168) vs. 6 mg (R6) group (n = 83). The prophylactic rasburicase vs. treatment rasburicase group had a significantly lower rate of receiving a xanthine oxidase inhibitor (48.0% vs. 64.3%, p = 0.009), a phosphate binder (6.4% vs. 17.5%, p = 0.007) and an additional dose of rasburicase (20.8% vs. 41.3%, p = 0.001). Intravenous hydration was neither significantly different between the rasburicase groups (p = 0.399) nor between the two rasburicase dosing groups (p = 0.874). Between the rasburicase dosing groups, there was no significant difference in the rate of receiving a xanthine oxidase inhibitor (p = 0.521) or a phosphate binder (p = 0.390). R6 patients had a significantly greater reduction in uric acid change compared to R3 patients (median = -7.9 (-10.1, -5.5) vs. -4.3 (-6.0, -2.7), p < 0.0001). There was no significant difference in uric acid change between the prophylactic rasburicase and treatment rasburicase groups (p = 0.875). CONCLUSION: The study's findings justified the need to implement a tumor lysis syndrome order set. In the study population, utilizing a flat dosing method was effective for hyperuricemia.

Current Concepts in Natural Killer Cell Biology and Application to Drug Safety Assessments.

Natural killer (NK) cells are lymphocytes capable of cytotoxicity against virally infected cells and tumor cells. The display of effector function by NK cells is the result of interactions between germline encoded activating/inhibitory NK cell receptors and their ligands (major histocompatibility complex class I, major histocompatibility complex class I-like, viral, and cellular stress-related surface molecules) expressed on target cells. Determination of NK cell number and function is a common element of the immunotoxicology assessment paradigm for the development of certain classes of pharmaceuticals across a range of modalities. This article summarizes the evidence associating NK cell dysfunction with infectious and cancer risks, reviews emerging NK cell biology, including the impact of immunogenetics on NK cell education and function, and provides perspectives about points to consider when assessing NK cell function in different species in the context of safety assessment.

The skin as a metabolic and immune-competent organ: Implications for drug-induced skin rash.

Current advances in the study of cutaneous adverse drug reactions can be attributed to the recent understanding that the skin is both a metabolically and immunologically competent organ. The ability of the skin to serve as a protective barrier with limited drug biotransformation ability, yet highly active immune function, has provided insights into its biological capability. While the immune response of the skin to drugs is vastly different from that of the liver due to evolutionary conditioning, it frequently occurs in response to various drug classes and manifests as a spectrum of hypersensitivity reactions. The skin is a common site of adverse and idiosyncratic drug reactions; drug-specific T-cells, as well as involvement of an innate immune response, appear to be key mechanistic drivers in such scenarios. Association of other factors such as human leukocyte antigen (HLA) polymorphisms may play a significant role for particular drugs. This review aims to integrate emerging findings into proposed mechanisms of drug metabolism and immunity in the skin that are likely responsible for rashes and other local allergic responses. These unique biological aspects of the skin, and their translation into implications for drug development and the use of animal models, will be discussed.

Enhanced NADPH oxidases and reactive oxygen species in the mechanism of methanol-initiated protein oxidation and embryopathies in vivo and in embryo culture.

Methanol (MeOH) teratogenicity in rodents may be mediated in part by reactive oxygen species (ROS), the source of which is unknown. To determine if MeOH enhances embryonic ROS-producing NADPH oxidases (NOXs), p22phox mRNA and protein and oxidatively damaged protein were measured in gestational day 12 MeOH-exposed CD-1 mouse embryos with or without pretreatment with the free radical spin trap phenylbutylnitrone (PBN) or the NOX inhibitor diphenyleneiodonium chloride (DPI). MeOH exposure upregulated p22phox mRNA and protein expression, and enhanced protein oxidation, within 3-6 h. Compared to embryos exposed to MeOH alone, PBN and DPI pretreatment decreased MeOH-enhanced p22phox mRNA expression, DPI but not PBN blocked p22phox protein expression, and both blocked protein oxidation. To assess developmental relevance, mouse embryos were exposed in culture for 24 h to MeOH or vehicle with or without pretreatment with PBN, DPI, or the prostaglandin H synthase (PHS) inhibitor eicosatetraynoic acid (ETYA), and evaluated for abnormalities. ETYA did not prevent MeOH embryopathies, despite blocking phenytoin embryopathies (ROS-initiating positive control), precluding bioactivation of MeOH or its metabolites by PHS. Concentration-dependent MeOH embryopathies were blocked by both DPI and PBN pretreatment, suggesting that enhanced embryonic NOX-catalyzed ROS formation and oxidative stress may contribute to the mechanism of MeOH embryopathies.

Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions.

Drug-induced skin rashes are poorly understood idiosyncratic reactions, and current methods cannot predict their occurrence. Most idiosyncratic drug reactions are thought to be caused by chemically reactive metabolites, and the skin is a frequent site of idiosyncratic reactions; however, the skin has a very limited capacity to metabolize drugs. To balance this, the skin represents a protective barrier with a very active immune response against pathogens and other types of skin injury. Therefore its response to reactive metabolites is quite different from that of the liver. The purpose of this review is to integrate emerging findings into proposed mechanisms of drug and carcinogen metabolism in the skin that are likely responsible for rashes and other immune responses of the skin. Current evidence suggests the skin possesses significant sulfotransferase and flavin monooxygenases activities, but very low cytochromes P450 activity. However, there are skin-specific P450s that are not present in the liver. The manner in which the skin responds to neoantigens through local antigen presentation and innate immune sensing is reviewed with a focus on insights gained from the contact hypersensitivity (CHS) field. The roles of keratinocytes and Langerhans cells, and the emerging function of NOD-like receptors, are highlighted.

Identification of danger signals in nevirapine-induced skin rash.

Nevirapine (NVP) can cause serious skin rashes and hepatotoxicity. It also causes an immune-mediated skin rash in rats but not hepatotoxicity. This rash is caused by a metabolite of NVP; specifically, NVP is oxidized in the liver to a benzylic alcohol (12-OH-NVP), which travels to the skin where it forms a reactive benzylic sulfate. This could both act as a hapten and induce a danger signal. In contrast, most of the covalent binding in the liver involves oxidation of the methyl group leading to a reactive quinone methide. In this study, we examined the effects of NVP and 12-OH-NVP on gene expression in the liver and skin. Both NVP and 12-OH-NVP induced changes in the liver, but the list of genes was different, presumably reflecting different bioactivation pathways. In contrast, many more genes were up-regulated in the skin by 12-OH-NVP than by NVP, which is consistent with the fact that 12-OH-NVP is an obligate intermediate in the formation of the reactive sulfate in the skin. Genes up-regulated by 12-OH-NVP in the skin included TRIM63 (18-fold increase), S100a7a (7-fold increase), IL22-RA2 (4-fold increase), and DAPK1 (3-fold increase). TRIM63 acts as a ubiquitin ligase, which is consistent with protein damage leading to an increase in protein turnover. In addition, TRIM proteins are involved in inflammasome activation, and it appears that inflammasome activation is an essential step in the induction of NVP-induced skin rash. S100A7 is considered a danger signal, and its upregulation supports the danger hypothesis. Upregulation of the IL-22 RA2 gene marks an immune response. DAPK1 is involved with inflammasome assembly through binding directly to NLRP3, a NOD-like receptor expressed in keratinocytes. These results provide important clues to how NVP causes the induction of an immune response, in this case leading to skin rash.

12-OH-nevirapine sulfate, formed in the skin, is responsible for nevirapine-induced skin rash.

Nevirapine (NVP) treatment is associated with a significant incidence of skin rash in humans, and it also causes a similar immune-mediated skin rash in Brown Norway (BN) rats. We have shown that the sulfate of a major oxidative metabolite, 12-OH-NVP, covalently binds in the skin. The fact that the sulfate metabolite is responsible for covalent binding in the skin does not prove that it is responsible for the rash. We used various inhibitors of sulfation to test whether this reactive sulfate is responsible for the skin rash. Salicylamide (SA), which depletes 3'-phosphoadenosine-5'-phosphosulfate (PAPS) in the liver, significantly decreased 12-OH-NVP sulfate in the blood, but it did not prevent covalent binding in the skin or the rash. Topical application of 1-phenyl-1-hexanol, a sulfotransferase inhibitor, prevented covalent binding in the skin as well as the rash, but only where it was applied. In vitro incubations of 12-OH-NVP with PAPS and cytosolic fractions from the skin of rats or from human skin also led to covalent binding that was inhibited by 1-phenyl-1-hexanol. Incubation of 12-OH-NVP with PAPS and sulfotransferase 1A1*1, a human isoform that is present in the skin, also led to covalent binding, and this binding was also inhibited by 1-phenyl-1-hexanol. We conclude that salicylamide did not deplete PAPS in the skin and was unable to prevent covalent binding or the rash, while topical 1-phenyl-1-hexanol inhibited sulfation of 12-OH-NVP in the skin and did prevent covalent binding and the rash. These results provide definitive evidence that 12-OH-NVP sulfate formed in skin is responsible for NVP-induced skin rashes. Sulfotransferase is one of the few metabolic enzymes with significant activity in the skin, and it may be responsible for the bioactivation of other drugs that cause skin rashes.

Nevirapine bioactivation and covalent binding in the skin.

Nevirapine (NVP) treatment is associated with serious skin rashes that appear to be immune-mediated. We previously developed a rat model of this skin rash that is immune-mediated and is very similar to the rash in humans. Treatment of rats with the major NVP metabolite, 12-OH-NVP, also caused the rash. Most idiosyncratic drug reactions are caused by reactive metabolites; 12-OH-NVP forms a benzylic sulfate, which was detected in the blood of animals treated with NVP or 12-OH-NVP. This sulfate is presumably formed in the liver; however, the skin also has significant sulfotransferase activity. In this study, we used a serum against NVP to detect covalent binding in the skin of rats. There was a large artifact band in immunoblots of whole skin homogenates that interfered with detection of covalent binding; however, when the skin was separated into dermal and epidermal fractions, covalent binding was clearly present in the epidermis, which is also the location of sulfotransferases. In contrast to rats, treatment of mice with NVP did not result in covalent binding in the skin or skin rash. Although the reaction of 12-OH-NVP sulfate with nucleophiles such as glutathione is slow, incubation of this sulfate with homogenized human and rat skin led to extensive covalent binding. Incubations of 12-OH-NVP with the soluble fraction from a 9,000g centrifugation (S9) of rat or human skin homogenate in the presence of 3'-phosphoadenosine-5'-phosphosulfate (PAPS) produced extensive covalent binding, but no covalent binding was detected with mouse skin S9, which suggests that the reason mice do not develop a rash is that they lack the required sulfotransferase. This is the first study to report covalent binding of NVP to rat and human skin. These data provide strong evidence that covalent binding of NVP in the skin is due to 12-OH-NVP sulfate, which is likely responsible for NVP-induced skin rash. Sulfation may represent a bioactivation pathway for other drugs that cause a skin rash.

Animal models of idiosyncratic drug reactions.

If we could predict and prevent idiosyncratic drug reactions (IDRs) it would have a profound effect on drug development and therapy. Given our present lack of mechanistic understanding, this goal remains elusive. Hypothesis testing requires valid animal models with characteristics similar to the idiosyncratic reactions that occur in patients. Although it has not been conclusively demonstrated, it appears that almost all IDRs are immune-mediated, and a dominant characteristic is a delay between starting the drug and the onset of the adverse reaction. In contrast, most animal models are acute and therefore involve a different mechanism than idiosyncratic reactions. There are, however, a few animal models such as the nevirapine-induced skin rash in rats that have characteristics very similar to the idiosyncratic reaction that occurs in humans and presumably have a very similar mechanism. These models have allowed testing hypotheses that would be impossible to test in any other way. In addition there are models in which there is a delayed onset of mild hepatic injury that resolves despite continued treatment similar to the "adaptation" reactions that are more common than severe idiosyncratic hepatotoxicity in humans. This probably represents the development of immune tolerance. However, most attempts to develop animal models by stimulating the immune system have been failures. A specific combination of MHC and T cell receptor may be required, but it is likely more complex. Animal studies that determine the requirements for an immune response would provide vital clues about risk factors for IDRs in patients.

Bioactivation of nevirapine to a reactive quinone methide: implications for liver injury.

Nevirapine (NVP) treatment is associated with a significant incidence of liver injury. We developed an anti-NVP antiserum to determine the presence and pattern of covalent binding of NVP to mouse, rat, and human hepatic tissues. Covalent binding to hepatic microsomes from male C57BL/6 mice and male Brown Norway rats was detected on Western blots; the major protein had a mass of ~55 kDa. Incubation of NVP with rat CYP3A1 and 2C11 or human CYP3A4 also led to covalent binding. Treatment of female Brown Norway rats or C57BL/6 mice with NVP led to extensive covalent binding to a wide range of proteins. Co-treatment with 1-aminobenzotriazole dramatically changed the pattern of binding. The covalent binding of 12-hydroxy-NVP, the pathway that leads to a skin rash, was much less than that of NVP, both in vitro and in vivo. An analogue of NVP in which the methyl hydrogens were replaced by deuterium also produced less covalent binding than NVP. These data provide strong evidence that covalent binding of NVP in the liver is due to a quinone methide formed by oxidation of the methyl group. Attempts were made to develop an animal model of NVP-induced liver injury in mice. There was a small increase in ALT in some NVP-treated male C57BL/6 mice at 3 weeks that resolved despite continued treatment. Male Cbl-b(-/-) mice dosed with NVP had an increase in ALT of >200 U/L, which also resolved despite continued treatment. Liver histology in these animals showed focal areas of complete necrosis, while most of the liver appeared normal. This is a different pattern from the histology of NVP-induced liver injury in humans. This is the first study to report hepatic covalent binding of NVP and also liver injury in mice. It is likely that the quinone methide metabolite is responsible for NVP-induced liver injury.

Labyrinth walking in corrections.

A 6 week labyrinth walking program was pilot tested in a correctional setting and goals were to: 1) determine the feasibility of a labyrinth walking curriculum; 2) pilot test measures of health related quality of life (QOL) (pre and post-surveys) and blood pressure; and 3) examine the influence of relationship-centered teaching on subject satisfaction. Relational communication was used as a framework for this study, emphasizing concepts of trust, competency and similarly in the teacher. A pretest/posttest descriptive design was used. The sample was 14 offenders at a Massachusetts county jail. The intervention included six 90 minute sessions, composed of a lecture, a labyrinth walk, and journal writing. Measures included a demographic survey; pre and post session walk blood pressures; pre and post program QOL measures; and a post program measure of satisfaction. The sample was 57% Caucasian, 36% Hispanic, and 7% African American, with an average age of 34, mostly high school educated and single. Drug of choice was alcohol with age of use at 12 and 1/2 years. Seventy-nine percent were previously incarcerated more than twice. QOL data were not changed pre to post. BP data trended in a healthy direction from weeks 1 to 6. Satisfaction with the teacher and the program was high. The labyrinth walking pilot program was proven feasible, low cost and satisfying for the participants. Recommendations for future studies are discussed.

DNA methylation alterations in multiple myeloma as a model for epigenetic changes in cancer.

Epigenetics refers to heritable modifications of the genome that are not a result of changes in the DNA sequence and result in phenotypic changes. These changes can be stably transmitted through cell division and are potentially reversible. Epigenetic events are very important during normal development wherein a single progenitor cell proliferates and differentiates into various somatic cell types. This process occurs through modification of the genome without changing the genetic code. Because epigenetic control of gene expression is so important, aberrant epigenetic regulation can lead to disease and cancer. This article reviews epigenetic changes seen in cancer by examining epigenetic changes commonly found in multiple myeloma, a common hematologic malignancy of plasma cells. Epigenetic control of gene expression can be exerted by changes in DNA methylation, histone modifications, and expression of noncoding RNAs. Each of these regulatory mechanisms interacts with the others at different genomic locations and can be measured quantitatively within the cell, requiring that we consider these mechanisms not individually but as a biological system. DNA methylation was the earliest discovered epigenetic regulator and has been the focus of most investigations in cancer. We have thus focused on DNA methylation changes in the pathogenesis of multiple myeloma, which promises to become an excellent model for systems biological studies of epigenomic dysregulation in human disease.

Neutron-stimulated emission computed tomography of a multi-element phantom.

This paper describes the implementation of neutron-stimulated emission computed tomography (NSECT) for non-invasive imaging and reconstruction of a multi-element phantom. The experimental apparatus and process for acquisition of multi-spectral projection data are described along with the reconstruction algorithm and images of the two elements in the phantom. Independent tomographic reconstruction of each element of the multi-element phantom was performed successfully. This reconstruction result is the first of its kind and provides encouraging proof of concept for proposed subsequent spectroscopic tomography of biological samples using NSECT.

Near-Field High-Energy Spectroscopic Gamma Imaging Using a Rotation Modulation Collimator.

Certain trace elements are vital to the body and elemental imbalances can be indicators of certain diseases including cancer and liver diseases. Neutron Stimulated Emission Computed Tomography (NSECT) is being developed as spectroscopic imaging technique to non-invasively and non-destructively measure and image elemental concentrations within the body. A region of interest is illuminated via a high-energy beam of neutrons that scatter inelastically with elemental nuclei within the body. The excited nuclei then relax by emitting characteristic gamma rays. Acquiring the gamma spectrum in a tomographic manner allows not only the identification of elements, but also the formation of images representing spatial distributions of specific elements. We are developing a high-energy position-sensitive gamma camera that allows full illumination of the entire region of interest. Because current scintillation crystal based position-sensitive gamma cameras operate in too low of an energy range, we are adapting high-energy gamma imaging techniques used in space-based imaging. A High Purity Germanium (HPGe) detector provides high-resolution energy spectra while a rotating modulation collimator (RMC) placed in front of the detector modulates the incoming signal to provide spatial information. The purpose of this manuscript is to describe the near-field RMC geometry, which varies greatly from the infinite-focus space-based applications, and how it modulates the incident gamma flux. A simple geometric model is presented and then used to reconstruct two-dimensional planar images of both simulated point sources and extended sources.

Breast cancer detection using neutron stimulated emission computed tomography: prominent elements and dose requirements.

Neutron stimulated emission computed tomography (NSECT) is being developed to noninvasively determine concentrations of trace elements in biological tissue. Studies have shown prominent differences in the trace element concentration of normal and malignant breast tissue. NSECT has the potential to detect these differences and diagnose malignancy with high accuracy with dose comparable to that of a single mammogram. In this study, NSECT imaging was simulated for normal and malignant human breast tissue samples to determine the significance of individual elements in determining malignancy. The normal and malignant models were designed with different elemental compositions, and each was scanned spectroscopically using a simulated 2.5 MeV neutron beam. The number of incident neutrons was varied from 0.5 million to 10 million neutrons. The resulting gamma spectra were evaluated through receiver operating characteristic (ROC) analysis to determine which trace elements were prominent enough to be considered markers for breast cancer detection. Four elemental isotopes (133Cs, 81Br, 79Br, and 87Rb) at five energy levels were shown to be promising features for breast cancer detection with an area under the ROC curve (A(Z)) above 0.85. One of these elements--87Rb at 1338 keV--achieved perfect classification at 10 million incident neutrons and could be detected with as low as 3 million incident neutrons. Patient dose was calculated for each gamma spectrum obtained and was found to range from between 0.05 and 0.112 mSv depending on the number of neutrons. This simulation demonstrates that NSECT has the potential to noninvasively detect breast cancer through five prominent trace element energy levels, at dose levels comparable to other breast cancer screening techniques.

Introduction to neutron stimulated emission computed tomography.

Neutron stimulated emission computed tomography (NSECT) is presented as a new technique for in vivo tomographic spectroscopic imaging. A full implementation of NSECT is intended to provide an elemental spectrum of the body or part of the body being interrogated at each voxel of a three-dimensional computed tomographic image. An external neutron beam illuminates the sample and some of these neutrons scatter inelastically, producing characteristic gamma emission from the scattering nuclei. These characteristic gamma rays are acquired by a gamma spectrometer and the emitting nucleus is identified by the emitted gamma energy. The neutron beam is scanned over the body in a geometry that allows for tomographic reconstruction. Tomographic images of each element in the spectrum can be reconstructed to represent the spatial distribution of elements within the sample. Here we offer proof of concept for the NSECT method, present the first single projection spectra acquired from multi-element phantoms, and discuss potential biomedical applications.

A finite-element method model of soft tissue response to impulsive acoustic radiation force.

Several groups are studying acoustic radiation force and its ability to image the mechanical properties of tissue. Acoustic radiation force impulse (ARFI) imaging is one modality using standard diagnostic ultrasound scanners to generate localized, impulsive, acoustic radiation forces in tissue. The dynamic response of tissue is measured via conventional ultrasonic speckle-tracking methods and provides information about the mechanical properties of tissue. A finite-element method (FEM) model has been developed that simulates the dynamic response of tissues, with and without spherical inclusions, to an impulsive acoustic radiation force excitation from a linear array transducer. These FEM models were validated with calibrated phantoms. Shear wave speed, and therefore elasticity, dictates tissue relaxation following ARFI excitation, but Poisson's ratio and density do not significantly alter tissue relaxation rates. Increased acoustic attenuation in tissue increases the relative amount of tissue displacement in the near field compared with the focal depth, but relaxation rates are not altered. Applications of this model include improving image quality, and distilling material and structural information from tissue's dynamic response to ARFI excitation. Future work on these models includes incorporation of viscous material properties and modeling the ultrasonic tracking of displaced scatterers.