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At least 1,045 records · Page 58
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

A novel role for the nuclear localization signal in regulating hnRNP K protein stability in vivo

hnRNP K is a highly conserved nucleocytoplasmic shuttling protein, which associates with RNAs through synergistic binding via its three KH domains. hnRNP K is required for proper nuclear export and translational control of its mRNA targets, and these processes are controlled by hnRNP K's movement between subcellular compartments. Whereas the nuclear export and localization of hnRNP K that is associated with mRNP complexes has been well studied, the trafficking of hnRNP K that is unbound to mRNA has yet to be elucidated. To that end, we expressed an EGFP-tagged RNA binding-defective form of hnRNP K in intact Xenopus embryos, and found it was rapidly degraded in vivo. Deleting hnRNP K's nuclear localization signal (NLS), which contains two prospective ubiquitination sites, rescued the protein from degradation. These data demonstrate a novel activity for the NLS of hnRNP K in regulating the protein's stability in vivo when it is unbound to nucleic acids. - Highlights: • An RNA-binding mutant of Xenopus hnRNP K is degraded in vivo. • hnRNP K's nuclear localization signal contains two predicted ubiquitination sites. • Deletion of the nuclear localization signal rescues RNA-binding mutant degradation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Identification of a DYRK1A-mediated phosphorylation site within the nuclear localization sequence of the hedgehog transcription factor GLI1

GLI1 is a key downstream transcription effector of the Hedgehog (Hh) signaling pathway that is involved in promoting cell growth, differentiation and tissue patterning in embryonic development. GLI1 over-activation and its nuclear localization has also been linked to the increased aggressiveness of a number of cancers. It has previously been demonstrated that DYRK1A (dual-specificity tyrosine-regulated kinase 1A) can phosphorylate GLI1 and promote GLI1 nuclear localization and its transcriptional activity. Utilizing recombinant human GLI1 and DYRK1A proteins and phospho-peptide mass spectrometry, we demonstrated that GLI1 is phosphorylated by DYRK1A at Ser408, a phospho-site that falls within the putative nuclear localization sequence (NLS) of GLI1, suggesting a possible mechanistic role in modulating its translocation. Further, we showed that the Ser408 site on GLI1 was not phosphorylated in the presence of the selective DYRK1A inhibitor harmine. The data described herein provide the first identification of a DYRK1A-mediated site of phosphorylation on GLI1 within its NLS and may serve as a valuable mechanism for further understanding Hh signaling modulation. - Highlights: • We describe a novel direct DYRK1A phosphorylation site on GLI1 at Ser408. • Harmine a selective DYRK1A inhibitor, blocks DYRK1A-mediated GLI1 phosphorylation. • The Ser408 phospho-site is within the GLI1 nuclear localization sequence (380–420). • This phosphorylation site provides a potential anti-Hh therapeutic target.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

High expression of Ki-67 acts a poor prognosis indicator in locally advanced nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy in Southern China and Southeast Asia compared with Western countries. The standard treatment for NPC is radiotherapy. However, radioresistance remains a serious obstacle to satisfactory treatment, it can cause local recurrence and distant metastases in some patients after treatment by radiation. We retrospectively reviewed 108 NPC patients (7th AJCC Ⅲ-Ⅳa) who have received intensity modulated radiation therapy (IMRT) between August 2008 and January 2012 at Xiangya Hospital of Central South University. Ninety-eight patients with >60% reduction of tumor size after radiation treatment were regarded as radiation sensitive, Ten patients with <40% reduction of tumor size after radiation treatment were regarded as radiation resistant. Using immunohistochemistry, we found that the high expression rate of Ki-67 in radiation resistant and radiation sensitive patients was 80.0% and 42.6%, respectively, and the difference was statistically significant (p = 0.025). The 5-year progress free survival rates in patients with low and high expression of Ki-67 was 70.7% and 48.0%, respectively, and the difference was statistically significant (p = 0.0008). Multivariate Cox regression analysis identified that high expression of Ki-67 was an independent negative prognostic factor in nasopharyngeal carcinoma patients [Hazard ratio (95% CI), 2.098(1.101, 3.996); p = 0.024]. These results demonstrate that high expression of Ki-67 contributes to radiation resistance and acts a poor prognosis indicator in patients with locally advanced nasopharyngeal carcinoma. - Highlights: • Radiation resistance remains a serious obstacle in some locally advanced nasopharyngeal carcinoma patients after treatment by radiation. • The proportion of Ki67 + cells after radiotherapy provided an independent variable of responsiveness to radiotherapy in squamous cell carcinoma of the head and neck. • The expression of Ki67 association with radiation resistance in locally advanced nasopharyngeal carcinoma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Visualization of local phosphatidylcholine synthesis within hippocampal neurons using a compartmentalized culture system and imaging mass spectrometry

Highlights: • A compartmentalized neuron culture system was combined with imaging mass spectrometry. • Phosphatidylcholine (PC) species within rat hippocampal neurons were visualized. • Differential synthetic activity of a PC species within neurons was observed. • Neurites synthesized a PC species using local extracellular free fatty acids in situ. Neurons extend neurites with an increased synthesis of phosphatidylcholine (PC) that is not only a membrane component but also a functional regulator with specific fatty acid composition. To analyze the local synthesis of the PC molecular species within neurons, we combined a compartmentalized culture system with matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). We observed that a newly synthesized PC, which contains exogenously administered palmitic acid-d{sub 3}, is accumulated at the cell bodies and the tips of the distal neurites. The local accumulation within distal neurites is formed by distinct metabolic activity from cell bodies, suggesting that the local extracellular composition of free fatty acid can be a key to regulate specific functions of each PC molecular species. We expect our simple method to be a starting point for more sophisticated in vitro analytical methods for unveiling detailed lipid metabolisms within neurons.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Transcription of blunt snout bream (Megalobrama amblycephala) HIF3α and its localization in the nucleus under both normoxic and hypoxic conditions

Highlights: • HIF3α cDNA was characterized the in hypoxia-sensitive blunt snout bream. • HIF3α mRNA was stably expressed during embryogenesis and different adult tissues. • HIF3α mRNA was upregulated in the liver, brain, and kidney under hypoxia. • HIF3α was distributed in the nucleus under normoxic and hypoxic conditions. • Hypoxia simulation caused a significant increase in HIF3α protein levels. • There was a nuclear localization signal (NLS) sequence at the C-terminus of HIF3α. Although hypoxia-inducible factor (HIF) 1α and 2α function as master regulators of the transcriptional response to hypoxia, the function of HIF3α and its responses to hypoxic stress remain unclear in teleost fish. Here, we characterized the HIF3α cDNA in hypoxia-sensitive blunt snout bream (Megalobrama amblycephala), with 3059 bp length, consisting of an open reading frame (ORF) encoding 643 amino acid residues. Blunt snout bream HIF3α mRNA was stably expressed during stages of embryonic development and in adult tissues. After a 4 h hypoxia stress, HIF3α mRNA of the juvenile fish was significantly upregulated in the liver, brain, and kidney, and restored to the pretreatment levels after a 24 h recovery. When tagged with enhanced green fluorescent protein (EGFP) and transfected into cultured HeLa cells, blunt snout bream HIF3α was mainly distributed in the nucleus under normoxia. Treatment of the cells with CoCl{sub 2} to mimic hypoxic conditions showed that there was no effect about the nuclear localization of HIF3α but a statistically significant increase in HIF3α protein levels. A nuclear localization signal (NLS) sequence at the C-terminus of HIF3α may exert positive effects in the process of nuclear localization. These results suggest that blunt snout bream HIF3α could be involved in different physiological functions under normoxia and hypoxia conditions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Kin1 kinase localizes at the hyphal septum and is dephosphorylated by calcineurin but is dispensable for septation and virulence in the human pathogen Aspergillus fumigatus

Highlights: • Kin1 deletion in A. fumigatus does not affect septation, growth and virulence. • Fluorescence microscopy revealed Kin1 localization at the center of the septum. • Bimolecular fluorescence assay confirmed interaction of Kin1 and calcineurin. • Phosphoproteomics identified Kin1 as a substrate of calcineurin. • Kin1 is differentially phosphorylated in vivo in the absence of calcineurin. Studies in yeasts have implicated the importance of Kin1 protein kinase, a member of the eukaryotic PAR1/MARK/MELK family, in polarized growth, cell division and septation through coordinated activity with the phosphatase, calcineurin. Kin1 is also required for virulence of the fungal pathogens Cryptococcus neoformans and Fusarium graminearum. Here we show that kin1 deletion in the human fungal pathogen Aspergillus fumigatus does not affect hyphal growth and septation but results in differential susceptibility to antifungals targeting the cell wall and cell membrane. The Δkin1 strain remained virulent in a Galleria mellonella model of invasive aspergillosis. Expression of Kin1 tagged to GFP or RFP showed its stable localization at the septum. Co-localization experiments revealed calcineurin (CnaA) localization on either side of Kin1 at the septum suggesting possible interaction. Bimolecular fluorescence complementation assay confirmed the interaction of Kin1 with CnaA at the hyphal tips and septa in the presence of the antifungal caspofungin. Furthermore, phosphoproteomic analyses for the first time revealed Kin1 as a substrate of calcineurin providing novel insight into Kin1 regulation through calcineurin-mediated dephosphorylation mechanism.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Bumble bee colony growth and reproduction depend on local flower dominance and natural habitat area in the surrounding landscape

Conservation measures for bees often focus on increasing the diversity and abundance of floral resources. But it has not been clear if observed benefits of floral enhancements result from greater population growth, which is critical for the long-term success of conservation, or from mobile foragers aggregating in high-resource locations. Experimental evidence is only beginning to emerge in favor of the former mechanism and it is not well-established how different aspects of floral resources affect population growth. For example, bumble bee colonies may benefit from greater overall floral abundance, richness, or relative dominance of resource species. Because bumble bees are highly mobile, resource variability in the surrounding landscape is also important for colonies and may mediate local-scale effects. We experimentally assessed the growth and reproduction of bumble bee colonies (Bombus impatiens) deployed in grasslands in different local- and landscape-scale resource environments. Furthermore, we found that floral dominance, rather than the overall abundance or richness of floral resources, was the most important local factor for colony growth and reproduction. This may reflect more efficient foraging on a few numerically dominant and abundant resource species. Local- and landscape-scale predictor variables had interacting effects on colony growth and reproduction, suggesting that foraging distance depends on where in the landscape efficiently used resources are located. Our results provide further evidence that conservation strategies aimed at enhancing floral resources can increase bumble bee population growth. However, the most effective form of floral enhancement may vary among bee species.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Band structure dependent electronic localization in macroscopic films of single-chirality single-wall carbon nanotubes

Significant understanding has been achieved over the last few decades regarding chirality-dependent properties of single-wall carbon nanotubes (SWCNTs), primarily through single-tube studies. However, macroscopic manifestations of chirality dependence have been limited, especially in electronic transport, despite the fact that such distinct behaviors are needed for many applications of SWCNT-based devices. In addition, developing reliable transport theory is challenging since a description of localization phenomena in an assembly of nanoobjects requires precise knowledge of disorder on multiple spatial scales, particularly if the ensemble is heterogeneous. Here, we report an observation of pronounced chirality-dependent electronic localization in temperature and magnetic field dependent conductivity measurements on macroscopic films of single-chirality SWCNTs. The samples included large-gap semiconducting (6,5) and (10,3) films, narrow-gap semiconducting (7,4) and (8,5) films, and armchair metallic (6,6) films. Experimental data and theoretical calculations revealed Mott variable-range-hopping dominated transport in all samples, while localization lengths fall into three distinct categories depending on their band gaps. Armchair films have the largest localization length. Here our detailed analyses on electronic transport properties of single-chirality SWCNT films provide significant new insight into electronic transport in ensembles of nanoobjects, offering foundations for designing and deploying macroscopic SWCNT solid-state devices.

36 MATERIALS SCIENCE↗
DOE OSTI2017

Asynchronous space–time domain decomposition method with localized uncertainty quantification

The computational cost associated with uncertainty quantification of engineering problems featuring localized phenomenon can be reduced by confining the random variability of the model parameters within a region of interest. Here in this case, a localized treatment of mesh and time resolutions is required to capture the effect of the confined material uncertainty on the global response. We present a computational approach for localized uncertainty quantification with the capability of asynchronous treatment of mesh and time resolutions. In particular, we allow each subdomain to have its local uncertainty representation and the corresponding mesh and time resolutions. As a result, computing resources can be directed toward a small region of interest where a model with high spatial and temporal resolutions is required. To verify the numerical implementation, we consider elastic wave propagation in an axially loaded beam. Moreover, we perform convergence studies with respect to the spatial and temporal discretizations as well as the size of an uncertain subdomain. A projectile impacting a composite sandwich plate is considered as an engineering application for the proposed method.

42 ENGINEERING↗
DOE OSTI2024

A B-spline based gradient-enhanced micropolar implicit material point method for large localized inelastic deformations

The quasi-brittle response of cohesive-frictional materials in numerical simulations is commonly represented by softening plasticity or continuum damage models, either individually or in combination. However, classical models, particularly when coupled with non-associated plasticity, often suffer from ill-posedness and a lack of objectivity in numerical simulations. Moreover, the performance of the finite element method significantly degrades in simulations involving finite strains when mesh distortion reaches excessive levels. This represents a challenge for modeling cohesive-frictional materials, given their tendency to experience strongly localized deformations, such as those occurring during shear band dominated failure. Hence, accurate modeling of the response of cohesive-frictional solids is a demanding task. To address these challenges, we present an extension of the material point method (MPM) for the unified gradient-enhanced micropolar continuum, aiming at the analysis of finite localized inelastic deformations in cohesive-frictional materials. The generalized gradient-enhanced micropolar continuum formulation is employed to tackle challenges related to localization and softening material behavior, while the MPM addresses issues arising from excessive deformations. The method utilizes a B-spline formulation for the rigid background mesh to mitigate the well-known cell crossing errors of the MPM. To demonstrate the performance of the method, 2D and 3D numerical studies on localized failure in sandstone in plane strain compression and triaxial extension tests are presented. A comparison with finite element results confirms the suitability of the formulation. Moreover, an efficient numerical implementation of the formulation is presented, and it is demonstrated that the additional MPM specific overhead is negligible.

B-spline↗
DOE OSTI2023

The large decline in carbonate $\delta^{238}$U from a PETM section at Tingri (South Tibet) was driven by local sea-level changes, not global oceanic anoxia

Uranium isotope compositions (δ 238 ) and Th/U in carbonates are being explored as paleoredox proxies to study global oceanic anoxia. However, the impact of changes to local depositional environments that might cause a decline in δ 238 U and an increase in Th/U has not been thoroughly investigated. Here we report a decline in δ 238 U (from +0.1 to -0.3‰) and an increase in Th/U from shallow-marine carbonates during the Paleocene-Eocene thermal maximum at Tingri (south Tibet). Changes of δ 238 U and Th/U are not fully coupled. The decline in δ 238 U coincided with a local sea-level fall, whereas the increase in Th/U occurred mainly during a sea-level rise. The decline in δ 238 U likely results from changes in redox conditions of pore waters and in primary carbonate mineralogy. The increase in Th/U is ascribed to reduced authigenic U(IV) accumulation. Here our results suggest that changes in local depositional environments can cause behavior of δ 238 U and Th/U resembling that induced by expanded global oceanic anoxia. This finding calls for caution to consider local factors before applying δ 238 U and Th/U as global paleoredox proxies.

58 GEOSCIENCES↗
DOE OSTI2021

Effect of neighboring grain orientation on strain localization in slip bands in HCP materials

Particularly in plastically anisotropic crystals, such as hexagonal close packed (HCP) materials, plastic deformation is realized by slip acting in the small volumes within individual crystals. Here we extend a full field fast Fourier transform (FFT)-based elasto-viscoplastic formulation to simulate the development of a single slip band on either prismatic or basal planes spanning a crystal. Calculations of the strain and stress fields induced locally within the band and parent crystal, and ahead of the band/grain boundary junction in the neighboring crystal are analyzed as the slip band intensifies under increasing applied strain. We report a substantial influence of the crystallographic orientation of the nearest neighboring grain on the rate of slip band localization. Performing the analysis on two materials, CP-Ti and Mg, indicates that the strength of the material affects the rate of localization, with stronger materials tending to localize more easily. A slip band tip stress-based criterion is proposed for identifying the nearest neighbor orientations in which slip band transmission is possible and the likely slip system for which it occurs. This indicator is validated against experimental studies on commercially pure Ti, an Mg–Y alloy, and Ti–6Al–4V. Finally, we show that for low GB misorientations, the slip band is likely to transmit into another slip band of the same type in the neighbor grain, while for high GB misorientations, it is likely to transmit into one of a different type or to not transmit at all.

36 MATERIALS SCIENCE↗
DOE OSTI2011

Accelerated Partial Breast Irradiation With Interstitial Implants: Risk Factors Associated With Increased Local Recurrence

Purpose: To analyze patient, disease, and treatment-related factors regarding their impact on local control after interstitial multicatheter accelerated partial breast irradiation (APBI). Methods and Materials: Between November 2000 and April 2005, 274 patients with early breast cancer were recruited for the German-Austrian APBI Phase II trial ( (ClinicalTrials.gov) identifier: NCT00392184). In all, 64% (175/274) of the patients received pulsed-dose-rate (PDR) brachytherapy and 36% (99/274) received high-dose-rate (HDR) brachytherapy. Prescribed reference dose for HDR brachytherapy was 32 Gy in eight fractions of 4 Gy, twice daily. Prescribed reference dose in PDR brachytherapy was 49.8 Gy in 83 consecutive fractions of 0.6 Gy each hour. Total treatment time was 3 to 4 days. Results: The median follow-up time was 64 months (range, 9-110). The actuarial 5-year local recurrence free survival rate (5-year LRFS) was 97.7%. Comparing patients with an age <50 years (49/274) vs. {>=}50 years (225/274), the 5-year LRFS resulted in 92.5% and 98.9% (exact p = 0.030; 99% confidence interval, 0.029-0.032), respectively. Antihormonal treatment (AHT) was not applied in 9% (24/274) of the study population. The 5-year LRFS was 99% and 84.9% (exact p = 0.0087; 99% confidence interval, 0.0079-0.0094) in favor of the patients who received AHT. Lobular histology (45/274) was not associated with worse local control compared with all other histologies (229/274). The 5-year LRFS rates were 97.6% and 97.8%, respectively. Conclusions: Local control at 5 years is excellent and comparable to therapeutic successes reported from corresponding whole-breast irradiation trials. Our data indicate that patients <50 years of age ought to be excluded from APBI protocols, and that patients with hormone-sensitive breast cancer should definitely receive adjuvant AHT when interstitial multicatheter APBI is performed. Lobular histology need not be an exclusion criterion for future APBI trials.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Local Tumor Control, Visual Acuity, and Survival After Hypofractionated Stereotactic Photon Radiotherapy of Choroidal Melanoma in 212 Patients Treated Between 1997 and 2007

Purpose: To evaluate long-term local tumor control, visual acuity, and survival after hypofractionated linear accelerator-based stereotactic photon radiotherapy in patients with choroidal melanoma. Methods and Materials: Between 1997 and 2007, 212 patients with choroidal melanoma unsuitable for ruthenium-106 brachytherapy or local resection were treated stereotactically at a linear accelerator with 6-MV photon beams at the Medical University of Vienna in five fractions over 7 days. Twenty-four patients received a total dose of 70 Gy (five fractions of 14 Gy), 158 a total dose of 60 Gy (five fractions of 12 Gy) and 30 patients a total dose of 50 Gy (five fractions of 10 Gy) applied on the 80% isodose. Ophthalmologic examinations were performed at baseline and every 3 months in the first 2 years, every 6 months until 5 years, and once a year thereafter until 10 years after radiotherapy. Assessment of visual acuity, routine ophthalmologic examinations, and measurement of tumor base dimension and height using standardized A-scan and B-scan echography were done at each visit. Funduscopy and fluorescein angiography were done when necessary to document tumor response. Results: Median tumor height and volume decreased from 4.8 mm and 270.7 mm{sup 3} at baseline to 2.6 mm and 86.6 mm{sup 3} at the last individual follow-up, respectively (p < 0.001, p < 0.001). Median visual acuity decreased from 0.55 at baseline to hand motion at the last individual follow-up (p < 0.001). Local tumor control was 95.9% after 5 years and 92.6% after 10 years. Thirty-two patients developed metastatic disease, and 22 of these patients died during the follow-up period. Conclusion: Hypofractionated stereotactic photon radiotherapy with 70 to 50 Gy delivered in five fractions in 7 days is sufficient to achieve excellent local tumor control in patients with malignant melanoma of the choroid. Disease outcome and vision are comparable to those achieved with proton beam radiotherapy. Decreasing the total dose below 60 Gy seems to be possible.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Retrospective Analysis of Local Control and Cosmetic Outcome of 147 Periorificial Carcinomas of the Face Treated With Low-Dose Rate Interstitial Brachytherapy

Purpose: Skin cancer is the most common malignancy in white populations. We evaluated the local cure rate and cosmetic outcome of patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) of the face treated with low-dose rate brachytherapy. Methods and Materials: Between February 1990 and May 2000, 147 facial carcinomas in 132 patients were treated by {sup 192}Ir wire implantation. Side effects of brachytherapy were noted. Follow-up was 2 years or more. Locoregional recurrence-free survival (LRFS) and overall survival were recorded. Group A included patients treated by primary brachytherapy, and Group B included those treated after recurrence. Results: A total of 121 carcinomas were BCCs (82.3%) and 26 were SCCs (17.7%); the median tumor size was 10 mm. Of the tumors, 86 (58.5%) were in men and 61 (41.5%) were in women; the median age was 71 years. Group A comprised 116 lesions (78.9%), and Group B, 31 (21.1%). There were 17 relapses (11.6%) after a median follow-up of 72 months: 12 local, 4 nodal, and 1 local and nodal. Locoregional-free survival was 96.6% at 2 years and 87.3% at 5 years. Five-year LRFS was 82.6% in men and 93.3% in women (p = 0.027). After adjustment for gender, LRFS was better after primary treatment than after recurrence (hasard ratio HR, 2.91; 95% confidence interval, 1.06-8.03; p = 0.039). Five-year LRFS was 90.4% for BCC and 70.8% for SCC (p = 0.03). There were no Grade 3 complications. Conclusions: Low-dose rate brachytherapy offers good local control and cosmetic outcome in patients with periorificial skin carcinomas, with no Grade 3 complications. Brchytherapy is more efficient when used as primary treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Higher Biologically Effective Dose of Radiotherapy Is Associated With Improved Outcomes for Locally Advanced Non-Small Cell Lung Carcinoma Treated With Chemoradiation: An Analysis of the Radiation Therapy Oncology Group

Purpose: Patients treated with chemoradiotherapy for locally advanced non-small-cell lung carcinoma (LA-NSCLC) were analyzed for local-regional failure (LRF) and overall survival (OS) with respect to radiotherapy dose intensity. Methods and Materials: This study combined data from seven Radiation Therapy Oncology Group (RTOG) trials in which chemoradiotherapy was used for LA-NSCLC: RTOG 88-08 (chemoradiation arm only), 90-15, 91-06, 92-04, 93-09 (nonoperative arm only), 94-10, and 98-01. The radiotherapeutic biologically effective dose (BED) received by each individual patient was calculated, as was the overall treatment time-adjusted BED (tBED) using standard formulae. Heterogeneity testing was done with chi-squared statistics, and weighted pooled hazard ratio estimates were used. Cox and Fine and Gray's proportional hazard models were used for OS and LRF, respectively, to test the associations between BED and tBED adjusted for other covariates. Results: A total of 1,356 patients were analyzed for BED (1,348 for tBED). The 2-year and 5-year OS rates were 38% and 15%, respectively. The 2-year and 5-year LRF rates were 46% and 52%, respectively. The BED (and tBED) were highly significantly associated with both OS and LRF, with or without adjustment for other covariates on multivariate analysis (p < 0.0001). A 1-Gy BED increase in radiotherapy dose intensity was statistically significantly associated with approximately 4% relative improvement in survival; this is another way of expressing the finding that the pool-adjusted hazard ratio for survival as a function of BED was 0.96. Similarly, a 1-Gy tBED increase in radiotherapy dose intensity was statistically significantly associated with approximately 3% relative improvement in local-regional control; this is another way of expressing the finding that the pool-adjusted hazard ratio as a function of tBED was 0.97. Conclusions: Higher radiotherapy dose intensity is associated with improved local-regional control and survival in the setting of chemoradiotherapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Prospective Study of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Concurrent With Individualized Radiotherapy for Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Purpose: To establish the safety profile and efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) concurrent with individualized radiotherapy (RT) in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Patients and Methods: Between June 2007 and January 2010, 26 patients with Stage III/IV NSCLC were enrolled in this prospective study. These patients were treated with EGFR-TKIs (gefitinib 250 mg or erlotinib 150 mg, oral daily) concurrent with individualized RT with curative intent. The thoracic RT plans were individually designed on the basis of tumor size and normal tissue volume constraints. All patients were assessed for toxicity, and 25 patients were available for efficacy. The primary endpoints were acute toxicity, overall survival, and median survival time. The secondary endpoints included local control rate, time to tumor progression, and progression-free survival (PFS). Results: Median gross tumor volume, mean lung dose, and lung V20 were 56 cm{sup 3}, 8.6 Gy, and 14%, respectively. Median thoracic radiation dose was 70 Gy at a margin of gross tumor volume (range, 42-82 Gy), and median biological equivalent dose was 105 Gy (range, 60-119 Gy). Acute skin, hematologic, esophageal, and pulmonary toxicities were acceptable and manageable. Severe adverse events included neutropenia (Grade 4, 4%) and thrombocytopenia (Grade 4, 8%), esophagitis (Grade 3, 4%), and pneumonitis (Grade 3, 4%). With a median follow-up of 10.2 months, a local control rate of 96% was achieved for thoracic tumor. Median time to progression, median PFS, and median survival time were 6.3, 10.2, and 21.8 months, respectively. The 1- and 2-year PFS rates were both 42%, and 1-, 2-, and 3-year overall survival rates were 57%, 45%, and 30%, respectively. Conclusion: Concurrent EGFR-TKIs with individualized RT shows a favorable safety profile and promising outcome, therefore serving as a therapeutic option for patients with locally advanced or metastatic NSCLC.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

A Retrospective Comparison of Robotic Stereotactic Body Radiotherapy and Three-Dimensional Conformal Radiotherapy for the Reirradiation of Locally Recurrent Nasopharyngeal Carcinoma

Purpose: We assessed therapeutic outcomes of reirradiation with robotic stereotactic radiotherapy (SBRT) for locally recurrent nasopharyngeal carcinoma (LRNPC) patients and compared those results with three-dimensional conformal radiotherapy (CRT) with or without brachytherapy (BRT). Methods and Materials: Treatment outcomes were evaluated retrospectively in 51 LRNPC patients receiving either robotic SBRT (24 patients) or CRT with or without BRT (27 patients) in our department. CRT was delivered with a 6-MV linear accelerator, and a median total reirradiation dose of 57 Gy in 2 Gy/day was given. Robotic SBRT was delivered with CyberKnife (Accuray, Sunnyvale, CA). Patients in the SBRT arm received 30 Gy over 5 consecutive days. We calculated actuarial local control and cancer-specific survival rates for the comparison of treatment outcomes in SBRT and CRT arms. The Common Terminology Criteria for Adverse Events v3.0 was used for toxicity evaluation. Results: The median follow-up was 24 months for all patients. Two-year actuarial local control rates were 82% and 80% for SBRT and CRT arms, respectively (p = 0.6). Two-year cancer-specific survival rates were 64% and 47% for the SBRT and CRT arms, respectively (p = 0.4). Serious late toxicities (Grade 3 and above) were observed in 21% of patients in the SBRT arm, whereas 48% of patients had serious toxicity in the CRT arm (p = 0.04). Fatal complications occurred in three patients (12.5%) of the SBRT arm, and four patients (14.8%) of the CRT arm (p = 0.8). T stage at recurrence was the only independent predictor for local control and survival. Conclusion: Our robotic SBRT protocol seems to be feasible and less toxic in terms of late effects compared with CRT arm for the reirradiation of LRNPC patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗