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At least 163 records · Page 9
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

SU-E-T-467: Definition of the Proper Tolerances for Beam-Position Accuracy and Beam Width for Quality Assurance in Active Proton Pencil Beam Scanning

Purpose: To estimate the correlation between different dosimetric indices and the clinical outcome, which was recorded at different time points after the treatment, regarding the structure of salivary glands in head and neck cancer radiotherapy. Methods: 218 salivary glands from patients with head and neck tumours treated at IPOCFG from 2007 to 2013 were included in this study. The follow up of those patients consisted on weekly medical visits during the treatment that take about seven weeks. After that the patients had consults every three months. Treatment complications were graded using the RTOG/EORTC guidelines. The response of the salivary glands (both parotids, oral cavity and both submandibular glands) was analyzed for six time periods: 7th week, 3rd, 7th, 12th, 18th and 24th months after the start of the radiotherapy. The total dose distributions, converted to a fractionation scheme of 2Gy fractional doses, were used to calculate the DVHs and dose-response plots of salivary glands. Results: The small differences obtained between the mean DVHs showed that patients should be grouped into: with complications (G1+G2) and without complications (G0). The mean dose/2Gy was 22.2±13.2 Gy (G0) and 33.2±8.0 Gy (G1+G2) for the 7th week, 31.9±9.6 Gy (G0) and 34.6±6.8 Gy (G1+G2) for the 12th month and, 32.9±9.3 Gy (G0) and 37.2±8.5 Gy (G1+G2) for the 24th month. The dose-response plots for the 7th week and 24th month were similar to the dose-response curves published in the literature. Conclusion: In some cases, there were not major differences between the mean DVHs of the groups with and without complications in the salivary glands, when comparing them at different time periods. More radiobiological analysis should thus be made to estimate the clinical impact of those differences.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

A Prospective Cohort Study on Radiation-induced Hypothyroidism: Development of an NTCP Model

Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. Methods and Materials: The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. Results: Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroid gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm{sup 3}). Model performance was good with an area under the curve (AUC) of 0.85. Conclusions: This is the first prospective study resulting in an NTCP model for radiation-induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Concurrent segmentation of the prostate on MRI and CT via linked statistical shape models for radiotherapy planning

Purpose: Prostate gland segmentation is a critical step in prostate radiotherapy planning, where dose plans are typically formulated on CT. Pretreatment MRI is now beginning to be acquired at several medical centers. Delineation of the prostate on MRI is acknowledged as being significantly simpler to perform, compared to delineation on CT. In this work, the authors present a novel framework for building a linked statistical shape model (LSSM), a statistical shape model (SSM) that links the shape variation of a structure of interest (SOI) across multiple imaging modalities. This framework is particularly relevant in scenarios where accurate boundary delineations of the SOI on one of the modalities may not be readily available, or difficult to obtain, for training a SSM. In this work the authors apply the LSSM in the context of multimodal prostate segmentation for radiotherapy planning, where the prostate is concurrently segmented on MRI and CT. Methods: The framework comprises a number of logically connected steps. The first step utilizes multimodal registration of MRI and CT to map 2D boundary delineations of the prostate from MRI onto corresponding CT images, for a set of training studies. Hence, the scheme obviates the need for expert delineations of the gland on CT for explicitly constructing a SSM for prostate segmentation on CT. The delineations of the prostate gland on MRI and CT allows for 3D reconstruction of the prostate shape which facilitates the building of the LSSM. In order to perform concurrent prostate MRI and CT segmentation using the LSSM, the authors employ a region-based level set approach where the authors deform the evolving prostate boundary to simultaneously fit to MRI and CT images in which voxels are classified to be either part of the prostate or outside the prostate. The classification is facilitated by using a combination of MRI-CT probabilistic spatial atlases and a random forest classifier, driven by gradient and Haar features. Results: The authors acquire a total of 20 MRI-CT patient studies and use the leave-one-out strategy to train and evaluate four different LSSMs. First, a fusion-based LSSM (fLSSM) is built using expert ground truth delineations of the prostate on MRI alone, where the ground truth for the gland on CT is obtained via coregistration of the corresponding MRI and CT slices. The authors compare the fLSSM against another LSSM (xLSSM), where expert delineations of the gland on both MRI and CT are employed in the model building; xLSSM representing the idealized LSSM. The authors also compare the fLSSM against an exclusive CT-based SSM (ctSSM), built from expert delineations of the gland on CT alone. In addition, two LSSMs trained using trainee delineations (tLSSM) on CT are compared with the fLSSM. The results indicate that the xLSSM, tLSSMs, and the fLSSM perform equivalently, all of them out-performing the ctSSM. Conclusions: The fLSSM provides an accurate alternative to SSMs that require careful expert delineations of the SOI that may be difficult or laborious to obtain. Additionally, the fLSSM has the added benefit of providing concurrent segmentations of the SOI on multiple imaging modalities.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Graves' disease radioiodine-therapy: Choosing target absorbed doses for therapy planning

Purpose: The precise determination of organ mass (m{sub th}) and total number of disintegrations within the thyroid gland (A{sup ~}) are essential for thyroid absorbed-dose calculations for radioiodine therapy. Nevertheless, these parameters may vary according to the method employed for their estimation, thus introducing uncertainty in the estimated thyroid absorbed dose and in any dose–response relationship derived using such estimates. In consideration of these points, thyroid absorbed doses for Graves’ disease (GD) treatment planning were calculated using different approaches to estimating the m{sub th} and the A{sup ~}. Methods: Fifty patients were included in the study. Thyroid{sup 131}I uptake measurements were performed at 2, 6, 24, 48, 96, and 220 h postadministration of a tracer activity in order to estimate the effective half-time (T{sub eff}) of {sup 131}I in the thyroid; the thyroid cumulated activity was then estimated using the T{sub eff} thus determined or, alternatively, calculated by numeric integration of the measured time-activity data. Thyroid mass was estimated by ultrasonography (USG) and scintigraphy (SCTG). Absorbed doses were calculated with the OLINDA/EXM software. The relationships between thyroid absorbed dose and therapy response were evaluated at 3 months and 1 year after therapy. Results: The average ratio (±1 standard deviation) betweenm{sub th} estimated by SCTG and USG was 1.74 (±0.64) and that between A{sup ~} obtained by T{sub eff} and the integration of measured activity in the gland was 1.71 (±0.14). These differences affect the calculated absorbed dose. Overall, therapeutic success, corresponding to induction of durable hypothyroidism or euthyroidism, was achieved in 72% of all patients at 3 months and in 90% at 1 year. A therapeutic success rate of at least 95% was found in the group of patients receiving doses of 200 Gy (p = 0.0483) and 330 Gy (p = 0.0131) when m{sub th} was measured by either USG or SCTG and A{sup ~} was determined by the integration of measured {sup 131}I activity in the thyroid gland and based on T{sub eff}, respectively. No statistically significant relationship was found between therapeutic response and patients’ age, administered {sup 131}I activity (MBq), 24-h thyroid {sup 131}I uptake (%) or T{sub eff} (p ≥ 0.064); nonetheless, a good relationship was found between the therapeutic response and m{sub th} (p ≤ 0.035). Conclusions: According to the results of this study, the most effective thyroid absorbed dose to be targeted in GD therapy should not be based on a fixed dose but rather should be individualized based on the patient'sm{sub th} and A{sup ~}. To achieve a therapeutic success (i.e., durable euthyroidism or hypothyroidism) rate of at least 95%, a thyroid absorbed dose of 200 or 330 Gy is required depending on the methodology used for estimating m{sub th} and A{sup ~}.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS1989

Cantilever clamp fitting

A device is disclosed for sealing and clamping a cylindrical element which is to be attached to an object such as a wall, a pressurized vessel or another cylindrical element. The device includes a gland having an inner cylindrical wall, which is threaded at one end and is attached at a bendable end to a deformable portion, which in turn is attached to one end of a conical cantilever structure. The other end of the cantilever structure connects at a bendable area to one end of an outer cylindrical wall. The opposite end of cylindrical wall terminates in a thickened portion, the radially outer surface of which is adapted to accommodate a tool for rotating the gland. The terminal end of cylindrical wall also includes an abutment surface, which is adapted to engage a seal, which in turn engages a surface of a receiver. The receiver further includes a threaded portion for engagement with the threaded portion of gland whereby a tightening rotation of gland relative to receiver will cause relative movement between cylindrical walls and of gland. This movement causes a rotation of the conical structure and thus a bending action at bending area and at the bending end of the upper end of inner cylindrical wall. These rotational and bending actions result in a forcing of the deformable portion radially inwardly so as to contact and deform a pipe. This forcible contact creates a seal between gland and pipe, and simultaneously clamps the pipe in position.

Melton, Patrick B.↗
DOE OSTI2011

Hypothyroidism After Head-and-Neck Radiotherapy in Children and Adolescents: Preliminary Results of the 'Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence' (RiSK)

Purpose: The 'Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence' (RiSK) has been established to prospectively characterize dose-volume effects of radiation in terms of side effects. The aim of this analysis was to characterize the function of the thyroid gland after radiotherapy to the head-and-neck region in children and adolescents. Methods and Materials: Detailed information regarding radiation doses to at-risk organs has been collected across Germany since 2001. Thyroid function was evaluated by blood value examinations of thyroid-stimulating hormone, triiodothyronine, and thyroxine. Information regarding thyroid hormone substitution was requested from the treating physicians. Results: Until May 2009, 1,086 patients from 62 centers were recruited, including 404 patients (median age, 10.9 years) who had received radiotherapy to the thyroid gland and/or hypophysis. Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values. In comparison to patients treated with prophylactic cranial irradiation (median dose, 12 Gy), patients with radiation doses of 15 to 25 Gy to the thyroid gland had a hazard ratio of 3.072 (p = 0.002) for the development of pathologic thyroid blood values. Patients with greater than 25 Gy to the thyroid gland and patients who underwent craniospinal irradiation had hazard ratios of 3.768 (p = 0.009) and 5.674 (p < 0.001), respectively. The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups. Conclusions: Radiation-induced thyroid function impairment, including damage to the thyroid gland and/or hypophysis, can frequently be observed after radiotherapy in children. A structured follow-up examination is advised.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Treatment Planning Constraints to Avoid Xerostomia in Head-and-Neck Radiotherapy: An Independent Test of QUANTEC Criteria Using a Prospectively Collected Dataset

Purpose: The severe reduction of salivary function (xerostomia) is a common complication after radiation therapy for head-and-neck cancer. Consequently, guidelines to ensure adequate function based on parotid gland tolerance dose-volume parameters have been suggested by the QUANTEC group and by Ortholan et al. We perform a validation test of these guidelines against a prospectively collected dataset and compared with a previously published dataset. Methods and Materials: Whole-mouth stimulated salivary flow data from 66 head-and-neck cancer patients treated with radiotherapy at the British Columbia Cancer Agency (BCCA) were measured, and treatment planning data were abstracted. Flow measurements were collected from 50 patients at 3 months, and 60 patients at 12-month follow-up. Previously published data from a second institution, Washington University in St. Louis (WUSTL), were used for comparison. A logistic model was used to describe the incidence of Grade 4 xerostomia as a function of the mean dose of the spared parotid gland. The rate of correctly predicting the lack of xerostomia (negative predictive value [NPV]) was computed for both the QUANTEC constraints and Ortholan et al. recommendation to constrain the total volume of both glands receiving more than 40 Gy to less than 33%. Results: Both datasets showed a rate of xerostomia of less than 20% when the mean dose to the least-irradiated parotid gland is kept to less than 20 Gy. Logistic model parameters for the incidence of xerostomia at 12 months after therapy, based on the least-irradiated gland, were D{sub 50} = 32.4 Gy and and {gamma} = 0.97. NPVs for QUANTEC guideline were 94% (BCCA data), and 90% (WUSTL data). For Ortholan et al. guideline NPVs were 85% (BCCA) and 86% (WUSTL). Conclusion: These data confirm that the QUANTEC guideline effectively avoids xerostomia, and this is somewhat more effective than constraints on the volume receiving more than 40 Gy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Dosimetric Predictors of Patient-Reported Xerostomia and Dysphagia With Deintensified Chemoradiation Therapy for HPV-Associated Oropharyngeal Squamous Cell Carcinoma

Purpose/Objective(s): To estimate the association between different dose-volume metrics of the salivary glands and pharyngeal constrictors with patient reported severity of xerostomia/dysphagia in the setting of deintensified chemoradiation therapy (CRT). Methods and Materials: Forty-five patients were treated on a phase 2 study assessing the efficacy of deintensified CRT for favorable-risk, HPV-associated oropharyngeal squamous cell carcinoma. Patients received 60 Gy intensity modulated radiation therapy with concurrent weekly cisplatin (30 mg/m{sup 2}), and reported the severity of their xerostomia/dysphagia (before and after treatment) using the patient-reported outcome version of the Common Terminology Criteria for Adverse Events (CTCAE) (PRO-CTCAE). Individual patient dosimetric data of the contralateral parotid and submandibular glands and pharyngeal constrictors were correlated with changes in PRO-CTCAE severity. A change in severity (from baseline) of ≥2 was considered clinically meaningful. Associations between dose-volume metrics and patient outcomes were assessed with receiver operating characteristic (ROC) curve and logistic regression model. Results: Six months after CRT, patients reporting <2 change in xerostomia severity (n=14) had an average D{sub mean} = 22 ± 9 Gy to the sum of the contralateral glands (parotid + submandibular) compared with the patients reporting ≥2 change (n=21), who had an average D{sub mean} = 34 ± 8 Gy. V15 to V55 for the combined contralateral glands showed the strongest association with xerostomia (area under the curve [AUC] = 0.83-0.86). Based on the regression analysis, a 20% risk of toxicity was associated with V15 = 48%, V25 = 30%, and D{sub mean}=21 Gy. Six months after CRT, patients reporting <2 change in dysphagia severity (n=26) had an average V55 = 76 ± 13 (%) to the superior pharyngeal constrictor compared with the patients reporting ≥2 change in severity (n=9), who had average V55 = 89 ± 13 (%). V55to V60 had the strongest association with dysphagia (AUC = 0.70-0.75). Based on the regression analysis, a 20% risk of toxicity was associated with V55 = 78%, V60 = 40%. The findings at 12 months were similar. Conclusions: After deintensified CRT, the rate of patient-reported xerostomia/dysphagia appears to be associated with the V15 of the combined contralateral salivary glands and V55 to V60 of the superior pharyngeal constrictors.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

A novel mechanism of filaggrin induction and sunburn prevention by β-damascenone in Skh-1 mice

Understanding how oral administration of aroma terpenes can prevent sunburn or skin cancer in mice could lead to more effective and safer ways of blocking sun damage to human skin. To establish sunburn preventive activity, female Skh-1 mice were given oral β-damascenone followed by irradiation with UVR from fluorescent ‘sunlamps’. The following endpoints were evaluated versus controls at various times between 1 and 12 days after the terpene: whole genome gene expression and in situ immunohistochemistry of PCNA, keratin10, filaggrin and caspase 14, and sunburn was evaluated at 5 days. UVR-induced sunburn was prevented by a single oral β-damascenone dose as low as 20 μL (0.95 mg/g body weight). Microarray analysis showed sunburn prevention doses of β-damascenone up-regulated several types of cornification genes, including keratins 1 and 10, filaggrin, caspase 14, loricrin, hornerin and 6 late cornified envelope genes. Immunohistochemical studies of PCNA labeling showed that β-damascenone increased the proliferation rates of the following cell types: epidermal basal cells, follicular outer root sheath cells and sebaceous gland cells. Keratin 10 was not affected by β-damascenone in epidermis, and filaggrin and caspase 14 were increased in enlarged sebaceous glands. The thickness of the cornified envelope plus sebum layer nearly doubled within 1 day after administration of the β-damascenone and remained at or above double thickness for at least 12 days. β-Damascenone protected against sunburn by activating a sebaceous gland-based pathway that fortified and thickened the cornified envelope plus sebum layer in a way that previously has been observed to occur only in keratinocytes. -- Highlights: ► Orally administered β-damascenone prevented UVB-induced sunburn in Skh-1 mice. ► Filaggrin and caspase 14 genes were induced in sebaceous gland cells. ► Numerous cornification genes were up-regulated by β-damascenone. ► β-Damascenone stimulated cell division in epidermal and follicular keratinocytes. ► Results explained by induction of a novel sebaceous gland system of UVR protection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-E-T-399: Determination of the Radiobiological Parameters That Describe the Dose-Response Relations of Xerostomia and Disgeusia From Head and Neck Radiotherapy

Purpose: To estimate the radiobiological parameters that describe the doseresponse relations of xerostomia and disgeusia from head and neck cancer radiotherapy. To identify the organs that are best correlated with the manifestation of those clinical endpoints. Finally, to evaluate the goodnessof- fit by comparing the model predictions against the actual clinical results. Methods: In this study, 349 head and neck cancer patients were included. For each patient the dose volume histograms (DVH) of parotids (separate and combined), mandible, submandibular glands (separate and combined) and salivary glands were calculated. The follow-up of those patients was recorded at different times after the completion of the treatment (7 weeks, 3, 7, 12, 18 and 24 months). Acute and late xerostomia and acute disgeusia were the clinical endpoints examined. A maximum likelihood fitting was performed to calculate the best estimates of the parameters used by the relative seriality model. The statistical methods of the error distribution, the receiver operating characteristic (ROC) curve, the Pearson's test and the Akaike's information criterion were utilized to assess the goodness-of-fit and the agreement between the pattern of the radiobiological predictions with that of the clinical records. Results: The estimated values of the radiobiological parameters of salivary glands are D50 = 25.2 Gy, γ = 0.52, s = 0.001. The statistical analysis confirmed the clinical validity of those parameters (area under the ROC curve = 0.65 and AIC = 38.3). Conclusion: The analysis proved that the treatment outcome pattern of the patient material can be reproduced by the relative seriality model and the estimated radiobiological parameters. Salivary glands were found to have strong volume dependence (low relative seriality). Diminishing the biologically effective uniform dose to salivary glands below 30 Gy may significantly reduce the risk of complications to the patients irradiated for prostate cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-J-218: Predicting Radiation-Induced Xerostomia by Dosimetrically Accounting for Daily Setup Uncertainty During Head and Neck IMRT

Purpose: To determine if the accumulated parotid dosimetry using planning CT to daily CBCT deformation and dose re-calculation can predict for radiation-induced xerostomia. Methods: To track and dosimetrically account for the effects of anatomical changes on the parotid glands, we propagated physicians’ contours from planning CT to daily CBCT using a deformable registration with iterative CBCT intensity correction. A surface mesh for each OAR was created with the deformation applied to the mesh to obtain the deformed parotid volumes. Daily dose was computed on the deformed CT and accumulated to the last fraction. For both the accumulated and the planned parotid dosimetry, we tested the prediction power of different dosimetric parameters including D90, D50, D10, mean, standard deviation, min/max dose to the combined parotids and patient age to severe xerostomia (NCI-CTCAE grade≥2 at 6 mo follow-up). We also tested the dosimetry to parotid sub-volumes. Three classification algorithms, random tree, support vector machine, and logistic regression were tested to predict severe xerostomia using a leave-one-out validation approach. Results: We tested our prediction model on 35 HN IMRT cases. Parameters from the accumulated dosimetry model demonstrated an 89% accuracy for predicting severe xerostomia. Compared to the planning dosimetry, the accumulated dose consistently demonstrated higher prediction power with all three classification algorithms, including 11%, 5% and 30% higher accuracy, sensitivity and specificity, respectively. Geometric division of the combined parotid glands into superior-inferior regions demonstrated ∼5% increased accuracy than the whole volume. The most influential ranked features include age, mean accumulated dose of the submandibular glands and the accumulated D90 of the superior parotid glands. Conclusion: We demonstrated that the accumulated parotid dosimetry using CT-CBCT registration and dose re-calculation more accurately predicts for severe xerostomia and that the superior portion of the parotid glands may be particularly important in predicting for severe xerostomia. This work was supported in part by NIH/NCI under grant R42CA137886 and in part by Toshiba big data research project funds.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Genetic analyses of leaf traits in an interspecific Zoysia japonica × Zoysia matrella F2 population

Zoysiagrass (Zoysia spp.) is an important warm-season turfgrass cultivated across tropical, subtropical, and temperate regions of the world. The genus is characterized by the presence of salt-secreting glands on the adaxial leaf surface, which contribute to its high salt tolerance. In this study, we analyzed an interspecific F2 population, derived from selfing an F1 from a cross between Z. japonica acc. Meyer and Z. matrella acc. PI 231146, for variation in adaxial salt gland density, leaf width, and vein count. Using composite interval mapping with a previously constructed genetic map as a framework, we identified three quantitative trait loci (QTL) for leaf width, two QTL for vein count, and two QTL for salt gland density. We complemented the QTL analysis with bulked segregant RNA-seq (BSR-seq) to identify shared genomic regions and candidate genes for leaf width and salt gland density. BSR-seq identified four trait-associated regions, but only a single region identified for leaf width on Chr08 overlapped with a QTL for the same trait. We highlight putative candidate genes underlying the leaf width and salt gland density QTL and discuss their potential roles in leaf development. Together, the QTL and candidate genes provide an important resource for breeding stress-resilient Zoysia germplasm.

Pradhan, Shreena [University of Georgia, Athens]↗
DOE OSTI2017

Iron oxide nanoparticles modulate heat shock proteins and organ specific markers expression in mice male accessory organs

With increased industrial utilization of iron oxide nanoparticles (Fe{sub 2}O{sub 3}-NPs), concerns on adverse reproductive health effects following exposure have been immensely raised. In the present study, the effects of Fe{sub 2}O{sub 3}-NPs exposure in the seminal vesicle and prostate gland were studied in mice. Mice were exposed to two different doses (25 and 50 mg/kg) of Fe{sub 2}O{sub 3}-NPs along with the control and analyzed the expressions of heat shock proteins (HSP60, HSP70 and HSP90) and organ specific markers (Caltrin, PSP94, and SSLP1). Fe{sub 2}O{sub 3}-NPs decreased food consumption, water intake, and organo-somatic index in mice with elevated iron levels in serum, urine, fecal matter, seminal vesicle and prostate gland. FTIR spectra revealed alterations in the functional groups of biomolecules on Fe{sub 2}O{sub 3}-NPs treatment. These changes are accompanied by increased lactate dehydrogenase levels with decreased total protein and fructose levels. The investigation of oxidative stress biomarkers demonstrated a significant increase in reactive oxygen species, nitric oxide, lipid peroxidation, protein carbonyl content and glutathione peroxidase with a concomitant decrement in the glutathione and ascorbic acid in the male accessory organs which confirmed the induction of oxidative stress. An increase in NADPH-oxidase-4 with a decrease in glutathione-S-transferase was observed in the seminal vesicle and prostate gland of the treated groups. An alteration in HSP60, HSP70, HSP90, Caltrin, PSP94, and SSLP1 expression was also observed. Moreover, accumulation of Fe{sub 2}O{sub 3}-NPs brought pathological changes in the seminal vesicle and prostate gland of treated mice. These findings provide evidence that Fe{sub 2}O{sub 3}-NPs could be an environmental risk factor for reproductive disease. - Highlights: • Fe{sub 2}O{sub 3}-NPs caused adverse effects on the seminal vesicle and prostate gland of mice • Heat shock proteins (Hsp60, 70 and 90) were modulated by Fe{sub 2}O{sub 3}-NPs exposure • Male accessory organs specific markers expression were altered by Fe{sub 2}O{sub 3}-NPs • Histopathology revealed damage to both the accessory organs on Fe{sub 2}O{sub 3}-NPs exposure.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects

Objectives: The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose–response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. Methods: This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands, and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site–specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). Results: Linear dose–response relationships over a wide range of radiation dose (0-50 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy = 0.27-0.36). The relative risk for thyroid cancer increased up to 15-20 Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries. Conclusions: The results suggest that the effect of high-dose irradiation is consistent with a linear dose–response for most organs, but they also reveal important organ-specific and host-specific differences in susceptibility and interactions between different aspects of treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Modeling the dosimetry of organ-at-risk in head and neck IMRT planning: An intertechnique and interinstitutional study

Purpose: To build a statistical model to quantitatively correlate the anatomic features of structures and the corresponding dose-volume histogram (DVH) of head and neck (HN) Tomotherapy (Tomo) plans. To study if the model built upon one intensity modulated radiation therapy (IMRT) technique (such as conventional Linac) can be used to predict anticipated organs-at-risk (OAR) DVH of patients treated with a different IMRT technique (such as Tomo). To study if the model built upon the clinical experience of one institution can be used to aid IMRT planning for another institution. Methods: Forty-four Tomotherapy intensity modulate radiotherapy plans of HN cases (Tomo-IMRT) from Institution A were included in the study. A different patient group of 53 HN fixed gantry IMRT (FG-IMRT) plans was selected from Institution B. The analyzed OARs included the parotid, larynx, spinal cord, brainstem, and submandibular gland. Two major groups of anatomical features were considered: the volumetric information and the spatial information. The volume information includes the volume of target, OAR, and overlapped volume between target and OAR. The spatial information of OARs relative to PTVs was represented by the distance-to-target histogram (DTH). Important anatomical and dosimetric features were extracted from DTH and DVH by principal component analysis. Two regression models, one for Tomotherapy plan and one for IMRT plan, were built independently. The accuracy of intratreatment-modality model prediction was validated by a leave one out cross-validation method. The intertechnique and interinstitution validations were performed by using the FG-IMRT model to predict the OAR dosimetry of Tomo-IMRT plans. The dosimetry of OARs, under the same and different institutional preferences, was analyzed to examine the correlation between the model prediction and planning protocol. Results: Significant patient anatomical factors contributing to OAR dose sparing in HN Tomotherapy plans have been analyzed and identified. For all the OARs, the discrepancies of dose indices between the model predicted values and the actual plan values were within 2.1%. Similar results were obtained from the modeling of FG-IMRT plans. The parotid gland was spared in a comparable fashion during the treatment planning of two institutions. The model based on FG-IMRT plans was found to predict the median dose of the parotid of Tomotherapy plans quite well, with a mean error of 2.6%. Predictions from the FG-IMRT model suggested the median dose of the larynx, median dose of the brainstem and D2 of the brainstem could be reduced by 10.5%, 12.8%, and 20.4%, respectively, in the Tomo-IMRT plans. This was found to be correlated to the institutional differences in OAR constraint settings. Re-planning of six Tomotherapy patients confirmed the potential of optimization improvement predicted by the FG-IMRT model was correct. Conclusions: The authors established a mathematical model to correlate the anatomical features and dosimetric indexes of OARs of HN patients in Tomotherapy plans. The model can be used for the setup of patient-specific OAR dose sparing goals and quality control of planning results. The institutional clinical experience was incorporated into the model which allows the model from one institution to generate a reference plan for another institution, or another IMRT technique.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Incorporating single-side sparing in models for predicting parotid dose sparing in head and neck IMRT

Purpose: Sparing of single-side parotid gland is a common practice in head-and-neck (HN) intensity modulated radiation therapy (IMRT) planning. It is a special case of dose sparing tradeoff between different organs-at-risk. The authors describe an improved mathematical model for predicting achievable dose sparing in parotid glands in HN IMRT planning that incorporates single-side sparing considerations based on patient anatomy and learning from prior plan data. Methods: Among 68 HN cases analyzed retrospectively, 35 cases had physician prescribed single-side parotid sparing preferences. The single-side sparing model was trained with cases which had single-side sparing preferences, while the standard model was trained with the remainder of cases. A receiver operating characteristics (ROC) analysis was performed to determine the best criterion that separates the two case groups using the physician's single-side sparing prescription as ground truth. The final predictive model (combined model) takes into account the single-side sparing by switching between the standard and single-side sparing models according to the single-side sparing criterion. The models were tested with 20 additional cases. The significance of the improvement of prediction accuracy by the combined model over the standard model was evaluated using the Wilcoxon rank-sum test. Results: Using the ROC analysis, the best single-side sparing criterion is (1) the predicted median dose of one parotid is higher than 24 Gy; and (2) that of the other is higher than 7 Gy. This criterion gives a true positive rate of 0.82 and a false positive rate of 0.19, respectively. For the bilateral sparing cases, the combined and the standard models performed equally well, with the median of the prediction errors for parotid median dose being 0.34 Gy by both models (p = 0.81). For the single-side sparing cases, the standard model overestimates the median dose by 7.8 Gy on average, while the predictions by the combined model differ from actual values by only 2.2 Gy (p = 0.005). Similarly, the sum of residues between the modeled and the actual plan DVHs is the same for the bilateral sparing cases by both models (p = 0.67), while the standard model predicts significantly higher DVHs than the combined model for the single-side sparing cases (p = 0.01). Conclusions: The combined model for predicting parotid sparing that takes into account single-side sparing improves the prediction accuracy over the previous model.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2012

Structural evolution and tissue-specific expression of tetrapod-specific second isoform of secretory pathway Ca{sup 2+}-ATPase

Highlights: Black-Right-Pointing-Pointer Full-length secretory pathway Ca-ATPase (SPCA2) cloned from rat duodenum. Black-Right-Pointing-Pointer ATP2C2 gene (encoding SPCA2) exists only in genomes of Tetrapoda. Black-Right-Pointing-Pointer Rat and pig SPCA2 are expressed in intestines, lung and some secretory glands. Black-Right-Pointing-Pointer Subcellular localization of SPCA2 may depend on tissue type. Black-Right-Pointing-Pointer In rat duodenum, SPCA2 is localized in plasma membrane-associated compartments. -- Abstract: Secretory pathway Ca-ATPases are less characterized mammalian calcium pumps than plasma membrane Ca-ATPases and sarco-endoplasmic reticulum Ca-ATPases. Here we report analysis of molecular evolution, alternative splicing, tissue-specific expression and subcellular localization of the second isoform of the secretory pathway Ca-ATPase (SPCA2), the product of the ATP2C2 gene. The primary structure of SPCA2 from rat duodenum deduced from full-length transcript contains 944 amino acid residues, and exhibits 65% sequence identity with known SPCA1. The rat SPCA2 sequence is also highly homologous to putative human protein KIAA0703, however, the latter seems to have an aberrant N-terminus originating from intron 2. The tissue-specificity of SPCA2 expression is different from ubiquitous SPCA1. Rat SPCA2 transcripts were detected predominantly in gastrointestinal tract, lung, trachea, lactating mammary gland, skin and preputial gland. In the newborn pig, the expression profile is very similar with one remarkable exception: porcine bulbourethral gland gave the strongest signal. Upon overexpression in cultured cells, SPCA2 shows an intracellular distribution with remarkable enrichment in Golgi. However, in vivo SPCA2 may be localized in compartments that differ among various tissues: it is intracellular in epidermis, but enriched in plasma membranes of the intestinal epithelium. Analysis of SPCA2 sequences from various vertebrate species argue that ATP2C2 gene radiated from ATP2C1 (encoding SPCA1) during adaptation of tetrapod ancestors to terrestrial habitats.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Targeted deletion of Atg5 reveals differential roles of autophagy in keratin K5-expressing epithelia

Highlights: Black-Right-Pointing-Pointer We generated mice lacking Atg5 and autophagy in keratin K5-positive epithelia. Black-Right-Pointing-Pointer Suppression of autophagy in thymic epithelium was not associated with signs of autoimmunity. Black-Right-Pointing-Pointer Autophagy was required for normal terminal differentiation of preputial gland cells. Black-Right-Pointing-Pointer Autophagy-deficient cells of the preputial glands degraded nuclear DNA prematurely. -- Abstract: Autophagy contributes to the homeostasis of many tissues, yet its role in epithelia is incompletely understood. A recent report proposed that Atg5-dependent autophagy in thymic epithelial cells is essential for their function in the negative selection of self-reactive T-cells and, thus, for the suppression of tissue inflammation. Here we crossed mice carrying floxed alleles of the Atg5 gene with mice expressing the Cre recombinase under the control of the keratin K5 promoter to suppress autophagy in all K5-positive epithelia. The efficiency of autophagy abrogation was confirmed by immunoanalyses of LC3, which was converted to the autophagy-associated LC3-II form in normal but not Atg5-deficient cells, and of p62, which accumulated in Atg5-deficient cells. Mice carrying the epithelium-specific deletion of Atg5 showed normal weight gain, absence of tissue inflammation, and a normal morphology of the thymic epithelium. By contrast, autophagy-deficient epithelial cells of the preputial gland showed aberrant eosinophilic staining in histology and premature degradation of nuclear DNA during terminal differentiation. Taken together, the results of this study suggest that autophagy is dispensable for the suppression of autoimmunity by thymic epithelial cells but essential for normal differentiation of the preputial gland in mice.

60 APPLIED LIFE SCIENCES↗