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All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Circulating levels of perfluoroalkyl substances are associated with dietary patterns – A cross sectional study in elderly Swedish men and women

Background: In our daily life, we are exposed to perfluoroalkyl substances (PFAS) with possible health implications. The main exposure route for these substances is diet but comparative studies on how dietary habits influence exposure are lacking. Objectives: To examine the relations between blood levels of PFAS and adherence to three predefined dietary patterns (a WHO recommended diet, a Mediterranean-like diet, and a Low-Carbohydrate High-Protein (LCHP) diet) in an elderly Swedish population. Methods: Dietary data from 7-day food records and serum concentrations of PFAS were obtained from a 70-year-old Swedish population (n=844), the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The Healthy Diet Indicator score (based on WHO recommendations), the Mediterranean Diet Score and LCHP score were used to assess adherence. Multivariate linear regression was used to assess the associations between eight major PFAS and adherence to each dietary pattern. Results: The WHO recommended diet was positively associated with perfluorohexane sulfonic acid (PFHxS). The LCHP diet was positively related to four out of eight PFAS; namely, perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUnDA). The Mediterranean-like diet was positively associated with most PFAS; namely perfluorooctanoic acid (PFOA), perfluorooctane sulfonamide (PFOSA), PFHxS, PFNA, PFDA, and PFUnDA. Conclusions: All dietary patterns were positively associated with blood levels of PFAS. The highest body burden of PFAS was found in individuals with high adherence to a Mediterranean-like diet, whilst individuals who more closely followed the officially recommended diet displayed a lower body burden of these compounds. - Highlights: • Perfluoroalkyl substances (PFAS) quantified in blood of 70-y-old Swedish subjects. • Adherence to predefined dietary patterns was associated with circulating PFAS. • A Mediterranean-like diet was positively associated with most circulating PFAS. • A low-carbohydrate high-protein diet was positively related to some PFAS in blood. • A WHO-recommended diet was only related to higher circulating levels of PFHxS.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1

Environmental hazards from natural or anthropological sources are widespread, especially in the north-central region of Mexico. Children represent a susceptible population due to their unique routes of exposure and special vulnerabilities. In this study we evaluated the association of exposure to environmental kidney toxicants with kidney injury biomarkers in children living in San Luis Potosi (SLP), Mexico. A cross-sectional study was conducted with 83 children (5–12 years of age) residents of Villa de Reyes, SLP. Exposure to arsenic, cadmium, chromium, fluoride and lead was assessed in urine, blood and drinking water samples. Almost all tap and well water samples had levels of arsenic (81.5%) and fluoride (100%) above the permissible levels recommended by the World Health Organization. Mean urine arsenic (45.6 ppb) and chromium (61.7 ppb) were higher than the biological exposure index, a reference value in occupational settings. Using multivariate adjusted models, we found a dose-dependent association between kidney injury molecule-1 (KIM-1) across chromium exposure tertiles [(T1: reference, T2: 467 pg/mL; T3: 615 pg/mL) (p-trend=0.001)]. Chromium upper tertile was also associated with higher urinary miR-200c (500 copies/μl) and miR-423 (189 copies/μL). Arsenic upper tertile was also associated with higher urinary KIM-1 (372 pg/mL). Other kidney injury/functional biomarkers such as serum creatinine, glomerular filtration rate, albuminuria, neutrophil gelatinase-associated lipocalin and miR-21 did not show any association with arsenic, chromium or any of the other toxicants evaluated. We conclude that KIM-1 might serve as a sensitive biomarker to screen children for kidney damage induced by environmental toxic agents. - Highlights: • Children living in Mexico had exceedingly high arsenic and chromium exposure. • Arsenic and chromium exposure was significantly associated with urinary KIM-1. • KIM-1 might serve as a sensitive biomarker to evaluate kidney injury in children.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Time-varying coefficient vector autoregressions model based on dynamic correlation with an application to crude oil and stock markets

This paper proposes a new time-varying coefficient vector autoregressions (VAR) model, in which the coefficient is a linear function of dynamic lagged correlation. The proposed model allows for flexibility in choices of dynamic correlation models (e.g. dynamic conditional correlation generalized autoregressive conditional heteroskedasticity (GARCH) models, Markov-switching GARCH models and multivariate stochastic volatility models), which indicates that it can describe many types of time-varying causal effects. Time-varying causal relations between West Texas Intermediate (WTI) crude oil and the US Standard and Poor’s 500 (S&P 500) stock markets are examined by the proposed model. The empirical results show that their causal relations evolve with time and display complex characters. Both positive and negative causal effects of the WTI on the S&P 500 in the subperiods have been found and confirmed by the traditional VAR models. Similar results have been obtained in the causal effects of S&P 500 on WTI. In addition, the proposed model outperforms the traditional VAR model.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Elemental content of the placenta: A comparison between two high-risk obstetrical populations, adult women carrying multiples and adolescents carrying singletons

Background: The placenta is responsible for the exchange of nutrients and for preventing harmful compounds from entering the fetal circulation. With increasing industrialization, exposures to commercial and toxic metals become a concern for both pregnant women and those planning a pregnancy. The understanding of transport mechanisms and pharmacokinetics for most inorganic elements is incomplete and limited to normal term deliveries. Objectives: To obtain novel data on 46 inorganic elements in placentae from two high-risk obstetric populations, women carrying multiples and adolescents carrying singletons, evaluating differences, if present, and identifying predictors of placental content. Methods: Placental tissue was collected from adolescents carrying singletons and adults carrying multiples. Elemental content was analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). Multivariate regression and factor analyses were used. Results: With the exception of Au and Pt, almost all placentae contained quantifiable concentrations of each element analyzed. All placentae contained the essential elements Ca, Fe, Mg, Se and Zn, which clustered together onto the same factor. Most elements were higher in placentae from women carrying multiples. Differences in placental content disappeared after adjusting for maternal age. Rare earth elements (REEs) clustered together and remained higher in the multiples even after adjusting for maternal age. Conclusion: Human placentae contain a wide range of elements, including REEs. Ranges differed considerably between cohorts. Elements with similar chemical properties, like REEs or nutritionally essential elements, clustered together. Maternal age, and therefore longer environmental exposure, was significantly associated with elevated element concentrations in the placenta. Placental concentrations of several metals that are known to be nutritionally essential (e.g., Fe, Ca, Mg, and Zn) did not differ significantly between cohorts, suggesting tight regulation, whereas concentrations of environmental contaminants differed significantly between groups, even after adjusting for maternal age. - Highlights: • Levels of 46 elements were measured in placentae from two high-risk cohorts. • Almost all placentae contained traces of the 46 elements, including REEs. • Maternal age was significantly associated with concentrations in the placenta. • Elements with similar properties and roles clustered together.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Use of electronic cigarettes in public and private settings in Barcelona (Spain)

Objectives: To describe the prevalence of e-cigarette users who use them in selected indoor public and workplaces, and private venues in Barcelona (Spain) in 2015. Methods: This is a cross-sectional study of a sample of e-cigarette users (≥ 18 years) from Barcelona (n = 600). We calculated the proportion of e-cigarette users who used the device in public and private settings (in the last 30 days). We fit multivariate logistic regression models adjusted for sex and age to calculate the odds ratios (OR) with their 95% confidence intervals (CI) of e-cigarette use by socio-demographic factors, dual use and nicotine-containing e-cigarettes. Results: The highest proportion of e-cigarette users who used them in public places was found at restaurants or bars (69.4%) and nightclubs or pubs (55.4%). Also being current conventional tobacco smokers (dual users) was significantly associated with lower use of e-cigarettes in workplaces (OR = 0.61, 95%CI:0.41–0.91), restaurants (OR = 0.66, 95%CI:0.45–0.97) and nightclubs (OR = 0.56, 95%CI:0.37–0.86). Moreover, being a nicotine-containing e-cigarette user was associated with higher odds of using the device in workplaces (OR = 2.01, 95%CI:1.34–3.01), and lower odds of using it in nightclubs (OR = 0.56, 95%CI:0.39–0.82). 96.8% of the included e-cigarette users declared to use the device at home. Being a current tobacco smoker was associated with increased odds of using e-cigarettes at home (OR = 3.17, 95%CI:1.22–8.22). Conclusions: E-cigarette use in private settings and in public settings where their use is not regulated by law is high. Therefore, the public health administration in Spain should consider expanding the prohibition of e-cigarette use to indoor public places and should take into account the possibility of exposure to aerosol from e-cigarettes. - Highlights: • Describe use e-cigarette in indoor public and workplaces. • Describe use e-cigarette in indoor private venues. • E-cigarette use in private settings is high. • Dual users declared a higher use of e-cigarettes. • Expanding the prohibition of e-cigarette use should be considered.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Geographic and social disparities in exposure to air neurotoxicants at U.S. public schools

Highlights: • Ambient neurotoxicants pose serious risks at US public schools. • There are social and spatial disparities in ambient neurotoxicant risks. • One-third of all schools in EPA Region 2 are at “high risk” for neurotoxicant exposure. • Schools with higher % of Hispanic, black, and Asian students face disparate risks. • Schools serving the youngest (vs. older) students face disparate risks. Children are especially vulnerable to the health and developmental impacts of environmental hazards and they spend significant portions of their days at school. Yet there are no national-level studies examining school-level environmental inequalities and few have examined disparate exposure to neurological air toxicants, even though chronic exposure to air pollution impacts children's brain functioning. We paired information about the geographic locations and demographics of each public school in the US with air neurotoxicant exposure estimates pertaining to 24 known neurotoxicants included in the US Environmental Protection Agency's National Air Toxics Assessment. Using bivariate and multivariate statistics, we tested for environmental injustices in air neurotoxicant exposure at 84,969 US public schools. Metropolitan New York City (EPA Region 2) is the geographic region most burdened by air neurotoxicant exposures at schools since one-third of all schools in that region are in the top 10% (at {sup h}igh risk{sup )} for ambient neurotoxicant exposure among all schools nationwide. Students attending “high risk” public schools nationwide are significantly more likely to be eligible for free/reduced price meals, and to be Hispanic, black, or Asian/Pacific Islander (API). They are significantly less likely to be white or of another race. In a multivariate generalized estimating equation controlling for school district effects, schools with greater proportions of Hispanic, black, and API students, schools with higher enrollment, and schools located in more urban (vs. rural) counties face greater risks. Schools serving the youngest students (e.g., pre-kindergarten) have greater levels of risk than schools serving older students. Across all analyses, this study shows that racial/ethnic minority children are bearing the brunt of air neurotoxicant exposures at school, which may be unequally impacting their school performance and future potential.

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

Relationship between serum trimethylamine N-oxide and exposure to dioxin-like pollutants

Highlights: • TMAO has been linked to cardiovascular disease risk in human studies and animal models. • TMAO was positively associated with 22 indexes of dioxin-like pollutant exposures in ACHS-II. • Associations with TMAO were significant among females (except at high BMIs) but not among males. • The dioxin TEQ: TMAO association was unaltered by adjustment for independent covariates of TMAO. Trimethylamine N-oxide (TMAO) is a diet and gut microbiota-derived metabolite that has been linked to cardiovascular disease risk in human studies and animal models. TMAO levels show wide inter and intra individual variability in humans that can likely be accounted for by multiple factors including diet, the gut microbiota, levels of the TMAO generating liver enzyme Flavin-containing monooxygenase 3 (FMO3) and kidney function. We recently found that dioxin-like (DL) environmental pollutants increased FMO3 expression to elevate circulating diet-derived TMAO in mice, suggesting that exposure to this class of pollutants might also contribute to inter-individual variability in circulating TMAO levels in humans. To begin to explore this possibility we examined the relationship between body burden of DL pollutants (reported by serum lipid concentrations) and serum TMAO levels (n = 340) in the Anniston, AL cohort, which was highly exposed to polychlorinated biphenyls (PCBs). TMAO concentrations in archived serum samples from the Anniston Community Health Survey (ACHS-II) were measured, and associations of TMAO with 28 indices of pollutant body burden, including total dioxins toxic equivalent (TEQ), were quantified. Twenty-three (22 after adjustment for multiple comparisons) of the 28 indices were significantly positively associated with TMAO. Although the design of ACHS-II does not enable quantitative assessment of the contributions of previously known determinants of TMAO variability to this relationship, limited multivariate modeling revealed that total dioxins TEQ was significantly associated with TMAO among females (except at high BMIs) but not among males. Our results from this cross-sectional study indicate that exposure to DL pollutants may contribute to elevated serum TMAO levels. Prospective longitudinal studies will be required to assess the joint relationship between DL pollutant exposures, other determinants of TMAO, and health outcomes.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Adipose tissue levels of polybrominated diphenyl ethers and breast cancer risk in Chinese women: A case–control study

Highlights: • Associations between adipose tissue PBDE levels and breast cancer risk were assessed. • Levels of most individual PBDE congeners were higher in breast-cancer cases than controls. • Breast-cancer risk was increased with both 2nd and 3rd tertiles of BDE-47 and BDE-209 levels with a trend. • Breast-cancer risk was also increased with the 3rd tertile of BDE-28, 99, 100, 138, 153, 154, and ∑PBDE levels. • PBDE concentrations are associated with breast-cancer risk in women in Chaoshan, China. Polybrominated diphenyl ethers (PBDEs) are suspected to be associated with breast cancer risk because of their estrogenic potencies. Epidemiological studies of PBDEs and breast cancer are scarce. Our study aimed to estimate the association between adipose-tissue PBDE concentrations and breast cancer risk. A total of 209 breast cancer cases and 165 controls were recruited from hospitals between January 2014 and May 2016 in Shantou, Chaoshan area, China. Concentrations of 14 PBDE congeners were measured in adipose tissues obtained from the breast for cases and the abdomen/breast for controls during surgery. Demographic and clinicopathologic characteristics were obtained from medical records. Breast cancer risk as well as clinicopathologic characteristics were evaluated by adipose-tissue PBDE level. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer risk associated with levels of PBDE congeners were estimated from logistic regression models for all cases and stratified by estrogen receptor (ER) status. Level of total PBDEs (∑PBDE) and most individual PBDE congeners were higher in breast cancer cases than controls (median ∑PBDE, 94.99 vs 73.72 ng/g lipid). In the adjusted univariate model for all cases, breast cancer risk was increased with both 2nd and 3rd tertiles versus the 1st tertile of BDE-47 level (OR 2.05 [95% CI 1.08–3.92]; 5.47 [2.96–10.11]) and BDE-209 level (2.48 [1.30–4.73]; 4.72 [2.52–8.83]) with trend (both P < 0.001) and with the 3rd tertile of BDE-28 level (2.83 [1.63–4.92]), BDE-99 (3.22 [1.85–5.60]), BDE-100 (5.45 [2.90–10.23]), BDE-138 (2.40 [1.37–4.20]), BDE-153 (1.74 [1.02–2.97]), BDE-154 (1.84 [1.05–3.22]), and ∑PBDE levels (1.83 [1.07–3.14]) but decreased with the 3rd tertile of BDE-71 level (0.38 [0.22–0.65]) with trend (all P < 0.01). After stratifying by ER-positive or -negative status, the adjusted results were similar for ER-positive patients except for BDE-153 and BDE-154, with no statistical significance. In the multivariate model for all cases, age, menarche age, BDE-47, 71, 99, 100, 183 and 209 were independent factors associated with breast-cancer risk. ∑PBDE and most individual PBDE congeners investigated were positively associated with breast cancer risk in women from the Chaoshan area, China. PBDE may play a role in the occurrence and development of breast cancer.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Comparative estrogenicity of endogenous, environmental and dietary estrogens in pregnant women I: Serum levels, variability and the basis for urinary biomonitoring of serum estrogenicity

Biomonitoring of human exposure to estrogens most frequently focuses on environmental and dietary estrogens, and infrequently includes measures of exposure to potent endogenous estrogens present in serum. Pregnancy is a developmentally sensitive period during which “added” serum estrogenicity exceeding normal intra-individual daily variability may be of particular relevance. Here, we made repeated measurements of serum concentrations of estrone (E1), estradiol (E2), estriol (E3), estetrol (E4), daidzein (DDZ), genistein (GEN) and bisphenol A (BPA) in thirty pregnant women using ultra-performance liquid chromatography coupled with tandem mass spectrometry detection (UPLC-MS/MS) and electrospray ionization (ESI). Serum E1, E2, and E3 concentrations varied significantly (coefficients of variation 9–10%) with broad ranges across the cohort: 1.61–85.1 nM, 9.09–69.7 nM, and 1.5–36.3 nM respectively. BPA (undetected, estimated from total exposure), DDZ and GEN concentrations were 1-5 orders of magnitude lower. The 24-h urinary elimination profiles of endogenous estrogens were each strongly correlated with their corresponding serum concentrations (Pearson's Correlation Coefficients of 0.83 (E1), 0.84 (E2) and 0.94 (E3)). Lastly, a multivariate regression analysis produced equations for estimating serum concentrations of E1, E2, E3, E4, GEN and DDZ from urinary elimination rates and gestation period, an important step towards non-invasive biomonitoring for assessment of “added” estrogenicity during pregnancy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2010

Incidence of Small Lymph Node Metastases With Evidence of Extracapsular Extension: Clinical Implications in Patients With Head and Neck Squamous Cell Carcinoma

Purpose: Small lymph nodes (LN) show evidence of extracapsular extension (ECE) in a significant number of patients. This study was performed to determine the impact of ECE in LN {<=}7 mm as compared with ECE in larger LN. Methods and Materials: All tumor-positive LN of 74 head and neck squamous cell carcinoma (HNSCC) patients with at least one ECE positive LN were analyzed retrospectively for the LN diameter and the extent of ECE. Clinical endpoints were regional relapse-free survival, distant metastasis-free survival, and overall survival. The median follow-up for the surviving patients was 2.1 years (range, 0.3-9.2 years). Results: Forty-four of 74 patients (60%) had at least one ECE positive LN {<=}10 mm. These small ECE positive LN had a median diameter of 7 mm, which was used as a cutoff. Thirty patients (41%) had at least one ECE positive LN {<=}7 mm. In both univariate and multivariate Cox regression analyses, the incidence of at least one ECE positive LN {<=}7 mm was a statistically significant prognostic factor for decreased regional relapse-free survival (adjusted hazard ratio [HR]: 2.7, p = 0.03, 95% confidence interval [CI]: 1.1-6.4), distant metastasis-free survival (HR: 2.6, p = 0.04, 95% CI: 1.0-6.6), and overall survival (HR: 2.5, p = 0.03, 95% CI: 1.1-5.8). Conclusions: The incidence of small ECE positive LN metastases is a significant prognostic factor in HNSCC patients. Small ECE positive LN may represent more invasive tumor biology and could be used as prognostic markers.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Cardiovascular Morbidity After Radiotherapy or Chemoradiation in Patients With Cervical Cancer

Purpose: To evaluate the risk of cardiovascular events (CVE) in patients with cervical cancer treated with radiotherapy or chemoradiation. Methods and Materials: The incidence of CVE in patients treated between 1989 and 2002 by radiotherapy or chemoradiation was compared with a Dutch reference population. Standardized incidence ratios (SIRs) were calculated for myocardial infarction (MI), angina pectoris (AP), congestive heart failure (CHF), cerebrovascular accident (CVA) separately and for any cardiac event combined (MI, AP, and CHF). Results: In 277 patients with a median follow-up of 4.5 years (range, 0.1-17 years) and a median survival of 9.2 years, 27 cardiac events occurred. The 5-, 10-, and 15-year actuarial incidence of any cardiac event were 9, 14, and 16%, respectively. For the whole population, the SIR for MI was elevated (2.05, 95% CI: 1.12-3.43). The radiotherapy group (n = 132) was older and had more cardiovascular risk factors than the chemoradiation group (n = 145). The SIR for MI in the radiotherapy group was 2.88 (95% CI: 1.44-5.15) and in the chemoradiation group 1.00 (95% CI: 0.21-7.47). In multivariate analyses, there was no relation between treatment modality and the risk for MI. Conclusions: In this cohort of cervical cancer patients, an increased risk for developing a MI was observed. This increased risk of MI, in combination with the high prevalence of cardiovascular risk factors in cervical cancer patients, urges the need to explore strategies to reduce their risk for cardiovascular morbidity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Candidate Dosimetric Predictors of Long-Term Swallowing Dysfunction After Oropharyngeal Intensity-Modulated Radiotherapy

Purpose: To investigate long-term swallowing function in oropharyngeal cancer patients treated with intensity-modulated radiotherapy (IMRT), and to identify novel dose-limiting criteria predictive for dysphagia. Methods and Materials: Thirty-one patients with Stage IV oropharyngeal squamous carcinoma enrolled on a Phase II trial were prospectively evaluated by modified barium swallow studies at baseline, and 6, 12, and 24 months post-IMRT treatment. Candidate dysphagia-associated organs at risk were retrospectively contoured into original treatment plans. Twenty-one (68%) cases were base of tongue and 10 (32%) were tonsil. Stage distribution was T1 (12 patients), T2 (10), T3 (4), T4 (2), and TX (3), and N2 (24), N3 (5), and NX (2). Median age was 52.8 years (range, 42-78 years). Thirteen patients (42%) received concurrent chemotherapy during IMRT. Thirteen (42%) were former smokers. Mean dose to glottic larynx for the cohort was limited to 18 Gy (range, 6-39 Gy) by matching IMRT to conventional low-neck fields. Results: Dose-volume constraints (V30 < 65% and V35 < 35% for anterior oral cavity and V55 < 80% and V65 < 30% for high superior pharyngeal constrictors) predictive for objective swallowing dysfunction were identified by univariate and multivariate analyses. Aspiration and feeding tube dependence were observed in only 1 patient at 24 months. Conclusions: In the context of glottic laryngeal shielding, we describe candidate oral cavity and superior pharyngeal constrictor organs at risk and dose-volume constraints associated with preserved long-term swallowing function; these constraints are currently undergoing prospective validation. Strict protection of the glottic larynx via beam-split IMRT techniques promises to make chronic aspiration an uncommon outcome.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Risk Factors for Cataract After Palladium-103 Ophthalmic Plaque Radiation Therapy

Purpose: To examine how tumor characteristics and dose affect cataract development after plaque radiation therapy. Methods and Materials: Three hundred and eighty-four patients were diagnosed with uveal melanoma and treated with palladium-103 ({sup 103}Pd) plaque radiation therapy. Of these, 282 (74%) inclusion met exclusion criteria for follow-up time, tumor location, and phakic status. Then patient-, ophthalmic-, and radiation-specific factors (patient age, diabetes, hypertension, tumor location, tumor dimensions, and lens dose) were examined (by a Cox proportional regression model) as predictors for the development of radiation-related cataract. Results: Radiation cataract developed in 76 (24%) of patients at a mean follow-up of 39.8 months (range, 1-192). Patients with anteriorly located tumors were noted to have a higher incidence of cataract at 43.0% (43 of 100 patients) vs. 18.1% (33 cataracts per 182 patients) for posteriorly located tumors (p <0.0001). However, multivariate Cox proportional modeling showed that increasing patient age at time of treatment (p for trend = 0.0003) and higher lens dose (p for trend = 0.001) were the best predictors (biomarkers) for radiation cataract. Conclusions: Although anterior tumor location, greater tumor height, and increased patient age (at treatment) were associated with significantly greater risk for radiation cataract, dose to lens was the most significant factor.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Scoring Systems to Estimate Intracerebral Control and Survival Rates of Patients Irradiated for Brain Metastases;Brain metastases; Radiation therapy; Local control; Survival; Prognostic scores

Purpose: To create and validate scoring systems for intracerebral control (IC) and overall survival (OS) of patients irradiated for brain metastases. Methods and Materials: In this study, 1,797 patients were randomly assigned to the test (n = 1,198) or the validation group (n = 599). Two scoring systems were developed, one for IC and another for OS. The scores included prognostic factors found significant on multivariate analyses. Age, performance status, extracerebral metastases, interval tumor diagnosis to RT, and number of brain metastases were associated with OS. Tumor type, performance status, interval, and number of brain metastases were associated with IC. The score for each factor was determined by dividing the 6-month IC or OS rate (given in percent) by 10. The total score represented the sum of the scores for each factor. The score groups of the test group were compared with the corresponding score groups of the validation group. Results: In the test group, 6-month IC rates were 17% for 14-18 points, 49% for 19-23 points, and 77% for 24-27 points (p < 0.0001). IC rates in the validation group were 19%, 52%, and 77%, respectively (p < 0.0001). In the test group, 6-month OS rates were 9% for 15-19 points, 41% for 20-25 points, and 78% for 26-30 points (p < 0.0001). OS rates in the validation group were 7%, 39%, and 79%, respectively (p < 0.0001). Conclusions: Patients irradiated for brain metastases can be given scores to estimate OS and IC. IC and OS rates of the validation group were similar to the test group demonstrating the validity and reproducibility of both scores.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Long-Term Outcomes of Patients With Spinal Cord Gliomas Treated by Modern Conformal Radiation Techniques

Purpose: This study retrospectively examines the long-term therapeutic outcomes of 32 patients with primary spinal cord gliomas at Massachusetts General Hospital between 1991 and 2005 treated by either photon intensity-modulated radiotherapy or conformal proton radiotherapy. Methods and Materials: Individual patient tumor types included 14 ependymomas, 17 astrocytomas, and one oligodendroglioma. Twenty-two patients were treated with photon beam radiation therapy, and 10 patients were treated with proton beam therapy. The overall survival and time to progression were analyzed. Average radiation dose for patients was 51 Gy in 1.8 median daily fractions over 29 treatments. Results: For all 32 patients, the overall 5-year survival was 65% and the progression-free survival was 61%, respectively. Overall survival was significantly worse for patients more than 55 years of age (p = 0.02). Ependymoma patients had significantly longer survival times than astrocytoma patients (p = 0.05). Patients who had undergone a biopsy developed worse outcomes then those with a resection (p = 0.05). With the caveat of a limited number of patients, the multivariate model seems to suggest improved overall survival for younger patients (<54 years of age), ependymoma histology, and photon vs. proton treatment. Conclusion: For patients with spinal cord gliomas, significant factors associated with patient outcome include tumor pathology, age, extent of surgery, and treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Development and Validation of a Prognostic Model Using Blood Biomarker Information for Prediction of Survival of Non-Small-Cell Lung Cancer Patients Treated With Combined Chemotherapy and Radiation or Radiotherapy Alone (NCT00181519, NCT00573040, and NCT00572325)

Purpose: Currently, prediction of survival for non-small-cell lung cancer patients treated with (chemo)radiotherapy is mainly based on clinical factors. The hypothesis of this prospective study was that blood biomarkers related to hypoxia, inflammation, and tumor load would have an added prognostic value for predicting survival. Methods and Materials: Clinical data and blood samples were collected prospectively (NCT00181519, NCT00573040, and NCT00572325) from 106 inoperable non-small-cell lung cancer patients (Stages I-IIIB), treated with curative intent with radiotherapy alone or combined with chemotherapy. Blood biomarkers, including lactate dehydrogenase, C-reactive protein, osteopontin, carbonic anhydrase IX, interleukin (IL) 6, IL-8, carcinoembryonic antigen (CEA), and cytokeratin fragment 21-1, were measured. A multivariate model, built on a large patient population (N = 322) and externally validated, was used as a baseline model. An extended model was created by selecting additional biomarkers. The model's performance was expressed as the area under the curve (AUC) of the receiver operating characteristic and assessed by use of leave-one-out cross validation as well as a validation cohort (n = 52). Results: The baseline model consisted of gender, World Health Organization performance status, forced expiratory volume, number of positive lymph node stations, and gross tumor volume and yielded an AUC of 0.72. The extended model included two additional blood biomarkers (CEA and IL-6) and resulted in a leave-one-out AUC of 0.81. The performance of the extended model was significantly better than the clinical model (p = 0.004). The AUC on the validation cohort was 0.66 and 0.76, respectively. Conclusions: The performance of the prognostic model for survival improved markedly by adding two blood biomarkers: CEA and IL-6.

62 RADIOLOGY AND NUCLEAR MEDICINE↗