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At least 1,099 records · Page 61
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Land use and air quality in urban environments: Human health risk assessment due to inhalation of airborne particles

Highlights: • Biomonitors showed intraurban differences in particles bound metals. • The PM{sub 10} limit (150 µg/m{sup 3}) was exceeded in almost all land uses categories. • Industrial sites had an unacceptable carcinogenic risk (> 1 × 10{sup −4}). • Adults and elder are the most susceptible age groups. • Land use influence health risk due to particle inhalation. Particle matter (PM) and its associated compounds are a serious problem for urban air quality and a threat to human health. In the present study, we assessed the intraurban variation of PM, and characterized the human health risk associated to the inhalation of particles measured on PM filters, considering different land use areas in the urban area of Cordoba city (Argentina) and different age groups. To assess the intraurban variation of PM, a biomonitoring network of T. capillaris was established in 15 sampling sites with different land use and the bioaccumulation of Co, Cu, Fe, Mn, Ni, Pb and Zn was quantified. After that, particles were collected by instrumental monitors placed at the most representative sampling sites of each land use category and an inhalation risk was calculated. A remarkable intraurban difference in the heavy metals content measured in the biomonitors was observed, in relation with the sampling site land use. The higher content was detected at industrial areas as well as in sites with intense vehicular traffic. Mean PM{sub 10} levels exceeded the standard suggested by the U.S. EPA in all land use areas, except for the downtown. Hazard Index values were below EPA's safe limit in all land use areas and in the different age groups. In contrast, the carcinogenic risk analysis showed that all urban areas exceeded the acceptable limit (1 × 10{sup −6}), while the industrial sampling sites and the elder group presented a carcinogenic risk higher that the unacceptable limit. These findings validate the use of T. capillaris to assess intraurban air quality and also show there is an important intraurban variation in human health risk associated to different land use.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Neurocognitive and physical functioning in the Seveso Women's Health Study

Highlights: • Little research exists on the neurotoxic effects of dioxins in older women. • TCDD was associated with grip strength but not other measures of physical function. • TCDD exposure was not adversely associated with working memory. • This relationship was not modified by menopause nor timing of TCDD exposure around menarche. • TCDD susceptibility may increase as the women age, warranting further research. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is neurotoxic in animals but few studies have investigated its effects on the human brain. Related dioxin-like compounds have been linked to poorer cognitive and motor function in older adults, with effects more pronounced in women, perhaps due to the loss of neuro-protective estrogen in menopause. On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in one of the highest known residential exposures to TCDD. In 1996, we initiated the Seveso Women's Health Study, a retrospective cohort study of the health of the women who were newborn to 40 years old in 1976. Here, we investigate whether TCDD exposure is associated with physical functioning and working memory more than 20 years later. Individual TCDD concentration (ppt) was measured in archived serum collected soon after the explosion. In 1996 and 2008, we measured physical functioning (n=154) and working memory (n=459), respectively. We examined associations between serum TCDD and motor and cognitive outcomes with multivariate linear regression and semi-parametric estimators. A 10-fold increase in serum TCDD was not associated with walking speed (adjusted β=0.0006 ft/s, 95% Confidence Interval (CI): −0.13, 0.13), upper body mobility (adjusted β=−0.06, 95% CI: −0.36, 0.23), or manual dexterity (adjusted β=0.34, 95% CI: −0.65, 1.33). We observed an inverted U-shaped association in grip strength, with poorer strength in the lowest and highest TCDD exposure levels. There was no association between TCDD and the Wechsler digit and spatial span tests. Neither menopause status at assessment nor developmental timing of exposure modified associations between TCDD and working memory. Our findings, in one of the only studies of TCDD's effects on neuropsychological and physical functioning in women, do not indicate an adverse effect on these domains, with the exception of a U-shaped relationship with grip strength. Given the limited assessment and relative youth of the women at this follow-up, future work examining additional neuropsychological outcomes is warranted.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Wi-Fi is an important threat to human health

Highlights: • 7 effects have each been repeatedly reported following Wi-Fi & other EMF exposures. • Established Wi-Fi effects, include apoptosis, oxidat. stress &: • testis/sperm dysfunct; Neuropsych; DNA impact; hormone change; Ca2+ rise. • Wi-Fi is thought to act via voltage-gated calcium channel activation. • One claim of no Wi-Fi effects was found to be deeply flawed. Repeated Wi-Fi studies show that Wi-Fi causes oxidative stress, sperm/testicular damage, neuropsychiatric effects including EEG changes, apoptosis, cellular DNA damage, endocrine changes, and calcium overload. Each of these effects are also caused by exposures to other microwave frequency EMFs, with each such effect being documented in from 10 to 16 reviews. Therefore, each of these seven EMF effects are established effects of Wi-Fi and of other microwave frequency EMFs. Each of these seven is also produced by downstream effects of the main action of such EMFs, voltage-gated calcium channel (VGCC) activation. While VGCC activation via EMF interaction with the VGCC voltage sensor seems to be the predominant mechanism of action of EMFs, other mechanisms appear to have minor roles. Minor roles include activation of other voltage-gated ion channels, calcium cyclotron resonance and the geomagnetic magnetoreception mechanism. Five properties of non-thermal EMF effects are discussed. These are that pulsed EMFs are, in most cases, more active than are non-pulsed EMFs; artificial EMFs are polarized and such polarized EMFs are much more active than non-polarized EMFs; dose-response curves are non-linear and non-monotone; EMF effects are often cumulative; and EMFs may impact young people more than adults. These general findings and data presented earlier on Wi-Fi effects were used to assess the Foster and Moulder (F&M) review of Wi-Fi. The F&M study claimed that there were seven important studies of Wi-Fi that each showed no effect. However, none of these were Wi-Fi studies, with each differing from genuine Wi-Fi in three distinct ways. F&M could, at most conclude that there was no statistically significant evidence of an effect. The tiny numbers studied in each of these seven F&M-linked studies show that each of them lack power to make any substantive conclusions. In conclusion, there are seven repeatedly found Wi-Fi effects which have also been shown to be caused by other similar EMF exposures. Each of the seven should be considered, therefore, as established effects of Wi-Fi.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Metabolites of organophosphate ester flame retardants in urine from Shanghai, China

Highlights: • Nine organophosphate ester (OPE) metabolites were determined in urine from a population in Shanghai. • Urinary levels of OPE metabolites were lower than those from more developed countries. • Age of donors and age of homes were determinants of diphenyl phosphate (DPHP) and di-n-butyl phosphate (DNBP) exposures. • Urinary DNBP levels were associated with self-reported symptoms of allergy. The metabolites of nine organophosphate ester (OPE) flame retardants were measured in 180 urine samples collected from a population (including adults and children) in western Shanghai, China, using liquid chromatography-tandem spectrometry (LC-MS/MS). The total urinary concentrations of nine OPE metabolites ranged 100–23800 pg/mL, with a geometric mean (GM) value of 1450 pg/mL. The concentrations of alkyl-OPE metabolites (879 pg/mL) were approximately an order of magnitude higher than those of aryl-OPE (53.7 pg/mL) and chlorinated-OPE metabolites (52.7 pg/mL). Diphenyl phosphate (DPHP), diethyl phosphate (DEP), di-n-butyl phosphate (DNBP), bis(2-ethylhexyl) phosphate (BEHP), and bis(2-butoxyethyl) phosphate (BBOEP) were the dominant OPE metabolites found in urine. The results showed that an increase in age was associated with a significant decrease in urinary DPHP (r = −0.278, p < 0.01) and DNBP (r = −0.314, p < 0.01) concentrations. The highest concentrations of DPHP (GM = 80.7 pg/mL) and DNBP (GM = 16.9 pg/mL) were found in urine from people living in homes that were less than 10 years old. The urinary DNBP concentration was significantly associated with self-reported symptoms of allergy. Our result establishes baseline value for OPE exposure in a population in China for comparison in future studies.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Assessment of human health risk associated with methylmercury in the imported fish marketed in the Caribbean

Highlights: • Levels of Hg species in the most popular imported fish were studied in Colombia. • Mean concentrations do not exceeded the maximum levels of Hg permitted in fish. • The estimated weekly intakes suggest that children should not eat any can of tuna. • Pregnant woman should eat no more than 2 cans of tuna per week (one can from brand D). The decline in marine and freshwaters catches in recent years in Colombia has led to a change in dietary habits, with an increase in the purchase and consumption of imported fish. This is of particular concern as fish are sometimes caught in mercury-contaminated waters, and are subsequently sold canned or uncanned. In addition, canned tuna has received little attention as it is widely assumed that concentrations are low. In this study, total mercury (THg) and methylmercury (MeHg) concentrations were evaluated in three imported fish species marketed in Colombia, Prochilodus lineatus, Prochilodus reticulatus, and Pangasianodon hypophthalmus, plus four brands of canned tuna and one of sardines. One brand of tuna showed the highest mean concentrations of THg (0.543 ± 0.237 μg/g, wet weight, ww) and MeHg (0.518 ± 0.337 μg/g ww), while concentrations in P. hypophthalmus were approximately 30 times lower (≈0.02 µg/g ww). The estimated weekly intake (EWI) in children was above the provisional tolerable weekly intake (PTWI) of MeHg established by the Joint FAO/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) in 2007, 1.6 μg/kg body weight (bw) per week, for all the canned tuna brands. Values for adults were below PTWI, whereas for women of childbearing age, values were above PTWI only for brand D of canned tuna. The estimate of the potential risk indicated that MeHg levels in canned tuna can generate negative effects in vulnerable groups, while the EWI of fresh fish did not pose a threat to the general population. Therefore, establishing strategies to address the high consumption of canned tuna, and continuous monitoring to control commercial food, are recommended to decrease Hg exposure.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Prenatal pesticide exposure associated with glycated haemoglobin and markers of metabolic dysfunction in adolescents

Highlights: • Prenatal pesticide exposure was associated with higher HbA1c in adolescents. • After stratification for sex, the association remained significant for girls. • The association was significant if the child or the mother had the PON1 192R-allele. • Prenatally pesticide exposed children had higher leptin-to-adiponectin ratio. Pesticide exposure has been associated with increased risk of diabetes mellitus in adults, but potential effects of prenatal exposure on glucose regulation have not been investigated. The aim of this study was to investigate if maternal occupational pesticide exposure in pregnancy was associated with glycated haemoglobin A1c (HbA1c) in adolescents and whether an association was modified by sex and paraoxonase-1 (PON1) Q192R polymorphism.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Short-and medium-term associations of particle number concentration with cardiovascular markers in a Puerto Rican cohort

Highlights: • Differential susceptibility to air pollution effects has been reported, but evidence is limited. • The Puerto Rican population may be susceptible based on high prevalence of chronic conditions. • Particle number is associated with C-reactive protein, but only among women. • The results show impacts of similar magnitude to other studies. Air pollution has been linked to adverse cardiovascular outcomes; however, susceptibility may vary by population. Puerto Rican adults living in the US may be a susceptible group due to a high rate of adverse cardiovascular events. We evaluated the effect of changes in ambient particle number concentration (PNC, a measure of ultrafine particles) and effects on biomarkers of cardiovascular risk in the Boston Puerto Rican Health Study (BPRHS), a longitudinal cohort (n = 1499). Ambient PNC was measured at a fixed site between 2004 and 2013 and daily mean concentrations were used to construct PNC metrics, including lags of 0, 1 and 2 days and moving averages (MAs) of 3, 7 and 28 days. We examined the association of each metric with C-reactive protein (CRP) and blood pressure. Each model included subject-specific random intercepts to account for multiple measurements. An interquartile range (IQR) increase in PNC was associated with CRP for all metrics, notably a 3-day increase in PNC was associated with a 7.1% (95% CI: 2.0%, 12.2%) increase in CRP. Significant associations with CRP were seen in women, but not men; with current and former (but not non-) smokers; participants younger (but not older) than 65 y; those without diabetes (but not with), and those with (but not without), hypertension. Our study extends knowledge about the health effects of air pollution to a vulnerable population that has been understudied.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Renal Function and exposure to Bisphenol A and phthalates in children with Chronic Kidney Disease

Highlights: • Exposure to bisphenol A and phthalates is lower in children with CKD than healthy controls. • Exposure to bisphenol A has no effect on kidney function in children with CKD. • Exposure to select phthalates is associated with increased GFR in children with CKD. • The long-term impact of these environmental chemicals requires further study. Exposure to Bisphenol A (BPA) and phthalates is ubiquitous among adults and children in the United States. Among children and adolescents, those with chronic kidney disease (CKD) are potentially at greater risk of adverse effects from BPA and phthalate exposure. The objective of this study was to evaluate BPA and phthalate exposure among children with CKD and evaluate associations with three measures of kidney function.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Urine and serum biomonitoring of exposure to environmental estrogens II: Soy isoflavones and zearalenone in pregnant women

Urine and serum biomonitoring was used to measure internal exposure to selected dietary estrogens in a cohort of 30 pregnant women. Herein exposure was measured over a period comprising one-half day in the field (6 h) and one day in a clinic (24 h). Biomonitoring of the dietary phytoestrogens genistein (GEN), daidzein (DDZ) and equol (EQ), as well as the mycoestrogen, zearalenone (ZEN) and its congeners, was conducted using UPLC-MS/MS. Biomonitoring revealed evidence of internal exposure to naturally occurring dietary estrogens during pregnancy. Urinary concentrations of total GEN, DDZ and EQ were similar to levels reported for general adult U.S. population. Measurable concentrations of total (parent and metabolites) GEN, DDZ and EQ were present in 240, 207 and 2 of 270 serum samples, respectively. Six out of 30 subjects had measurable concentrations of unconjugated GEN and/or DDZ in serum between 0.6 and 7.1 nM. Urine to serum total isoflavone ratios for GEN, DDZ and EQ were 13, 47, and 180, respectively. ZEN and its reductive metabolite, a-zearalenol (a-ZEL), were present in pregnant women (11 out of 30 subjects) as conjugates at levels near the limit of quantification. The average total urinary concentration was 0.10 mg/L for ZEN and 0.11 mg/L for a-ZEL.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Range-wide population assessments for subalpine fir indicate widespread disturbance-driven decline

Subalpine forests in western North America are threatened by rapid climate change, increased activity by endemic and exotic insects and diseases, and changing wildfire regimes. The interactive effects of these stressors have resulted in pronounced population declines in many subalpine tree species; however, a systematic assessment of the status and trends of subalpine forests is lacking. Subalpine fir (Abies lasiocarpa) is a widespread species across the western United States, with documented population declines in many parts of its distribution. Here we use subalpine fir as an initial leverage point to build a more complete understanding of subalpine forest baseline conditions and responses to environmental change. Specifically, we leverage the USDA Forest Service Forest Inventory and Analysis (FIA) database to (1) ask how subalpine fir populations are changing across the species’ distribution in the western US, (2) assess the drivers of recent subalpine fir population trends, and (3) explore whether those changes imply generalized species-wide and/or system-wide decline. We found that subalpine fir abundance and basal area are declining concurrently across ~ 62% of the species’ distribution, and increasing across ~ 19%. Range-wide, we estimated 25.02 ± 2.74 % subalpine fir mortality between 2000 and 2009 and 2010–2019 FIA inventory periods, with higher mortality concentrated in the eastern Oregon Cascades, central Idaho, and parts of southern Colorado. High regeneration density did not predict positive population trajectories, which were instead associated with higher rates of adult recruitment. While the importance of different mortality agents varied substantially between ecoregions, 83.4% of total range-wide mortality was related to fire or biological disturbance. Declining subalpine fir basal area coincided with declines in the basal area of other co-occurring tree species in 39% of subalpine forest area, and with increases in conspecific basal area in 22% of forest area. Fire disturbance was the single largest cause of subalpine fir mortality; however, even where subalpine fir fire mortality was high, mortality among other species was primarily caused by insects. In conclusion, our results suggest that subalpine fir declines across large portions of the western United States are driven by forest disturbance, and that declines in subalpine fir populations may be indicative of negative change in subalpine forest systems broadly.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Recovery of DNA from fired and unfired cartridge casings: comparison of two DNA collection methods

For over 10 years, various studies have attempted to increase the recovery of DNA from ammunition by modifying the DNA collection, extraction, purification, and amplification procedures, with varying levels of success. This study focused on the “soaking” method of Montpetit & O’Donnell [1] and the “rinse-and-swab" method of Bille et al. [2]. First, testing for the presence of exogenous DNA, 210 boxed cartridges (brass, steel, and nickel-plated) from nine manufacturers were swabbed and DNA was extracted, concentrated, and quantified. Extracts that quantified > 0 ng/µL (44 of 210) were amplified and genotyped with GlobalFiler™. Of those, only one extract yielded two alleles indicating that the manufacturing and packaging of ammunition was virtually DNA free. Next, to obtain a baseline comparison of two DNA collection methods on a non-metallic substrate and identify a suitable number of cells to spot on cartridges, different DNA input amounts of primary human adult epidermal keratinocytes (HEKa) were tested. Thereafter, 300 brass and 300 nickel-plated, cartridges were spotted with HEKa cells containing ~5 ng of DNA, fired or unfired, and processed with either method. Finally, five methods representing hybrids of the soaking and rinse-and-swab methods were tested to determine if variations of those methods could be used to increase DNA yield and recovery. The results show that the soaking method consistently yielded more DNA than the rinse-and-swab method from a non-metallic substrate. However, the comparison study demonstrated that both methods performed comparably for cartridges. On average, the soaking method recovered 0.25 ng of DNA (5.1% recovery) and the rinse-and-swab method recovered 0.28 ng (5.8% recovery). However, average recoveries were significantly different among three analysts and considerable variation in yields were observed, possibly due to storage time. Furthermore, consistent with prior reports, the DNA recovered from brass casings was only 16% of that recovered from nickel-plated casings and the average yield of DNA from fired casings was reduced to 67% of unfired casings. Moreover, DNA extracts from brass or nickel-plated casings did not appear to contain amplification inhibitors and only 30/596 appeared severely degraded. Finally, both the published rinse-and-swab and soaking methods yielded more DNA than all modifications of the two methods. Overall, both methods yielded equivalent DNA quantities. Additionally, recovery of DNA from any given cartridge casing may be dependent on storage time as well as the skill, proficiency, and experience of the analyst and may reflect stochastic effects, particularly for casings containing low copy and/or degraded DNA.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Investigating the Determinants of Household Capabilities Burden During Power Outages: The Case of Winter Storm Uri

Existing research primarily uses census data to identify the vulnerability of communities to hazards. These vulnerability indices provide aggregated data and are not hazard-specific nor well-validated with post-event data. In contrast, our study uses household survey data (n=1065) to understand which Texan households suffered the greatest loss of their capabilities due to power outages and other utility service disruptions during Winter Storm Uri. Inspired by the Capabilities Approach, our measures of burden include the number of household capability types disrupted during the outages (e.g., cooking, heating, refrigeration), the severity of impact for each disrupted capability, and the additional time and financial costs of coping with these disruptions. We perform a clustering analysis, and find two distinct groups in our data, consisting of ‘lesser burden' and ‘heavier burden' households. Results indicate that the households experiencing the heaviest capabilities burden were most likely to experience longer power outages and the loss of water services. They were also more likely to have a Hispanic-Latino household member, lack access to a generator, live in a rented home, have larger households with more young children, fewer adults over 65, lower household incomes, been impacted by the COVID-19 pandemic, and more family characteristics that made life harder. We also fit a logistic regression model to assess the role of outage, household, and community characteristics in predicting differences in capabilities burden. Our results offer insights into enumerating the consequences of utility service disruptions on households, which can inform more targeted and equitable resilience strategies.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2013

Evaluating Swallowing Muscles Essential for Hyolaryngeal Elevation by Using Muscle Functional Magnetic Resonance Imaging

Purpose: Reduced hyolaryngeal elevation, a critical event in swallowing, is associated with radiation therapy. Two muscle groups that suspend the hyoid, larynx, and pharynx have been proposed to elevate the hyolaryngeal complex: the suprahyoid and longitudinal pharyngeal muscles. Thought to assist both groups is the thyrohyoid, a muscle intrinsic to the hyolaryngeal complex. Intensity modulated radiation therapy guidelines designed to preserve structures important to swallowing currently exclude the suprahyoid and thyrohyoid muscles. This study used muscle functional magnetic resonance imaging (mfMRI) in normal healthy adults to determine whether both muscle groups are active in swallowing and to test therapeutic exercises thought to be specific to hyolaryngeal elevation. Methods and Materials: mfMRI data were acquired from 11 healthy subjects before and after normal swallowing and after swallowing exercise regimens (the Mendelsohn maneuver and effortful pitch glide). Whole-muscle transverse relaxation time (T2 signal, measured in milliseconds) profiles of 7 test muscles were used to evaluate the physiologic response of each muscle to each condition. Changes in effect size (using the Cohen d measure) of whole-muscle T2 profiles were used to determine which muscles underlie swallowing and swallowing exercises. Results: Post-swallowing effect size changes (where a d value of >0.20 indicates significant activity during swallowing) for the T2 signal profile of the thyrohyoid was a d value of 0.09; a d value of 0.40 for the mylohyoid, 0.80 for the geniohyoid, 0.04 for the anterior digastric, and 0.25 for the posterior digastric-stylohyoid in the suprahyoid muscle group; and d values of 0.47 for the palatopharyngeus and 0.28 for the stylopharyngeus muscles in the longitudinal pharyngeal muscle group. The Mendelsohn maneuver and effortful pitch glide swallowing exercises showed significant effect size changes for all muscles tested, except for the thyrohyoid. Conclusions: Muscles of both the suprahyoid and the longitudinal pharyngeal muscle groups are active in swallowing, and both swallowing exercises effectively target muscles elevating the hyolaryngeal complex. mfMRI is useful in testing swallowing muscle function.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Influence of Age on the Relative Biological Effectiveness of Carbon Ion Radiation for Induction of Rat Mammary Carcinoma

Purpose: The risk of developing secondary cancer after radiotherapy, especially after treatment of childhood cancers, remains a matter of concern. The high biological effects of carbon-ion radiation have enabled powerful radiotherapy, yet the approach is commonly restricted to the treatment of adults. Susceptibility of the fetus to particle radiation–induced cancer is also unclear. The present study is aimed to investigate the effect of carbon-ion irradiation in childhood on breast carcinogenesis. Methods and Materials: We irradiated female Sprague-Dawley rats of various ages (embryonic days 3, 13, and 17 and 1, 3, 7, and 15 weeks after birth) with {sup 137}Cs γ rays or a 290-MeV/u monoenergetic carbonion beam (linear energy transfer, 13 keV/μm). All animals were screened weekly for mammary carcinoma by palpation until they were 90 weeks old. Results: Irradiation of fetal and mature (15-week-old) rats with either radiation source at a dose of 0.2 or 1 Gy did not substantially increase the hazard ratio compared with the nonirradiated group. Dose responses (0.2-2.0 Gy) to γ rays were similar among the groups of rats irradiated 1, 3, and 7 weeks after birth. The effect of carbon ions increased along with the age at the time of irradiation, indicating relative biological effectiveness values of 0.2 (−0.3, 0.7), 1.3 (1.0, 1.6), and 2.8 (1.8, 3.9) (mean and 95% confidence interval) for animals that were 1, 3, and 7 weeks of age, respectively. Conclusions: Our findings imply that carbonion therapy may be associated with a risk of secondary breast cancer in humans, the extent of which may depend on the age of the patient at the time of irradiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas

Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. Conclusions: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival

Purpose: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS). Methods and Materials: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. Results: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, −0.09 to 1.17), independently of RTOG RPA class and seizure history. Conclusions: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Radiation, Atherosclerotic Risk Factors, and Stroke Risk in Survivors of Pediatric Cancer: A Report From the Childhood Cancer Survivor Study

Purpose: To test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the stroke risk in cancer survivors. Methods and Materials: The Childhood Cancer Survivor Study is a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancer and 4023 randomly selected sibling controls with longitudinal follow-up. Age-adjusted incidence rates of self-reported late-occurring (≥5 years after diagnosis) first stroke were calculated. Multivariable Cox proportional hazards models were used to identify independent stroke predictors. Results: During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% confidence interval [CI] 62-96), compared with 9.3 (95% CI 4-23) for siblings. Treatment with CRT increased stroke risk in a dose-dependent manner: hazard ratio 5.9 (95% CI 3.5-9.9) for 30-49 Gy CRT and 11.0 (7.4-17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4-1.8%) at 10 years after diagnosis and 12% (95% CI 8.9-15.0%) at 30 years. Hypertension increased stroke hazard by 4-fold (95% CI 2.8-5.5) and in black survivors by 16-fold (95% CI 6.9-36.6). Conclusion: Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose-dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Patterns of Local Recurrence and Dose Fractionation of Adjuvant Radiation Therapy in 462 Patients With Soft Tissue Sarcoma of Extremity and Trunk Wall

Purpose: To study the impact of dose fractionation of adjuvant radiation therapy (RT) on local recurrence (LR) and the relation of LR to radiation fields. Methods and Materials: LR rates were analyzed in 462 adult patients with soft tissue sarcoma who underwent surgical excision and adjuvant RT at five Scandinavian sarcoma centers from 1998 to 2009. Medical records were reviewed for dose fractionation parameters and to determine the location of the LR relative to the radiation portals. Results: Fifty-five of 462 patients developed a LR (11.9%). Negative prognostic factors included intralesional surgical margin (hazard ratio [HR]: 7.83, 95% confidence interval [CI]: 3.08-20.0), high malignancy grade (HR: 5.82, 95% CI: 1.31-25.8), age at diagnosis (HR per 10 years: 1.27, 95% CI: 1.03-1.56), and malignant peripheral nerve sheath tumor histological subtype (HR: 6.66, 95% CI: 2.56-17.3). RT dose was tailored to margin status. No correlation between RT dose and LR rate was found in multiple Cox regression analysis. The majority (65%) of LRs occurred within the primary RT volume. Conclusions: No significant dose–response effect of adjuvant RT was demonstrated. Interestingly, patients given 45-Gy accelerated RT (1.8 Gy twice daily/2.5 weeks) had the best local outcome. A total dose of 50 Gy in 25 fractions seemed adequate following wide margin surgery. The risk of LR was associated with histopathologic subtype, which should be included in the treatment algorithm of adjuvant RT in soft tissue sarcoma.

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