Antiandrogen Therapy Radiosensitizes Androgen Receptor-Positive Cancers to 18F-FDG.

A subset (35%) of triple-negative breast cancers (TNBCs) expresses androgen receptor (AR) activity. However, clinical trials with antiandrogen drugs have shown limited efficacy, with about a 19% clinical benefit rate. We investigated the therapeutic enhancement of antiandrogens as radiosensitizers in combination with 18F-FDG in TNBC. Methods: We screened 5 candidate drugs to evaluate shared toxicity when combined with either 18F-FDG, x-rays, or ultraviolet radiation, at doses below their respective half-maximal inhibitory concentrations. Cytotoxic enhancement of antiandrogen in combination with 18F-FDG was evaluated using cell proliferation and DNA damage assays. Finally, the therapeutic efficacy of the combination treatment was evaluated in mouse tumor models of TNBC and prostate cancer. Results: Bicalutamide, an antiandrogen drug, was found to share similar toxicity in combination with either 18F-FDG or x-rays, indicating its sensitivity as a radiosensitizer to 18F-FDG. Cell proliferation assays demonstrated selective toxicity of combination bicalutamide-18F-FDG in AR-positive 22RV1 and MDA-MB-231 cells in comparison to AR-negative PC3 cells. Quantitative DNA damage and cell cycle arrest assays further confirmed radiation-induced damage to cells, suggesting the role of bicalutamide as a radiosensitizer to 18F-FDG-mediated radiation damage. Animal studies in MDA-MB-231, 22RV1, and PC3 mouse tumor models demonstrated significant attenuation of tumor growth through combination of bicalutamide and 18F-FDG in the AR-positive model in comparison to the AR-negative model. Histopathologic examination corroborated the in vitro and in vivo data and confirmed the absence of off-target toxicity to vital organs. Conclusion: These data provide evidence that 18F-FDG in conjunction with antiandrogens serving as radiosensitizers has utility as a radiotherapeutic agent in the ablation of AR-positive cancers.

MEASUREMENT AND ANALYSIS OF THE NEUTRON ENERGY SPECTRUM AND ASSOCIATED OCCUPATIONAL EXPOSURE FROM A SHIELDED241AM-BE SOURCE.

A set of five Bonner spheres was used to measure the ambient neutron H*(10) dose around an orphan 241Am-Be neutron source shielded with different arrangements and types of neutron-absorbing materials. These results were compared to measurements obtained using a portable radiation dosemeter. The Bonner sphere measurement results identified the presence of a large thermal and intermediate neutron component from the shielded 241Am-Be source that was not revealed using the portable instrument.

Radio-Fluorogenic Gel Dosimetry with Coumarin.

Gel dosimeters are attractive detectors for radiation therapy, with properties similar to biological tissue and the potential to visualize volumetric dose distributions. Radio-fluorogenesis is the yield of fluorescent chemical products in response to energy deposition from ionizing radiation. This report shares the development of a novel radio-fluorogenic gel (RFG) dosimeter, gelatin infused with coumarin-3-carboxlyic acid (C3CA), for the quantification of imparted energy. Aqueous solutions exposed to ionizing radiation result in the production of hydroxyl free radicals through water radiolysis. Interactions between hydroxyl free radicals and coumarin-3-carboxylic acid produce a fluorescent product. 7-hydroxy-coumarin-3-carboxylic acid has a blue (445 nm) emission following ultra-violet (UV) to near UV (365⁻405 nm) excitation. Effects of C3CA concentration and pH buffers were investigated. The response of the RFG was explored with respect to strength, type, and exposure rate of high-energy radiation. Results show a linear dose response relationship independent of energy and type, with a dose-rate dependency. This report demonstrates increased photo-yield with high pH and the utility of gelatin-RFG for phantom studies of radiation dosimetry.

Uranium mobility across annual growth rings in three deciduous tree species.

Black walnut (Juglans nigra), slippery elm (Ulmus rubra), and white ash (Fraxinus americana) trees were evaluated as potential archives of past uranium (U) contamination. Like other metals, U mobility in annual growth rings of trees is dependent on the tree species. Uranium concentrations and isotopic compositions (masses 234, 235, 236, and 238) were analyzed by thermal ionization mass spectrometry to test the efficacy of using tree rings to retroactively monitor U pollution from the FFMPC, a U purification facility operating from 1951 to 1989. This study found non-natural U (depleted U and detectable 236U) in growth rings of all three tree species that pre-dated the start of operations at FFMPC and compositional trends that did not correspond with known contamination events. Therefore, the annual growth rings of these tree species cannot be used to reliably monitor the chronology of U contamination.

In vitro dissolution of uranium-contaminated soil in simulated lung fluid containing a pulmonary surfactant.

During the latter part of the twentieth century, the United States developed a highly technical nuclear weapons complex that involved workers at many facilities performing complex missions at a number of different industrial sites across the country. Now, many of these sites are being remediated to remove legacy materials including chemical and radioactive wastes. Along with remediation comes the responsibility to adequately assess risk to cleanup workers who could be exposed to any hazardous materials, including resuspended uranium dust, encountered during environmental restoration. Inhalation of resuspended uranium represents one of the exposure hazards at an abandoned former metal rolling mill where approximately 11 thousand tons of uranium metal was rolled between 1947 and 1958. Residual uranium contamination in the dirt floor of this abandoned site has been exposed to rain, ice, snow, and other environmental factors for more than 50 y. This report describes the solubility of the uranium contamination in this dirt measured in vitro using a modified recipe for simulated lung fluid that contains a pulmonary surfactant. Small (0.1 g) aliquots of dirt collected at this site were sequentially dissolved in simulated lung fluid for increasing periods of time up to 30 d. Solubility was classified according to the ICRP categories as fast, medium, and slow. Results demonstrate that the solubility designation for the uranium contamination in the dirt is approximately 50% fast, 15% medium, and 35-40% slow. There was no observed difference in solubility when a pulmonary surfactant was added to the simulated lung fluid.

In vivo measurement of 241Am in the lungs confounded by activity deposited in other organs.

Radioactive material deposited in multiple organs of the body is likely to confound a result of an in vivo measurement performed over the lungs, the most frequently monitored organ for occupational exposure. The significance of this interference was evaluated by measuring anthropometric torso phantoms containing lungs, liver, skeleton, and axillary lymph nodes, each with a precisely known quantity of 241Am uniformly distributed in the organs. Arrays of multiple high-resolution germanium detectors were positioned over organs within the torso phantom containing 241Am or over proximal organs without activity to determine the degree of measurement confounding due to photons emitted from other source organs. A set of four mathematical response functions describes the measured count rate with detectors positioned over each of the relevant organs and 241Am contained in the measured organ or one of the other organs selected as a confounder. Simultaneous solution of these equations by matrix algebra, where the diagonal terms of the matrix are calibration factors for a direct measurement of activity in an organ and the off-diagonal terms reflect the contribution (i.e., interference or cross-talk) produced by 241Am in a confounding organ, yields the activity deposited in each of the relevant organs. The matrix solution described in this paper represents a method for adjusting a result of 241Am measured directly in one organ for interferences that may arise from 241Am deposited elsewhere and represents a technically valid procedure to aid in evaluating internal dose based upon in vivo measurements for those radioactive materials known to deposit in multiple organs.

Evaluation of residual uranium contamination in the dirt floor of an abandoned metal rolling mill.

A single, large, bulk sample of uranium-contaminated material from the dirt floor of an abandoned metal rolling mill was separated into different types and sizes of aliquots to simulate samples that would be collected during site remediation. The facility rolled approximately 11,000 tons of hot-forged ingots of uranium metal approximately 60 y ago, and it has not been used since that time. Thirty small mass (≈ 0.7 g) and 15 large mass (≈ 70 g) samples were prepared from the heterogeneously contaminated bulk material to determine how measurements of the uranium contamination vary with sample size. Aliquots of bulk material were also resuspended in an exposure chamber to produce six samples of respirable particles that were obtained using a cascade impactor. Samples of removable surface contamination were collected by wiping 100 cm of the interior surfaces of the exposure chamber with 47-mm-diameter fiber filters. Uranium contamination in each of the samples was measured directly using high-resolution gamma ray spectrometry. As expected, results for isotopic uranium (i.e., U and U) measured with the large-mass and small-mass samples are significantly different (p < 0.001), and the coefficient of variation (COV) for the small-mass samples was greater than for the large-mass samples. The uranium isotopic concentrations measured in the air and on the wipe samples were not significantly different and were also not significantly different (p > 0.05) from results for the large- or small-mass samples. Large-mass samples are more reliable for characterizing heterogeneously distributed radiological contamination than small-mass samples since they exhibit the least variation compared to the mean. Thus, samples should be sufficiently large in mass to insure that the results are truly representative of the heterogeneously distributed uranium contamination present at the facility. Monitoring exposure of workers and the public as a result of uranium contamination resuspended during site remediation should be evaluated using samples of sufficient size and type to accommodate the heterogeneous distribution of uranium in the bulk material.

Detection efficiency for measuring 241Am in axillary lymph nodes using different types and sizes of detectors.

The detection efficiency and interference susceptibility of four different types of low energy photon detectors, each with a unique geometric arrangement, were compared for direct measurement of Am deposited in the axillary lymph nodes. Although the most efficient detector was a single large 23,226 mm square phoswich detector, it was also the most susceptible to confounding depositions from activity deposited in adjacent organs. The array of two 2,800 mm high purity germanium detectors exhibited the highest efficiency per unit detector area with some resistance to confounding from activity deposited in the lungs. The array of two 4,560 mm NaI(Tl) detectors was the least susceptible to confounding and nearly as efficient per square millimeter as the high purity germanium detector array. Thus, selection of a detector system for in vivo measurement of activity deposited in the axillary lymph nodes should consider whether there is a likelihood for activity deposited in other organs, such as the lungs, skeleton, or liver, to create an interference that will confound the measurement result.

Significant systemic therapeutic effects of high-LET immunoradiation by 212Pb-trastuzumab against prostatic tumors of androgen-independent human prostate cancer in mice.

The purpose of this study was to determine therapeutic effects and systemic toxicity of 212Pb-trastuzumab in an orthotopic model of human prostate cancer cells in nude mice. TCMC-Trastuzumab was radiolabeled with 212Pb. The 212Pb-trastuzumab generated from the procedure was intact and had high binding affinity with a dissociation constant (of 3.9±0.99 nM. PC-3MM2 cells, which expressed a lower level of HER2 both in culture and in tumors, were used in therapy studies. A single intravenous injection of 212Pb-trastuzumab reduced tumor growth by 60-80%, reduced aortic lymph node metastasis, and prolonged the survival of tumor-bearing mice. Treatment with 212Pb-trastuzumab did not cause significant changes in body weight, serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), hematological profiles, and histological morphology of several major organs of tumor-bearing mice. These findings suggest that a systemic delivery of 212Pb-trastuzumab could be an effective modality for management of advanced human prostate cancer.

The influence of bone-density on in vivo K x-ray fluorescence bone-lead measurements.

Mathematical simulations and benchmark measurements were performed to assess the impact that normal variations in human calcium content have on in vivo K x-ray fluorescence measurements of lead in bone. Four sets of cortical bone tissue simulants were fabricated containing from 20.8% to 23.8% calcium (by weight) for measurement in a surrogate (phantom) of the human leg. The net counts detected in the coherent backscatter peak at 88.034 keV using a Cd source indicate a positive trend, with a variability of up to 17% over the range of assessed calcium content. Mathematical simulations confirm this trend and also demonstrate that the contribution of 87.3 keV Pb Kß2 counts, which are unresolved in measurements, do not contribute significantly to the coherent peak at low levels of bone-lead content. Both measurements and simulations confirm that calcium is a statistically significant parameter in predicting the K-XRF response and suggest that lead levels may be over-predicted for individuals having low bone density compared to the calibration matrix. Simulations identify a 4.5% negative bias in measured lead values for each 1% increase in calcium weight percent in the bone matrix as compared to the calibration matrix. It is therefore important to accommodate this uncertainty when performing epidemiological studies of populations having a wide range of bone densities.

A calibration phantom for direct, in vivo measurement of 241Am in the axillary lymph nodes.

A calibration phantom was developed at the University of Cincinnati (UC) to determine detection efficiency and estimate the quantity of activity deposited in the axillary lymph nodes of a worker who had unknowingly sustained a wound contaminated with 241Am at some distant time in the past. This paper describes how the Livermore Torso Phantom was modified for calibrating direct, in vivo measurements of 241Am deposited in the axillary lymph nodes. Modifications involved milling a pair of parallel, flat bottom, cylindrical holes into the left and right shoulders (below the humeral head) of the Livermore Torso Phantom in which solid, 1.40-cm-diameter cylindrical rods were inserted. Each rod was fabricated using a muscle tissue substitute. One end of each rod contained a precisely known quantity of Am sealed in a 1-cm-diameter, 2.54-cm-deep well to simulate the axillary lymph nodes when inserted into the modified Livermore Torso Phantom. The fixed locations for the axillary lymph nodes in the phantom were determined according to the position of the Level I and the combined Level II + III axillary lymph nodes reported in the literature. Discrete calibration measurements for 241Am in the simulated axillary lymph nodes located in the right and left sides of the thorax were performed using pairs of high-resolution germanium detectors at UC and Lawrence Livermore National Laboratory. The percent efficiency for measuring the 59.5 keV photon from Am deposited in the right and left axillary lymph nodes using a pair of 3,000 mm2 detectors is 2.60 +/- 0.03 counts gamma-1 and 5.45 +/- 0.07 counts gamma-1, respectively. Activity deposited in the right and left axillary lymph nodes was found to contribute 12.5% and 19.7%, respectively, to a lung measurement and 1.2% and 0.2%, respectively, to a liver measurement. Thus, radioactive material mobilized from a wound in a finger or hand and deposited in the axillary lymph nodes has been shown to confound results of a direct, in vivo measurement of the lungs.

School bus pollution and changes in the air quality at schools: a case study.

Millions of children attending US schools are exposed to traffic-related air pollutants, including health-relevant ultrafine aerosols generated from school buses powered with diesel fuel. This case study was established in a midwestern (USA) metropolitan area to determine the concentration and elemental composition of aerosol in the vicinity of a public school during morning hours when the bus traffic in and out of the adjacent depot was especially intense. Simultaneous measurements were performed at a control site. The ambient aerosol was first characterized in real time using a particle size selective aerosol spectrometer and then continuously monitored at each site with a real-time non-size-selective instrument that detected particles of 20 nm to >1 microm. In addition, air samples were collected with PM2.5 Harvard Impactors and analyzed for elemental composition using the X-ray fluorescence technique (for 38 elements) and thermal-optical transmittance (for carbon). The measurements were conducted during two seasons: in March at ambient temperature around 0 degrees C and in May when it ranged mostly between 10 and 20 degrees C. The particle number concentration at the test site exhibited high temporal variability while it was time independent at the control site. Overall, the aerosol particle count at the school was 4.7 +/- 1.0 times (March) and 2.2 +/- 0.4 times (May) greater than at the control site. On some days, a 15 min-averaged particle number concentration showed significant correlation with the number of school bus arrivals and departures during these time intervals. On other days, the correlation was less than statistically significant. The 3 h time-averaged particle concentrations determined in the test site on days when the school buses operated were found to be more than two-fold greater (on average) than those measured on bus-free days at the same location, and this difference was statistically significant. Overall, the data suggest a possible association between the number of detected aerosol particles and the school bus traffic intensity. Analysis of the filter samples collected at the school site between 6:00 and 9:00 AM revealed higher concentrations of elemental carbon as compared to the control site (2.8 +/- 0.9 times in March and 3.1 +/- 1.1 times in May). The data collected in this case study suggest that school buses significantly contribute to exposure of children to aerosol pollutants (including diesel exhaust particles) in the school vicinity.

Monte Carlo simulation of an anthropometric phantom used for calibrating in vivo K-XRF spectroscopy measurements of stable lead in bone.

An anthropometric surrogate (phantom) of the human leg was defined in the constructs of the Monte Carlo N Particle (MCNP) code to predict the response when used in calibrating K x-ray fluorescence (K-XRF) spectrometry measurements of stable lead in bone. The predicted response compared favorably with measurements using the anthropometric phantom containing a tibia with increasing stable lead content. These benchmark measurements confirmed the validity of a modified MCNP code to accurately simulate K-XRF spectrometry measurements of stable lead in bone. A second, cylindrical leg phantom was simulated to determine whether the shape of the calibration phantom is a significant factor in evaluating K-XRF performance. Simulations of the cylindrical and anthropometric calibration phantoms suggest that a cylindrical calibration standard overestimates lead content of a human leg up to 4%. A two-way analysis of variance determined that phantom shape is a statistically significant factor in predicting the K-XRF response. These results suggest that an anthropometric phantom provides a more accurate calibration standard compared to the conventional cylindrical shape, and that a cylindrical shape introduces a 4% positive bias in measured lead values.

Population monitoring for acute exposure to 210Po.

OBJECTIVE: To investigate the feasibility of using single void urine samples to monitor internal radiation exposure of first responders and large populations int he event of a radiological incident involving the intentional dispersal of 210Po. METHODS: Urinary excretion of 210Po was evaluated and organ absorbed and effective doses were calculated subsequent to an acute unit intake of 210Po. RESULTS: 210Po can be detected in single void urine samples at levels sufficient to detect effective dose below recommended limits. Minimum intakes of 210Po that would result in clinically significant effects were estimated. CONCLUSIONS: Collection and analysis of single void urine samples is adequate to identify persons who may be exposed in the event of a radiological emergency involving 210Po. Also, the first responder limit appears to be sufficiently protective to prevent clinically significant deterministic effects.

Modification to the Monte Carlo N-particle code for simulating direct, in vivo measurement of stable lead in bone.

Monte Carlo N-Particle version 4C (MCNP4C) was used to simulate photon interactions associated with in vivo x-ray fluorescence (XRF) measurement of stable lead in bone. Experimental measurements, performed using a cylindrical anthropometric phantom (i.e., surrogate) of the human leg made from tissue substitutes for muscle and bone, revealed a significant difference between the intensity of the observed and predicted coherent backscatter peak. The observed difference was due to the failure of MCNP4C to simulate photon scatter associated with greater than six inverse angstroms of momentum transfer. The MCNP4C source code, photon directory, and photon library were modified to incorporate atomic form factors up to 7.1 inverse angstroms for the high Z elements defined in the K XRF simulation. The intensity of the predicted coherent photon backscatter peak at 88 keV using the modified code increased from 3.50 x 10(-9) to 8.59 x 10(-7) (roughly two orders of magnitude) and compares favorably with the experimental measurements.

Radiation exposure from work-related medical X-rays at the Portsmouth Naval Shipyard.

BACKGROUND: Previous analyses suggest that worker radiation dose may be significantly increased by routine occupational X-ray examinations. Medical exposures are investigated for 570 civilian workers employed at the Portsmouth Naval Shipyard (PNS) at Kittery, Maine. The research objective was to determine the radiation exposure contribution of work-related chest X-rays (WRX) relative to conventional workplace radiation sources. METHODS: Methods were developed to estimate absorbed doses to the active (hematopoietic) bone marrow from X-ray examinations and workplace exposures using data extracted from worker dosimetry records (8,468) and health records (2,453). Dose distributions were examined for radiation and non-radiation workers. RESULTS: Photofluorographic chest examinations resulted in 82% of the dose from medical sources. Radiation workers received 26% of their collective dose from WRX and received 66% more WRX exposure than non-radiation workers. CONCLUSIONS: WRX can result in a significant fraction of the total dose, especially for radiation workers who were more likely to be subjected to routine medical monitoring. Omission of WRX from the total dose is a likely source of bias that can lead to dose category misclassification and may skew the epidemiologic dose-response assessment for cancers induced by the workplace.

Long-term stewardship of the environmental legacy at restored sites within the Department of Energy nuclear weapons complex.

It is readily apparent, as the Department of Energy Office of Environmental Management proceeds in remediating its vast network of contaminated nuclear weapons facilities, that final cleanup at many facilities will not be performed to a level allowing unrestricted use of the facility. Instead, these facilities must rely on engineering, administrative, and institutional controls to ensure the level of cleanup performed at the site remains adequately protective of public health and the environment. In order for these controls to remain effective, however, a plan for long-term stewardship of these sites must be developed that is approved by the U.S. Congress. Although this sounds simple enough for the present, serious questions remain regarding how best to implement a program of stewardship to ensure its effectiveness over time, particularly for sites with residual contamination of radionuclides with half-lives on the order of thousands of years. Individual facilities have attempted to answer these questions at the site-specific level. However, the complexities of the issues require federal support and oversight to ensure the programs implemented at each of the facilities are consistent and effective. The Department of Energy recently submitted a report to Congress outlining the extent of long-term stewardship needs at each of its facilities. As a result, the time is ripe for forward thinking Congressional action to address the relevant issues and ensure the remedy of long-term stewardship successfully carries out its intended purpose and remains protective of public health and the environment. The regulatory elements necessary for the stewardship program to succeed can only be implemented through the plenary powers of the U.S. Congress.